Simon E. Fisher

Publications

Displaying 1 - 100 of 260
  • Nayak, S., Coleman, P. L., Ladányi, E., Nitin, R., Gustavson, D. E., Fisher, S. E., Magne, C. L., & Gordon, R. L. (in press). The Musical Abilities, Pleiotropy, Language, and Environment (MAPLE) framework for understanding musicality-language links across the lifespan. Neurobiology of Language.
  • Tielbeek, J. J., Uffelmann, E., Williams, B. S., Colodro-Conde, L., Gagnon, É., Mallard, T. T., Levitt, B., Jansen, P. R., Johansson, A., Sallis, H., Pistis, G., Saunders, G. R. B., Allegrini, A. G., Rimfeld, K., Konte, B., Klein, M., Hartmann, A. M., Salvatore, J. E., Nolte, I. M., Demontis, D. and 64 moreTielbeek, J. J., Uffelmann, E., Williams, B. S., Colodro-Conde, L., Gagnon, É., Mallard, T. T., Levitt, B., Jansen, P. R., Johansson, A., Sallis, H., Pistis, G., Saunders, G. R. B., Allegrini, A. G., Rimfeld, K., Konte, B., Klein, M., Hartmann, A. M., Salvatore, J. E., Nolte, I. M., Demontis, D., Malmberg, A., Burt, S. A., Savage, J., Sugden, K., Poulton, R., Harris, K. M., Vrieze, S., McGue, M., Iacono, W. G., Mota, N. R., Mill, J., Viana, J. F., Mitchell, B. L., Morosoli, J. J., Andlauer, T., Ouellet-Morin, I., Tremblay, R. E., Côté, S., Gouin, J.-P., Brendgen, M., Dionne, G., Vitaro, F., Lupton, M. K., Martin, N. G., COGA Consortium, Spit for Science Working Group, Castelao, E., Räikkönen, K., Eriksson, J., Lahti, J., Hartman, C. A., Oldehinkel, A. J., Snieder, H., Liu, H., Preisig, M., Whipp, A., Vuoksimaa, E., Lu, Y., Jern, P., Rujescu, D., Giegling, I., Palviainen, T., Kaprio, J., Harden, K. P., Munafò, M. R., Morneau-Vaillancourt, G., Plomin, R., Viding, E., Boutwell, B. B., Aliev, F., Dick, D., Popma, A., Faraone, S. V., Børglum, A. D., Medland, S. E., Franke, B., Boivin, M., Pingault, J.-B., Glennon, J. C., Barnes, J. C., Fisher, S. E., Moffitt, T. E., Caspi, A., Polderman, T. J., Posthuma, D., & Broad Antisocial Behavior Consortium collaborators (in press). Uncovering the genetic architecture of broad antisocial behavior through a genome-wide association study meta-analysis. Molecular Psychiatry.
  • Alagöz, G., Molz, B., Eising, E., Schijven, D., Francks, C., Jason L., S., & Fisher, S. E. (2022). Using neuroimaging genomics to investigate the evolution of human brain structure. Proceedings of the National Academy of Sciences of the United States of America, 119(40): e2200638119. doi:10.1073/pnas.2200638119.

    Abstract

    Alterations in brain size and organization represent some of the most distinctive changes in the emergence of our species. Yet, there is limited understanding of how genetic factors contributed to altered neuroanatomy during human evolution. Here, we analyze neuroimaging and genetic data from up to 30,000 people in the UK Biobank and integrate with genomic annotations for different aspects of human evolution, including those based on ancient DNA and comparative genomics. We show that previously reported signals of recent polygenic selection for cortical anatomy are not replicable in a more ancestrally homogeneous sample. We then investigate relationships between evolutionary annotations and common genetic variants shaping cortical surface area and white-matter connectivity for each hemisphere. Our analyses identify single-nucleotide polymorphism heritability enrichment in human-gained regulatory elements that are active in early brain development, affecting surface areas of several parts of the cortex, including left-hemispheric speech-associated regions. We also detect heritability depletion in genomic regions with Neanderthal ancestry for connectivity of the uncinate fasciculus; this is a white-matter tract involved in memory, language, and socioemotional processing with relevance to neuropsychiatric disorders. Finally, we show that common genetic loci associated with left-hemispheric pars triangularis surface area overlap with a human-gained enhancer and affect regulation of ZIC4, a gene implicated in neurogenesis. This work demonstrates how genomic investigations of present-day neuroanatomical variation can help shed light on the complexities of our evolutionary past.

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    supplementary information
  • De Boer, E., Ockeloen, C. W., Kampen, R. A., Hampstead, J. E., Dingemans, A. J. M., Rots, D., Lütje, L., Ashraf, T., Baker, R., Barat-Houari, M., Angle, B., Chatron, N., Denommé-Pichon, A.-S., Devinsky, O., Dubourg, C., Elmslie, F., Elloumi, H. Z., Faivre, L., Fitzgerald-Butt, S., Geneviève, D. and 30 moreDe Boer, E., Ockeloen, C. W., Kampen, R. A., Hampstead, J. E., Dingemans, A. J. M., Rots, D., Lütje, L., Ashraf, T., Baker, R., Barat-Houari, M., Angle, B., Chatron, N., Denommé-Pichon, A.-S., Devinsky, O., Dubourg, C., Elmslie, F., Elloumi, H. Z., Faivre, L., Fitzgerald-Butt, S., Geneviève, D., Goos, J. A. C., Helm, B. M., Kini, U., Lasa-Aranzasti, A., Lesca, G., Lynch, S. A., Mathijssen, I. M. J., McGowan, R., Monaghan, K. G., Odent, S., Pfundt, R., Putoux, A., Van Reeuwijk, J., Santen, G. W. E., Sasaki, E., Sorlin, A., Van der Spek, P. J., Stegmann, A. P. A., Swagemakers, S. M. A., Valenzuela, I., Viora-Dupont, E., Vitobello, A., Ware, S. M., Wéber, M., Gilissen, C., Low, K. J., Fisher, S. E., Vissers, L. E. L. M., Wong, M. M. K., & Kleefstra, T. (2022). Missense variants in ANKRD11 cause KBG syndrome by impairment of stability or transcriptional activity of the encoded protein. Genetics in Medicine, 24(10), 2051-2064. doi:10.1016/j.gim.2022.06.007.

    Abstract

    Purpose Although haploinsufficiency of ANKRD11 is among the most common genetic causes of neurodevelopmental disorders, the role of rare ANKRD11 missense variation remains unclear. We characterized clinical, molecular, and functional spectra of ANKRD11 missense variants. Methods We collected clinical information of individuals with ANKRD11 missense variants and evaluated phenotypic fit to KBG syndrome. We assessed pathogenicity of variants through in silico analyses and cell-based experiments. Results We identified 20 unique, mostly de novo, ANKRD11 missense variants in 29 individuals, presenting with syndromic neurodevelopmental disorders similar to KBG syndrome caused by ANKRD11 protein truncating variants or 16q24.3 microdeletions. Missense variants significantly clustered in repression domain 2 at the ANKRD11 C-terminus. Of the 10 functionally studied missense variants, 6 reduced ANKRD11 stability. One variant caused decreased proteasome degradation and loss of ANKRD11 transcriptional activity. Conclusion Our study indicates that pathogenic heterozygous ANKRD11 missense variants cause the clinically recognizable KBG syndrome. Disrupted transrepression capacity and reduced protein stability each independently lead to ANKRD11 loss-of-function, consistent with haploinsufficiency. This highlights the diagnostic relevance of ANKRD11 missense variants, but also poses diagnostic challenges because the KBG-associated phenotype may be mild and inherited pathogenic ANKRD11 (missense) variants are increasingly observed, warranting stringent variant classification and careful phenotyping.

    Additional information

    supplementary material
  • Boyce, J. O., Jackson, V. E., Van Reyk, O., Parker, R., Vogel, A. P., Eising, E., Horton, S. E., Gillespie, N. A., Scheffer, I. E., Amor, D. J., Hildebrand, M. S., Fisher, S. E., Martin, N. G., Reilly, S., Bahlo, M., & Morgan, A. T. (2022). Self-reported impact of developmental stuttering across the lifespan. Developmental Medicine & Child Neurology, 64(10), 1297-1306. doi:10.1111/dmcn.15211.

    Abstract

    Aim To examine the phenomenology of stuttering across the lifespan in the largest prospective cohort to date. Method Participants aged 7 years and older with a history of developmental stuttering were recruited. Self-reported phenotypic data were collected online including stuttering symptomatology, co-occurring phenotypes, genetic predisposition, factors associated with stuttering severity, and impact on anxiety, education, and employment. Results A total of 987 participants (852 adults: 590 males, 262 females, mean age 49 years [SD = 17 years 10 months; range = 18–93 years] and 135 children: 97 males, 38 females, mean age 11 years 4 months [SD = 3 years; range = 7–17 years]) were recruited. Stuttering onset occurred at age 3 to 6 years in 64.0%. Blocking (73.2%) was the most frequent phenotype; 75.9% had sought stuttering therapy and 15.5% identified as having recovered. Half (49.9%) reported a family history. There was a significant negative correlation with age for both stuttering frequency and severity in adults. Most were anxious due to stuttering (90.4%) and perceived stuttering as a barrier to education and employment outcomes (80.7%). Interpretation The frequent persistence of stuttering and the high proportion with a family history suggest that stuttering is a complex trait that does not often resolve, even with therapy. These data provide new insights into the phenotype and prognosis of stuttering, information that is critically needed to encourage the development of more effective speech therapies.
  • Brouwer, R. M., Klein, M., Grasby, K. L., Schnack, H. G., Jahanshad, N., Teeuw, J., Thomopoulos, S. I., Sprooten, E., Franz, C. E., Gogtay, N., Kremen, W. S., Panizzon, M. S., Olde Loohuis, L. M., Whelan, C. D., Aghajani, M., Alloza, C., Alnæs, D., Artiges, E., Ayesa-Arriola, R., Barker, G. J. and 180 moreBrouwer, R. M., Klein, M., Grasby, K. L., Schnack, H. G., Jahanshad, N., Teeuw, J., Thomopoulos, S. I., Sprooten, E., Franz, C. E., Gogtay, N., Kremen, W. S., Panizzon, M. S., Olde Loohuis, L. M., Whelan, C. D., Aghajani, M., Alloza, C., Alnæs, D., Artiges, E., Ayesa-Arriola, R., Barker, G. J., Bastin, M. E., Blok, E., Bøen, E., Breukelaar, I. A., Bright, J. K., Buimer, E. E. L., Bülow, R., Cannon, D. M., Ciufolini, S., Crossley, N. A., Damatac, C. G., Dazzan, P., De Mol, C. L., De Zwarte, S. M. C., Desrivières, S., Díaz-Caneja, C. M., Doan, N. T., Dohm, K., Fröhner, J. H., Goltermann, J., Grigis, A., Grotegerd, D., Han, L. K. M., Harris, M. A., Hartman, C. A., Heany, S. J., Heindel, W., Heslenfeld, D. J., Hohmann, S., Ittermann, B., Jansen, P. R., Janssen, J., Jia, T., Jiang, J., Jockwitz, C., Karali, T., Keeser, D., Koevoets, M. G. J. C., Lenroot, R. K., Malchow, B., Mandl, R. C. W., Medel, V., Meinert, S., Morgan, C. A., Mühleisen, T. W., Nabulsi, L., Opel, N., Ortiz-García de la Foz, V., Overs, B. J., Paillère Martinot, M.-L., Redlich, R., Marques, T. R., Repple, J., Roberts, G., Roshchupkin, G. V., Setiaman, N., Shumskaya, E., Stein, F., Sudre, G., Takahashi, S., Thalamuthu, A., Tordesillas-Gutiérrez, D., Van der Lugt, A., Van Haren, N. E. M., Wardlaw, J. M., Wen, W., Westeneng, H.-J., Wittfeld, K., Zhu, A. H., Zugman, A., Armstrong, N. J., Bonfiglio, G., Bralten, J., Dalvie, S., Davies, G., Di Forti, M., Ding, L., Donohoe, G., Forstner, A. J., Gonzalez-Peñas, J., Guimaraes, J. P. O. F. T., Homuth, G., Hottenga, J.-J., Knol, M. J., Kwok, J. B. J., Le Hellard, S., Mather, K. A., Milaneschi, Y., Morris, D. W., Nöthen, M. M., Papiol, S., Rietschel, M., Santoro, M. L., Steen, V. M., Stein, J. L., Streit, F., Tankard, R. M., Teumer, A., Van 't Ent, D., Van der Meer, D., Van Eijk, K. R., Vassos, E., Vázquez-Bourgon, J., Witt, S. H., the IMAGEN Consortium, Adams, H. H. H., Agartz, I., Ames, D., Amunts, K., Andreassen, O. A., Arango, C., Banaschewski, T., Baune, B. T., Belangero, S. I., Bokde, A. L. W., Boomsma, D. I., Bressan, R. A., Brodaty, H., Buitelaar, J. K., Cahn, W., Caspers, S., Cichon, S., Crespo Facorro, B., Cox, S. R., Dannlowski, U., Elvsåshagen, T., Espeseth, T., Falkai, P. G., Fisher, S. E., Flor, H., Fullerton, J. M., Garavan, H., Gowland, P. A., Grabe, H. J., Hahn, T., Heinz, A., Hillegers, M., Hoare, J., Hoekstra, P. J., Ikram, M. A., Jackowski, A. P., Jansen, A., Jönsson, E. G., Kahn, R. S., Kircher, T., Korgaonkar, M. S., Krug, A., Lemaitre, H., Malt, U. F., Martinot, J.-L., McDonald, C., Mitchell, P. B., Muetzel, R. L., Murray, R. M., Nees, F., Nenadic, I., Oosterlaan, J., Ophoff, R. A., Pan, P. M., Penninx, B. W. J. H., Poustka, L., Sachdev, P. S., Salum, G. A., Schofield, P. R., Schumann, G., Shaw, P., Sim, K., Smolka, M. N., Stein, D. J., Trollor, J., Van den Berg, L. H., Veldink, J. H., Walter, H., Westlye, L. T., Whelan, R., White, T., Wright, M. J., Medland, S. E., Franke, B., Thompson, P. M., & Hulshoff Pol, H. E. (2022). Genetic variants associated with longitudinal changes in brain structure across the lifespan. Nature Neuroscience, 25, 421-432. doi:10.1038/s41593-022-01042-4.

    Abstract

    Human brain structure changes throughout the lifespan. Altered brain growth or rates of decline are implicated in a vast range of psychiatric, developmental and neurodegenerative diseases. In this study, we identified common genetic variants that affect rates of brain growth or atrophy in what is, to our knowledge, the first genome-wide association meta-analysis of changes in brain morphology across the lifespan. Longitudinal magnetic resonance imaging data from 15,640 individuals were used to compute rates of change for 15 brain structures. The most robustly identified genes GPR139, DACH1 and APOE are associated with metabolic processes. We demonstrate global genetic overlap with depression, schizophrenia, cognitive functioning, insomnia, height, body mass index and smoking. Gene set findings implicate both early brain development and neurodegenerative processes in the rates of brain changes. Identifying variants involved in structural brain changes may help to determine biological pathways underlying optimal and dysfunctional brain development and aging.
  • Chormai, P., Pu, Y., Hu, H., Fisher, S. E., Francks, C., & Kong, X. (2022). Machine learning of large-scale multimodal brain imaging data reveals neural correlates of hand preference. NeuroImage, 262: 119534. doi:10.1016/j.neuroimage.2022.119534.

    Abstract

    Lateralization is a fundamental characteristic of many behaviors and the organization of the brain, and atypical lateralization has been suggested to be linked to various brain-related disorders such as autism and schizophrenia. Right-handedness is one of the most prominent markers of human behavioural lateralization, yet its neurobiological basis remains to be determined. Here, we present a large-scale analysis of handedness, as measured by self-reported direction of hand preference, and its variability related to brain structural and functional organization in the UK Biobank (N = 36,024). A multivariate machine learning approach with multi-modalities of brain imaging data was adopted, to reveal how well brain imaging features could predict individual's handedness (i.e., right-handedness vs. non-right-handedness) and further identify the top brain signatures that contributed to the prediction. Overall, the results showed a good prediction performance, with an area under the receiver operating characteristic curve (AUROC) score of up to 0.72, driven largely by resting-state functional measures. Virtual lesion analysis and large-scale decoding analysis suggested that the brain networks with the highest importance in the prediction showed functional relevance to hand movement and several higher-level cognitive functions including language, arithmetic, and social interaction. Genetic analyses of contributions of common DNA polymorphisms to the imaging-derived handedness prediction score showed a significant heritability (h2=7.55%, p <0.001) that was similar to and slightly higher than that for the behavioural measure itself (h2=6.74%, p <0.001). The genetic correlation between the two was high (rg=0.71), suggesting that the imaging-derived score could be used as a surrogate in genetic studies where the behavioural measure is not available. This large-scale study using multimodal brain imaging and multivariate machine learning has shed new light on the neural correlates of human handedness.

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    supplementary material
  • Dima, D., Modabbernia, A., Papachristou, E., Doucet, G. E., Agartz, I., Aghajani, M., Akudjedu, T. N., Albajes‐Eizagirre, A., Alnæs, D., Alpert, K. I., Andersson, M., Andreasen, N. C., Andreassen, O. A., Asherson, P., Banaschewski, T., Bargallo, N., Baumeister, S., Baur‐Streubel, R., Bertolino, A., Bonvino, A. and 182 moreDima, D., Modabbernia, A., Papachristou, E., Doucet, G. E., Agartz, I., Aghajani, M., Akudjedu, T. N., Albajes‐Eizagirre, A., Alnæs, D., Alpert, K. I., Andersson, M., Andreasen, N. C., Andreassen, O. A., Asherson, P., Banaschewski, T., Bargallo, N., Baumeister, S., Baur‐Streubel, R., Bertolino, A., Bonvino, A., Boomsma, D. I., Borgwardt, S., Bourque, J., Brandeis, D., Breier, A., Brodaty, H., Brouwer, R. M., Buitelaar, J. K., Busatto, G. F., Buckner, R. L., Calhoun, V., Canales‐Rodríguez, E. J., Cannon, D. M., Caseras, X., Castellanos, F. X., Cervenka, S., Chaim‐Avancini, T. M., Ching, C. R. K., Chubar, V., Clark, V. P., Conrod, P., Conzelmann, A., Crespo‐Facorro, B., Crivello, F., Crone, E. A., Dale, A. M., Davey, C., De Geus, E. J. C., De Haan, L., De Zubicaray, G. I., Den Braber, A., Dickie, E. W., Di Giorgio, A., Doan, N. T., Dørum, E. S., Ehrlich, S., Erk, S., Espeseth, T., Fatouros‐Bergman, H., Fisher, S. E., Fouche, J., Franke, B., Frodl, T., Fuentes‐Claramonte, P., Glahn, D. C., Gotlib, I. H., Grabe, H., Grimm, O., Groenewold, N. A., Grotegerd, D., Gruber, O., Gruner, P., Gur, R. E., Gur, R. C., Harrison, B. J., Hartman, C. A., Hatton, S. N., Heinz, A., Heslenfeld, D. J., Hibar, D. P., Hickie, I. B., Ho, B., Hoekstra, P. J., Hohmann, S., Holmes, A. J., Hoogman, M., Hosten, N., Howells, F. M., Hulshoff Pol, H. E., Huyser, C., Jahanshad, N., James, A., Jernigan, T. L., Jiang, J., Jönsson, E. G., Joska, J. A., Kahn, R., Kalnin, A., Kanai, R., Klein, M., Klyushnik, T. P., Koenders, L., Koops, S., Krämer, B., Kuntsi, J., Lagopoulos, J., Lázaro, L., Lebedeva, I., Lee, W. H., Lesch, K., Lochner, C., Machielsen, M. W. J., Maingault, S., Martin, N. G., Martínez‐Zalacaín, I., Mataix‐Cols, D., Mazoyer, B., McDonald, C., McDonald, B. C., McIntosh, A. M., McMahon, K. L., McPhilemy, G., Menchón, J. M., Medland, S. E., Meyer‐Lindenberg, A., Naaijen, J., Najt, P., Nakao, T., Nordvik, J. E., Nyberg, L., Oosterlaan, J., Ortiz‐García de la Foz, V., Paloyelis, Y., Pauli, P., Pergola, G., Pomarol‐Clotet, E., Portella, M. J., Potkin, S. G., Radua, J., Reif, A., Rinker, D. A., Roffman, J. L., Rosa, P. G. P., Sacchet, M. D., Sachdev, P. S., Salvador, R., Sánchez‐Juan, P., Sarró, S., Satterthwaite, T. D., Saykin, A. J., Serpa, M. H., Schmaal, L., Schnell, K., Schumann, G., Sim, K., Smoller, J. W., Sommer, I., Soriano‐Mas, C., Stein, D. J., Strike, L. T., Swagerman, S. C., Tamnes, C. K., Temmingh, H. S., Thomopoulos, S. I., Tomyshev, A. S., Tordesillas‐Gutiérrez, D., Trollor, J. N., Turner, J. A., Uhlmann, A., Van den Heuvel, O. A., Van den Meer, D., Van der Wee, N. J. A., Van Haren, N. E. M., Van't Ent, D., Van Erp, T. G. M., Veer, I. M., Veltman, D. J., Voineskos, A., Völzke, H., Walter, H., Walton, E., Wang, L., Wang, Y., Wassink, T. H., Weber, B., Wen, W., West, J. D., Westlye, L. T., Whalley, H., Wierenga, L. M., Williams, S. C. R., Wittfeld, K., Wolf, D. H., Worker, A., Wright, M. J., Yang, K., Yoncheva, Y., Zanetti, M. V., Ziegler, G. C., Thompson, P. M., Frangou, S., & Karolinska Schizophrenia Project (KaSP) (2022). Subcortical volumes across the lifespan: Data from 18,605 healthy individuals aged 3–90 years. Human Brain Mapping, 43(1), 452-469. doi:10.1002/hbm.25320.

    Abstract

    Age has a major effect on brain volume. However, the normative studies available are constrained by small sample sizes, restricted age coverage and significant methodological variability. These limitations introduce inconsistencies and may obscure or distort the lifespan trajectories of brain morphometry. In response, we capitalized on the resources of the Enhancing Neuroimaging Genetics through Meta‐Analysis (ENIGMA) Consortium to examine age‐related trajectories inferred from cross‐sectional measures of the ventricles, the basal ganglia (caudate, putamen, pallidum, and nucleus accumbens), the thalamus, hippocampus and amygdala using magnetic resonance imaging data obtained from 18,605 individuals aged 3–90 years. All subcortical structure volumes were at their maximum value early in life. The volume of the basal ganglia showed a monotonic negative association with age thereafter; there was no significant association between age and the volumes of the thalamus, amygdala and the hippocampus (with some degree of decline in thalamus) until the sixth decade of life after which they also showed a steep negative association with age. The lateral ventricles showed continuous enlargement throughout the lifespan. Age was positively associated with inter‐individual variability in the hippocampus and amygdala and the lateral ventricles. These results were robust to potential confounders and could be used to examine the functional significance of deviations from typical age‐related morphometric patterns.
  • Eising, E., Mirza-Schreiber, N., de Zeeuw, E. L., Wang, C. A., Truong, D. T., Allegrini, A. G., Shapland, C. Y., Zhu, G., Wigg, K. G., Gerritse, M., Molz, B., Alagöz, G., Gialluisi, A., Abbondanza, F., Rimfeld, K., Van Donkelaar, M. M. J., Liao, Z., Jansen, P. R., Andlauer, T. F. M., Bates, T. C. and 70 moreEising, E., Mirza-Schreiber, N., de Zeeuw, E. L., Wang, C. A., Truong, D. T., Allegrini, A. G., Shapland, C. Y., Zhu, G., Wigg, K. G., Gerritse, M., Molz, B., Alagöz, G., Gialluisi, A., Abbondanza, F., Rimfeld, K., Van Donkelaar, M. M. J., Liao, Z., Jansen, P. R., Andlauer, T. F. M., Bates, T. C., Bernard, M., Blokland, K., Børglum, A. D., Bourgeron, T., Brandeis, D., Ceroni, F., Dale, P. S., Landerl, K., Lyytinen, H., de Jong, P. F., DeFries, J. C., Demontis, D., Feng, Y., Gordon, S. D., Guger, S. L., Hayiou-Thomas, M. E., Hernández-Cabrera, J. A., Hottenga, J.-J., Hulme, C., Kerr, E. N., Koomar, T., Lovett, M. W., Martin, N. G., Martinelli, A., Maurer, U., Michaelson, J. J., Moll, K., Monaco, A. P., Morgan, A. T., Nöthen, M. M., Pausova, Z., Pennell, C. E., Pennington, B. F., Price, K. M., Rajagopal, V. M., Ramus, F., Richer, L., Simpson, N. H., Smith, S., Snowling, M. J., Stein, J., Strug, L. J., Talcott, J. B., Tiemeier, H., van de Schroeff, M. M., Verhoef, E., Watkins, K. E., Wilkinson, M., Wright, M. J., Barr, C. L., Boomsma, D. I., Carreiras, M., Franken, M.-C.-J., Gruen, J. R., Luciano, M., Müller-Myhsok, B., Newbury, D. F., Olson, R. K., Paracchini, S., Paus, T., Plomin, R., Schulte-Körne, G., Reilly, S., Tomblin, J. B., van Bergen, E., Whitehouse, A. J., Willcutt, E. G., St Pourcain, B., Francks, C., & Fisher, S. E. (2022). Genome-wide analyses of individual differences in quantitatively assessed reading- and language-related skills in up to 34,000 people. Proceedings of the National Academy of Sciences of the United States of America, 119(35): e2202764119. doi:10.1073/pnas.2202764119.

    Abstract

    The use of spoken and written language is a fundamental human capacity. Individual differences in reading- and language-related skills are influenced by genetic variation, with twin-based heritability estimates of 30 to 80% depending on the trait. The genetic architecture is complex, heterogeneous, and multifactorial, but investigations of contributions of single-nucleotide polymorphisms (SNPs) were thus far underpowered. We present a multicohort genome-wide association study (GWAS) of five traits assessed individually using psychometric measures (word reading, nonword reading, spelling, phoneme awareness, and nonword repetition) in samples of 13,633 to 33,959 participants aged 5 to 26 y. We identified genome-wide significant association with word reading (rs11208009, P = 1.098 × 10−8) at a locus that has not been associated with intelligence or educational attainment. All five reading-/language-related traits showed robust SNP heritability, accounting for 13 to 26% of trait variability. Genomic structural equation modeling revealed a shared genetic factor explaining most of the variation in word/nonword reading, spelling, and phoneme awareness, which only partially overlapped with genetic variation contributing to nonword repetition, intelligence, and educational attainment. A multivariate GWAS of word/nonword reading, spelling, and phoneme awareness maximized power for follow-up investigation. Genetic correlation analysis with neuroimaging traits identified an association with the surface area of the banks of the left superior temporal sulcus, a brain region linked to the processing of spoken and written language. Heritability was enriched for genomic elements regulating gene expression in the fetal brain and in chromosomal regions that are depleted of Neanderthal variants. Together, these results provide avenues for deciphering the biological underpinnings of uniquely human traits.
  • Frangou, S., Modabbernia, A., Williams, S. C. R., Papachristou, E., Doucet, G. E., Agartz, I., Aghajani, M., Akudjedu, T. N., Albajes‐Eizagirre, A., Alnæs, D., Alpert, K. I., Andersson, M., Andreasen, N. C., Andreassen, O. A., Asherson, P., Banaschewski, T., Bargallo, N., Baumeister, S., Baur‐Streubel, R., Bertolino, A. and 181 moreFrangou, S., Modabbernia, A., Williams, S. C. R., Papachristou, E., Doucet, G. E., Agartz, I., Aghajani, M., Akudjedu, T. N., Albajes‐Eizagirre, A., Alnæs, D., Alpert, K. I., Andersson, M., Andreasen, N. C., Andreassen, O. A., Asherson, P., Banaschewski, T., Bargallo, N., Baumeister, S., Baur‐Streubel, R., Bertolino, A., Bonvino, A., Boomsma, D. I., Borgwardt, S., Bourque, J., Brandeis, D., Breier, A., Brodaty, H., Brouwer, R. M., Buitelaar, J. K., Busatto, G. F., Buckner, R. L., Calhoun, V., Canales‐Rodríguez, E. J., Cannon, D. M., Caseras, X., Castellanos, F. X., Cervenka, S., Chaim‐Avancini, T. M., Ching, C. R. K., Chubar, V., Clark, V. P., Conrod, P., Conzelmann, A., Crespo‐Facorro, B., Crivello, F., Crone, E. A., Dale, A. M., Davey, C., De Geus, E. J. C., De Haan, L., De Zubicaray, G. I., Den Braber, A., Dickie, E. W., Di Giorgio, A., Doan, N. T., Dørum, E. S., Ehrlich, S., Erk, S., Espeseth, T., Fatouros‐Bergman, H., Fisher, S. E., Fouche, J., Franke, B., Frodl, T., Fuentes‐Claramonte, P., Glahn, D. C., Gotlib, I. H., Grabe, H., Grimm, O., Groenewold, N. A., Grotegerd, D., Gruber, O., Gruner, P., Gur, R. E., Gur, R. C., Harrison, B. J., Hartman, C. A., Hatton, S. N., Heinz, A., Heslenfeld, D. J., Hibar, D. P., Hickie, I. B., Ho, B., Hoekstra, P. J., Hohmann, S., Holmes, A. J., Hoogman, M., Hosten, N., Howells, F. M., Hulshoff Pol, H. E., Huyser, C., Jahanshad, N., James, A., Jernigan, T. L., Jiang, J., Jönsson, E. G., Joska, J. A., Kahn, R., Kalnin, A., Kanai, R., Klein, M., Klyushnik, T. P., Koenders, L., Koops, S., Krämer, B., Kuntsi, J., Lagopoulos, J., Lázaro, L., Lebedeva, I., Lee, W. H., Lesch, K., Lochner, C., Machielsen, M. W. J., Maingault, S., Martin, N. G., Martínez‐Zalacaín, I., Mataix‐Cols, D., Mazoyer, B., McDonald, C., McDonald, B. C., McIntosh, A. M., McMahon, K. L., McPhilemy, G., Menchón, J. M., Medland, S. E., Meyer‐Lindenberg, A., Naaijen, J., Najt, P., Nakao, T., Nordvik, J. E., Nyberg, L., Oosterlaan, J., Ortiz‐García Foz, V., Paloyelis, Y., Pauli, P., Pergola, G., Pomarol‐Clotet, E., Portella, M. J., Potkin, S. G., Radua, J., Reif, A., Rinker, D. A., Roffman, J. L., Rosa, P. G. P., Sacchet, M. D., Sachdev, P. S., Salvador, R., Sánchez‐Juan, P., Sarró, S., Satterthwaite, T. D., Saykin, A. J., Serpa, M. H., Schmaal, L., Schnell, K., Schumann, G., Sim, K., Smoller, J. W., Sommer, I., Soriano‐Mas, C., Stein, D. J., Strike, L. T., Swagerman, S. C., Tamnes, C. K., Temmingh, H. S., Thomopoulos, S. I., Tomyshev, A. S., Tordesillas‐Gutiérrez, D., Trollor, J. N., Turner, J. A., Uhlmann, A., Van den Heuvel, O. A., Van den Meer, D., Van der Wee, N. J. A., Van Haren, N. E. M., Van 't Ent, D., Van Erp, T. G. M., Veer, I. M., Veltman, D. J., Voineskos, A., Völzke, H., Walter, H., Walton, E., Wang, L., Wang, Y., Wassink, T. H., Weber, B., Wen, W., West, J. D., Westlye, L. T., Whalley, H., Wierenga, L. M., Wittfeld, K., Wolf, D. H., Worker, A., Wright, M. J., Yang, K., Yoncheva, Y., Zanetti, M. V., Ziegler, G. C., Karolinska Schizophrenia Project (KaSP), Thompson, P. M., & Dima, D. (2022). Cortical thickness across the lifespan: Data from 17,075 healthy individuals aged 3–90 years. Human Brain Mapping, 43(1), 431-451. doi:10.1002/hbm.25364.

    Abstract

    Delineating the association of age and cortical thickness in healthy individuals is critical given the association of cortical thickness with cognition and behavior. Previous research has shown that robust estimates of the association between age and brain morphometry require large‐scale studies. In response, we used cross‐sectional data from 17,075 individuals aged 3–90 years from the Enhancing Neuroimaging Genetics through Meta‐Analysis (ENIGMA) Consortium to infer age‐related changes in cortical thickness. We used fractional polynomial (FP) regression to quantify the association between age and cortical thickness, and we computed normalized growth centiles using the parametric Lambda, Mu, and Sigma method. Interindividual variability was estimated using meta‐analysis and one‐way analysis of variance. For most regions, their highest cortical thickness value was observed in childhood. Age and cortical thickness showed a negative association; the slope was steeper up to the third decade of life and more gradual thereafter; notable exceptions to this general pattern were entorhinal, temporopolar, and anterior cingulate cortices. Interindividual variability was largest in temporal and frontal regions across the lifespan. Age and its FP combinations explained up to 59% variance in cortical thickness. These results may form the basis of further investigation on normative deviation in cortical thickness and its significance for behavioral and cognitive outcomes.
  • Guadalupe, T., Kong, X., Akkermans, S. E. A., Fisher, S. E., & Francks, C. (2022). Relations between hemispheric asymmetries of grey matter and auditory processing of spoken syllables in 281 healthy adults. Brain Structure & Function, 227, 561-572. doi:10.1007/s00429-021-02220-z.

    Abstract

    Most people have a right-ear advantage for the perception of spoken syllables, consistent with left hemisphere dominance for speech processing. However, there is considerable variation, with some people showing left-ear advantage. The extent to which this variation is reflected in brain structure remains unclear. We tested for relations between hemispheric asymmetries of auditory processing and of grey matter in 281 adults, using dichotic listening and voxel-based morphometry. This was the largest study of this issue to date. Per-voxel asymmetry indexes were derived for each participant following registration of brain magnetic resonance images to a template that was symmetrized. The asymmetry index derived from dichotic listening was related to grey matter asymmetry in clusters of voxels corresponding to the amygdala and cerebellum lobule VI. There was also a smaller, non-significant cluster in the posterior superior temporal gyrus, a region of auditory cortex. These findings contribute to the mapping of asymmetrical structure–function links in the human brain and suggest that subcortical structures should be investigated in relation to hemispheric dominance for speech processing, in addition to auditory cortex.

    Additional information

    supplementary information
  • Kaspi, A., Hildebrand, M. S., Jackson, V. E., Braden, R., Van Reyk, O., Howell, T., Debono, S., Lauretta, M., Morison, L., Coleman, M. J., Webster, R., Coman, D., Goel, H., Wallis, M., Dabscheck, G., Downie, L., Baker, E. K., Parry-Fielder, B., Ballard, K., Harrold, E. and 10 moreKaspi, A., Hildebrand, M. S., Jackson, V. E., Braden, R., Van Reyk, O., Howell, T., Debono, S., Lauretta, M., Morison, L., Coleman, M. J., Webster, R., Coman, D., Goel, H., Wallis, M., Dabscheck, G., Downie, L., Baker, E. K., Parry-Fielder, B., Ballard, K., Harrold, E., Ziegenfusz, S., Bennett, M. F., Robertson, E., Wang, L., Boys, A., Fisher, S. E., Amor, D. J., Scheffer, I. E., Bahlo, M., & Morgan, A. T. (2022). Genetic aetiologies for childhood speech disorder: Novel pathways co-expressed during brain development. Molecular Psychiatry. Advance online publication. doi:10.1038/s41380-022-01764-8.

    Abstract

    Childhood apraxia of speech (CAS), the prototypic severe childhood speech disorder, is characterized by motor programming and planning deficits. Genetic factors make substantive contributions to CAS aetiology, with a monogenic pathogenic variant identified in a third of cases, implicating around 20 single genes to date. Here we aimed to identify molecular causation in 70 unrelated probands ascertained with CAS. We performed trio genome sequencing. Our bioinformatic analysis examined single nucleotide, indel, copy number, structural and short tandem repeat variants. We prioritised appropriate variants arising de novo or inherited that were expected to be damaging based on in silico predictions. We identified high confidence variants in 18/70 (26%) probands, almost doubling the current number of candidate genes for CAS. Three of the 18 variants affected SETBP1, SETD1A and DDX3X, thus confirming their roles in CAS, while the remaining 15 occurred in genes not previously associated with this disorder. Fifteen variants arose de novo and three were inherited. We provide further novel insights into the biology of child speech disorder, highlighting the roles of chromatin organization and gene regulation in CAS, and confirm that genes involved in CAS are co-expressed during brain development. Our findings confirm a diagnostic yield comparable to, or even higher, than other neurodevelopmental disorders with substantial de novo variant burden. Data also support the increasingly recognised overlaps between genes conferring risk for a range of neurodevelopmental disorders. Understanding the aetiological basis of CAS is critical to end the diagnostic odyssey and ensure affected individuals are poised for precision medicine trials.
  • Kong, X., ENIGMA Laterality Working Group, & Francks, C. (2022). Reproducibility in the absence of selective reporting: An illustration from large‐scale brain asymmetry research. Human Brain Mapping, 43(1), 244-254. doi:10.1002/hbm.25154.

    Abstract

    The problem of poor reproducibility of scientific findings has received much attention over recent years, in a variety of fields including psychology and neuroscience. The problem has been partly attributed to publication bias and unwanted practices such as p‐hacking. Low statistical power in individual studies is also understood to be an important factor. In a recent multisite collaborative study, we mapped brain anatomical left–right asymmetries for regional measures of surface area and cortical thickness, in 99 MRI datasets from around the world, for a total of over 17,000 participants. In the present study, we revisited these hemispheric effects from the perspective of reproducibility. Within each dataset, we considered that an effect had been reproduced when it matched the meta‐analytic effect from the 98 other datasets, in terms of effect direction and significance threshold. In this sense, the results within each dataset were viewed as coming from separate studies in an “ideal publishing environment,” that is, free from selective reporting and p hacking. We found an average reproducibility rate of 63.2% (SD = 22.9%, min = 22.2%, max = 97.0%). As expected, reproducibility was higher for larger effects and in larger datasets. Reproducibility was not obviously related to the age of participants, scanner field strength, FreeSurfer software version, cortical regional measurement reliability, or regional size. These findings constitute an empirical illustration of reproducibility in the absence of publication bias or p hacking, when assessing realistic biological effects in heterogeneous neuroscience data, and given typically‐used sample sizes.
  • Kong, X., Postema, M., Guadalupe, T., De Kovel, C. G. F., Boedhoe, P. S. W., Hoogman, M., Mathias, S. R., Van Rooij, D., Schijven, D., Glahn, D. C., Medland, S. E., Jahanshad, N., Thomopoulos, S. I., Turner, J. A., Buitelaar, J., Van Erp, T. G. M., Franke, B., Fisher, S. E., Van den Heuvel, O. A., Schmaal, L. and 2 moreKong, X., Postema, M., Guadalupe, T., De Kovel, C. G. F., Boedhoe, P. S. W., Hoogman, M., Mathias, S. R., Van Rooij, D., Schijven, D., Glahn, D. C., Medland, S. E., Jahanshad, N., Thomopoulos, S. I., Turner, J. A., Buitelaar, J., Van Erp, T. G. M., Franke, B., Fisher, S. E., Van den Heuvel, O. A., Schmaal, L., Thompson, P. M., & Francks, C. (2022). Mapping brain asymmetry in health and disease through the ENIGMA consortium. Human Brain Mapping, 43(1), 167-181. doi:10.1002/hbm.25033.

    Abstract

    Left-right asymmetry of the human brain is one of its cardinal features, and also a complex, multivariate trait. Decades of research have suggested that brain asymmetry may be altered in psychiatric disorders. However, findings have been inconsistent and often based on small sample sizes. There are also open questions surrounding which structures are asymmetrical on average in the healthy population, and how variability in brain asymmetry relates to basic biological variables such as age and sex. Over the last four years, the ENIGMA-Laterality Working Group has published six studies of grey matter morphological asymmetry based on total sample sizes from roughly 3,500 to 17,000 individuals, which were between one and two orders of magnitude larger than those published in previous decades. A population-level mapping of average asymmetry was achieved, including an intriguing fronto-occipital gradient of cortical thickness asymmetry in healthy brains. ENIGMA’s multidataset approach also supported an empirical illustration of reproducibility of hemispheric differences across datasets. Effect sizes were estimated for grey matter asymmetry based on large, international, samples in relation to age, sex, handedness, and brain volume, as well as for three psychiatric disorders:Autism Spectrum Disorder was associated with subtly reduced asymmetry of cortical thickness at regions spread widely over the cortex; Pediatric Obsessive-Compulsive Disorder was associated with altered subcortical asymmetry; Major Depressive Disorder was not significantly associated with changes of asymmetry. Ongoing studies are examining brain asymmetry in other disorders. Moreover, a groundwork has been laid for possibly identifying shared genetic contributions to brain asymmetry and disorders.
  • Park, B.-y., Larivière, S., Rodríguez-Cruces, R., Royer, J., Tavakol, S., Wang, Y., Caciagli, L., Caligiuri, M. E., Gambardella, A., Concha, L., Keller, S. S., Cendes, F., Alvim, M. K. M., Yasuda, C., Bonilha, L., Gleichgerrcht, E., Focke, N. K., Kreilkamp, B. A. K., Domin, M., Von Podewils, F. and 66 morePark, B.-y., Larivière, S., Rodríguez-Cruces, R., Royer, J., Tavakol, S., Wang, Y., Caciagli, L., Caligiuri, M. E., Gambardella, A., Concha, L., Keller, S. S., Cendes, F., Alvim, M. K. M., Yasuda, C., Bonilha, L., Gleichgerrcht, E., Focke, N. K., Kreilkamp, B. A. K., Domin, M., Von Podewils, F., Langner, S., Rummel, C., Rebsamen, M., Wiest, R., Martin, P., Kotikalapudi, R., Bender, B., O’Brien, T. J., Law, M., Sinclair, B., Vivash, L., Desmond, P. M., Malpas, C. B., Lui, E., Alhusaini, S., Doherty, C. P., Cavalleri, G. L., Delanty, N., Kälviäinen, R., Jackson, G. D., Kowalczyk, M., Mascalchi, M., Semmelroch, M., Thomas, R. H., Soltanian-Zadeh, H., Davoodi-Bojd, E., Zhang, J., Lenge, M., Guerrini, R., Bartolini, E., Hamandi, K., Foley, S., Weber, B., Depondt, C., Absil, J., Carr, S. J. A., Abela, E., Richardson, M. P., Devinsky, O., Severino, M., Striano, P., Parodi, C., Tortora, D., Hatton, S. N., Vos, S. B., Duncan, J. S., Galovic, M., Whelan, C. D., Bargalló, N., Pariente, J., Conde, E., Vaudano, A. E., Tondelli, M., Meletti, S., Kong, X., Francks, C., Fisher, S. E., Caldairou, B., Ryten, M., Labate, A., Sisodiya, S. M., Thompson, P. M., McDonald, C. R., Bernasconi, A., Bernasconi, N., & Bernhardt, B. C. (2022). Topographic divergence of atypical cortical asymmetry and atrophy patterns in temporal lobe epilepsy. Brain, 145(4), 1285-1298. doi:10.1093/brain/awab417.

    Abstract

    Temporal lobe epilepsy (TLE), a common drug-resistant epilepsy in adults, is primarily a limbic network disorder associated with predominant unilateral hippocampal pathology. Structural MRI has provided an in vivo window into whole-brain grey matter structural alterations in TLE relative to controls, by either mapping (i) atypical inter-hemispheric asymmetry or (ii) regional atrophy. However, similarities and differences of both atypical asymmetry and regional atrophy measures have not been systematically investigated. Here, we addressed this gap using the multi-site ENIGMA-Epilepsy dataset comprising MRI brain morphological measures in 732 TLE patients and 1,418 healthy controls. We compared spatial distributions of grey matter asymmetry and atrophy in TLE, contextualized their topographies relative to spatial gradients in cortical microstructure and functional connectivity calculated using 207 healthy controls obtained from Human Connectome Project and an independent dataset containing 23 TLE patients and 53 healthy controls, and examined clinical associations using machine learning. We identified a marked divergence in the spatial distribution of atypical inter-hemispheric asymmetry and regional atrophy mapping. The former revealed a temporo-limbic disease signature while the latter showed diffuse and bilateral patterns. Our findings were robust across individual sites and patients. Cortical atrophy was significantly correlated with disease duration and age at seizure onset, while degrees of asymmetry did not show a significant relationship to these clinical variables. Our findings highlight that the mapping of atypical inter-hemispheric asymmetry and regional atrophy tap into two complementary aspects of TLE-related pathology, with the former revealing primary substrates in ipsilateral limbic circuits and the latter capturing bilateral disease effects. These findings refine our notion of the neuropathology of TLE and may inform future discovery and validation of complementary MRI biomarkers in TLE.

    Additional information

    awab417_supplementary_data.pdf
  • Schlag, F., Allegrini, A. G., Buitelaar, J., Verhoef, E., Van Donkelaar, M. M. J., Plomin, R., Rimfeld, K., Fisher, S. E., & St Pourcain, B. (2022). Polygenic risk for mental disorder reveals distinct association profiles across social behaviour in the general population. Molecular Psychiatry, 27, 1588-1598. doi:10.1038/s41380-021-01419-0.

    Abstract

    Many mental health conditions present a spectrum of social difficulties that overlaps with social behaviour in the general population including shared but little characterised genetic links. Here, we systematically investigate heterogeneity in shared genetic liabilities with attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASD), bipolar disorder (BP), major depression (MD) and schizophrenia across a spectrum of different social symptoms. Longitudinally assessed low-prosociality and peer-problem scores in two UK population-based cohorts (4–17 years; parent- and teacher-reports; Avon Longitudinal Study of Parents and Children(ALSPAC): N ≤ 6,174; Twins Early Development Study(TEDS): N ≤ 7,112) were regressed on polygenic risk scores for disorder, as informed by genome-wide summary statistics from large consortia, using negative binomial regression models. Across ALSPAC and TEDS, we replicated univariate polygenic associations between social behaviour and risk for ADHD, MD and schizophrenia. Modelling variation in univariate genetic effects jointly using random-effect meta-regression revealed evidence for polygenic links between social behaviour and ADHD, ASD, MD, and schizophrenia risk, but not BP. Differences in age, reporter and social trait captured 45–88% in univariate effect variation. Cross-disorder adjusted analyses demonstrated that age-related heterogeneity in univariate effects is shared across mental health conditions, while reporter- and social trait-specific heterogeneity captures disorder-specific profiles. In particular, ADHD, MD, and ASD polygenic risk were more strongly linked to peer problems than low prosociality, while schizophrenia was associated with low prosociality only. The identified association profiles suggest differences in the social genetic architecture across mental disorders when investigating polygenic overlap with population-based social symptoms spanning 13 years of child and adolescent development.
  • Sha, Z., Van Rooij, D., Anagnostou, E., Arango, C., Auzias, G., Behrmann, M., Bernhardt, B., Bolte, S., Busatto, G. F., Calderoni, S., Calvo, R., Daly, E., Deruelle, C., Duan, M., Duran, F. L. S., Durston, S., Ecker, C., Ehrlich, S., Fair, D., Fedor, J. and 38 moreSha, Z., Van Rooij, D., Anagnostou, E., Arango, C., Auzias, G., Behrmann, M., Bernhardt, B., Bolte, S., Busatto, G. F., Calderoni, S., Calvo, R., Daly, E., Deruelle, C., Duan, M., Duran, F. L. S., Durston, S., Ecker, C., Ehrlich, S., Fair, D., Fedor, J., Fitzgerald, J., Floris, D. L., Franke, B., Freitag, C. M., Gallagher, L., Glahn, D. C., Haar, S., Hoekstra, L., Jahanshad, N., Jalbrzikowski, M., Janssen, J., King, J. A., Lazaro, L., Luna, B., McGrath, J., Medland, S. E., Muratori, F., Murphy, D. G., Neufeld, J., O’Hearn, K., Oranje, B., Parellada, M., Pariente, J. C., Postema, M., Remnelius, K. L., Retico, A., Rosa, P. G. P., Rubia, K., Shook, D., Tammimies, K., Taylor, M. J., Tosetti, M., Wallace, G. L., Zhou, F., Thompson, P. M., Fisher, S. E., Buitelaar, J. K., & Francks, C. (2022). Subtly altered topological asymmetry of brain structural covariance networks in autism spectrum disorder across 43 datasets from the ENIGMA consortium. Molecular Psychiatry, 27, 2114-2125. doi:10.1038/s41380-022-01452-7.

    Abstract

    Small average differences in the left-right asymmetry of cerebral cortical thickness have been reported in individuals with autism spectrum disorder (ASD) compared to typically developing controls, affecting widespread cortical regions. The possible impacts of these regional alterations in terms of structural network effects have not previously been characterized. Inter-regional morphological covariance analysis can capture network connectivity between different cortical areas at the macroscale level. Here, we used cortical thickness data from 1455 individuals with ASD and 1560 controls, across 43 independent datasets of the ENIGMA consortium’s ASD Working Group, to assess hemispheric asymmetries of intra-individual structural covariance networks, using graph theory-based topological metrics. Compared with typical features of small-world architecture in controls, the ASD sample showed significantly altered average asymmetry of networks involving the fusiform, rostral middle frontal, and medial orbitofrontal cortex, involving higher randomization of the corresponding right-hemispheric networks in ASD. A network involving the superior frontal cortex showed decreased right-hemisphere randomization. Based on comparisons with meta-analyzed functional neuroimaging data, the altered connectivity asymmetry particularly affected networks that subserve executive functions, language-related and sensorimotor processes. These findings provide a network-level characterization of altered left-right brain asymmetry in ASD, based on a large combined sample. Altered asymmetrical brain development in ASD may be partly propagated among spatially distant regions through structural connectivity.
  • Sønderby, I. E., Ching, C. R. K., Thomopoulos, S. I., Van der Meer, D., Sun, D., Villalon‐Reina, J. E., Agartz, I., Amunts, K., Arango, C., Armstrong, N. J., Ayesa‐Arriola, R., Bakker, G., Bassett, A. S., Boomsma, D. I., Bülow, R., Butcher, N. J., Calhoun, V. D., Caspers, S., Chow, E. W. C., Cichon, S. and 84 moreSønderby, I. E., Ching, C. R. K., Thomopoulos, S. I., Van der Meer, D., Sun, D., Villalon‐Reina, J. E., Agartz, I., Amunts, K., Arango, C., Armstrong, N. J., Ayesa‐Arriola, R., Bakker, G., Bassett, A. S., Boomsma, D. I., Bülow, R., Butcher, N. J., Calhoun, V. D., Caspers, S., Chow, E. W. C., Cichon, S., Ciufolini, S., Craig, M. C., Crespo‐Facorro, B., Cunningham, A. C., Dale, A. M., Dazzan, P., De Zubicaray, G. I., Djurovic, S., Doherty, J. L., Donohoe, G., Draganski, B., Durdle, C. A., Ehrlich, S., Emanuel, B. S., Espeseth, T., Fisher, S. E., Ge, T., Glahn, D. C., Grabe, H. J., Gur, R. E., Gutman, B. A., Haavik, J., Håberg, A. K., Hansen, L. A., Hashimoto, R., Hibar, D. P., Holmes, A. J., Hottenga, J., Hulshoff Pol, H. E., Jalbrzikowski, M., Knowles, E. E. M., Kushan, L., Linden, D. E. J., Liu, J., Lundervold, A. J., Martin‐Brevet, S., Martínez, K., Mather, K. A., Mathias, S. R., McDonald‐McGinn, D. M., McRae, A. F., Medland, S. E., Moberget, T., Modenato, C., Monereo Sánchez, J., Moreau, C. A., Mühleisen, T. W., Paus, T., Pausova, Z., Prieto, C., Ragothaman, A., Reinbold, C. S., Reis Marques, T., Repetto, G. M., Reymond, A., Roalf, D. R., Rodriguez‐Herreros, B., Rucker, J. J., Sachdev, P. S., Schmitt, J. E., Schofield, P. R., Silva, A. I., Stefansson, H., Stein, D. J., Tamnes, C. K., Tordesillas‐Gutiérrez, D., Ulfarsson, M. O., Vajdi, A., Van 't Ent, D., Van den Bree, M. B. M., Vassos, E., Vázquez‐Bourgon, J., Vila‐Rodriguez, F., Walters, G. B., Wen, W., Westlye, L. T., Wittfeld, K., Zackai, E. H., Stefánsson, K., Jacquemont, S., Thompson, P. M., Bearden, C. E., Andreassen, O. A., the ENIGMA-CNV Working Group, & the ENIGMA 22q11.2 Deletion Syndrome Working Group (2022). Effects of copy number variations on brain structure and risk for psychiatric illness: Large‐scale studies from the ENIGMAworking groups on CNVs. Human Brain Mapping, 43(1), 300-328. doi:10.1002/hbm.25354.

    Abstract

    The Enhancing NeuroImaging Genetics through Meta‐Analysis copy number variant (ENIGMA‐CNV) and 22q11.2 Deletion Syndrome Working Groups (22q‐ENIGMA WGs) were created to gain insight into the involvement of genetic factors in human brain development and related cognitive, psychiatric and behavioral manifestations. To that end, the ENIGMA‐CNV WG has collated CNV and magnetic resonance imaging (MRI) data from ~49,000 individuals across 38 global research sites, yielding one of the largest studies to date on the effects of CNVs on brain structures in the general population. The 22q‐ENIGMA WG includes 12 international research centers that assessed over 533 individuals with a confirmed 22q11.2 deletion syndrome, 40 with 22q11.2 duplications, and 333 typically developing controls, creating the largest‐ever 22q11.2 CNV neuroimaging data set. In this review, we outline the ENIGMA infrastructure and procedures for multi‐site analysis of CNVs and MRI data. So far, ENIGMA has identified effects of the 22q11.2, 16p11.2 distal, 15q11.2, and 1q21.1 distal CNVs on subcortical and cortical brain structures. Each CNV is associated with differences in cognitive, neurodevelopmental and neuropsychiatric traits, with characteristic patterns of brain structural abnormalities. Evidence of gene‐dosage effects on distinct brain regions also emerged, providing further insight into genotype–phenotype relationships. Taken together, these results offer a more comprehensive picture of molecular mechanisms involved in typical and atypical brain development. This “genotype‐first” approach also contributes to our understanding of the etiopathogenesis of brain disorders. Finally, we outline future directions to better understand effects of CNVs on brain structure and behavior.
  • Van der Spek, J., Den Hoed, J., Snijders Blok, L., Dingemans, A. J. M., Schijven, D., Nellaker, C., Venselaar, H., Astuti, G. D. N., Barakat, T. S., Bebin, E. M., Beck-Wödl, S., Beunders, G., Brown, N. J., Brunet, T., Brunner, H. G., Campeau, P. M., Čuturilo, G., Gilissen, C., Haack, T. B., Hüning, I. and 26 moreVan der Spek, J., Den Hoed, J., Snijders Blok, L., Dingemans, A. J. M., Schijven, D., Nellaker, C., Venselaar, H., Astuti, G. D. N., Barakat, T. S., Bebin, E. M., Beck-Wödl, S., Beunders, G., Brown, N. J., Brunet, T., Brunner, H. G., Campeau, P. M., Čuturilo, G., Gilissen, C., Haack, T. B., Hüning, I., Husain, R. A., Kamien, B., Lim, S. C., Lovrecic, L., Magg, J., Maver, A., Miranda, V., Monteil, D. C., Ockeloen, C. W., Pais, L. S., Plaiasu, V., Raiti, L., Richmond, C., Rieß, A., Schwaibold, E. M. C., Simon, M. E. H., Spranger, S., Tan, T. Y., Thompson, M. L., De Vries, B. B., Wilkins, E. J., Willemsen, M. H., Francks, C., Vissers, L. E. L. M., Fisher, S. E., & Kleefstra, T. (2022). Inherited variants in CHD3 show variable expressivity in Snijders Blok-Campeau syndrome. Genetics in Medicine, 24(6), 1283-1296. doi:10.1016/j.gim.2022.02.014.

    Abstract

    Purpose Common diagnostic next-generation sequencing strategies are not optimized to identify inherited variants in genes associated with dominant neurodevelopmental disorders as causal when the transmitting parent is clinically unaffected, leaving a significant number of cases with neurodevelopmental disorders undiagnosed. Methods We characterized 21 families with inherited heterozygous missense or protein-truncating variants in CHD3, a gene in which de novo variants cause Snijders Blok-Campeau syndrome. Results Computational facial and Human Phenotype Ontology–based comparisons showed that the phenotype of probands with inherited CHD3 variants overlaps with the phenotype previously associated with de novo CHD3 variants, whereas heterozygote parents are mildly or not affected, suggesting variable expressivity. In addition, similarly reduced expression levels of CHD3 protein in cells of an affected proband and of healthy family members with a CHD3 protein-truncating variant suggested that compensation of expression from the wild-type allele is unlikely to be an underlying mechanism. Notably, most inherited CHD3 variants were maternally transmitted. Conclusion Our results point to a significant role of inherited variation in Snijders Blok-Campeau syndrome, a finding that is critical for correct variant interpretation and genetic counseling and warrants further investigation toward understanding the broader contributions of such variation to the landscape of human disease.
  • Wierenga, L. M., Doucet, G. E., Dima, D., Agartz, I., Aghajani, M., Akudjedu, T. N., Albajes-Eizagirre, A., Alnæs, D., Alpert, K. I., Andreassen, O. A., Anticevic, A., Asherson, P., Banaschewski, T., Bargallo, N., Baumeister, S., Baur-Streubel, R., Bertolino, A., Bonvino, A., Boomsma, D. I., Borgwardt, S. and 139 moreWierenga, L. M., Doucet, G. E., Dima, D., Agartz, I., Aghajani, M., Akudjedu, T. N., Albajes-Eizagirre, A., Alnæs, D., Alpert, K. I., Andreassen, O. A., Anticevic, A., Asherson, P., Banaschewski, T., Bargallo, N., Baumeister, S., Baur-Streubel, R., Bertolino, A., Bonvino, A., Boomsma, D. I., Borgwardt, S., Bourque, J., Den Braber, A., Brandeis, D., Breier, A., Brodaty, H., Brouwer, R. M., Buitelaar, J. K., Busatto, G. F., Calhoun, V. D., Canales-Rodríguez, E. J., Cannon, D. M., Caseras, X., Castellanos, F. X., Chaim-Avancini, T. M., Ching, C. R. K., Clark, V. P., Conrod, P. J., Conzelmann, A., Crivello, F., Davey, C. G., Dickie, E. W., Ehrlich, S., Van 't Ent, D., Fisher, S. E., Fouche, J.-P., Franke, B., Fuentes-Claramonte, P., De Geus, E. J. C., Di Giorgio, A., Glahn, D. C., Gotlib, I. H., Grabe, H. J., Gruber, O., Gruner, P., Gur, R. E., Gur, R. C., Gurholt, T. P., De Haan, L., Haatveit, B., Harrison, B. J., Hartman, C. A., Hatton, S. N., Heslenfeld, D. J., Van den Heuvel, O. A., Hickie, I. B., Hoekstra, P. J., Hohmann, S., Holmes, A. J., Hoogman, M., Hosten, N., Howells, F. M., Hulshoff Pol, H. E., Huyser, C., Jahanshad, N., James, A. C., Jiang, J., Jönsson, E. G., Joska, J. A., Kalnin, A. J., Karolinska Schizophrenia Project (KaSP) Consortium, Klein, M., Koenders, L., Kolskår, K. K., Krämer, B., Kuntsi, J., Lagopoulos, J., Lazaro, L., Lebedeva, I. S., Lee, P. H., Lochner, C., Machielsen, M. W. J., Maingault, S., Martin, N. G., Martínez-Zalacaín, I., Mataix-Cols, D., Mazoyer, B., McDonald, B. C., McDonald, C., McIntosh, A. M., McMahon, K. L., McPhilemy, G., Van der Meer, D., Menchón, J. M., Naaijen, J., Nyberg, L., Oosterlaan, J., Paloyelis, Y., Pauli, P., Pergola, G., Pomarol-Clotet, E., Portella, M. J., Radua, J., Reif, A., Richard, G., Roffman, J. L., Rosa, P. G. P., Sacchet, M. D., Sachdev, P. S., Salvador, R., Sarró, S., Satterthwaite, T. D., Saykin, A. J., Serpa, M. H., Sim, K., Simmons, A., Smoller, J. W., Sommer, I. E., Soriano-Mas, C., Stein, D. J., Strike, L. T., Szeszko, P. R., Temmingh, H. S., Thomopoulos, S. I., Tomyshev, A. S., Trollor, J. N., Uhlmann, A., Veer, I. M., Veltman, D. J., Voineskos, A., Völzke, H., Walter, H., Wang, L., Wang, Y., Weber, B., Wen, W., West, J. D., Westlye, L. T., Whalley, H. C., Williams, S. C. R., Wittfeld, K., Wolf, D. H., Wright, M. J., Yoncheva, Y. N., Zanetti, M. V., Ziegler, G. C., De Zubicaray, G. I., Thompson, P. M., Crone, E. A., Frangou, S., & Tamnes, C. K. (2022). Greater male than female variability in regional brain structure across the lifespan. Human Brain Mapping, 43(1), 470-499. doi:10.1002/hbm.25204.

    Abstract

    For many traits, males show greater variability than females, with possible implications for understanding sex differences in health and disease. Here, the ENIGMA (Enhancing Neuro Imaging Genetics through Meta‐Analysis) Consortium presents the largest‐ever mega‐analysis of sex differences in variability of brain structure, based on international data spanning nine decades of life. Subcortical volumes, cortical surface area and cortical thickness were assessed in MRI data of 16,683 healthy individuals 1‐90 years old (47% females). We observed significant patterns of greater male than female between‐subject variance for all subcortical volumetric measures, all cortical surface area measures, and 60% of cortical thickness measures. This pattern was stable across the lifespan for 50% of the subcortical structures, 70% of the regional area measures, and nearly all regions for thickness. Our findings that these sex differences are present in childhood implicate early life genetic or gene‐environment interaction mechanisms. The findings highlight the importance of individual differences within the sexes, that may underpin sex‐specific vulnerability to disorders.
  • Braden, R. O., Amor, D. J., Fisher, S. E., Mei, C., Myers, C. T., Mefford, H., Gill, D., Srivastava, S., Swanson, L. C., Goel, H., Scheffer, I. E., & Morgan, A. T. (2021). Severe speech impairment is a distinguishing feature of FOXP1-related disorder. Developmental Medicine & Child Neurology, 63(12), 1417-1426. doi:10.1111/dmcn.14955.

    Abstract

    Aim To delineate the speech and language phenotype of a cohort of individuals with FOXP1-related disorder. Method We administered a standardized test battery to examine speech and oral motor function, receptive and expressive language, non-verbal cognition, and adaptive behaviour. Clinical history and cognitive assessments were analysed together with speech and language findings. Results Twenty-nine patients (17 females, 12 males; mean age 9y 6mo; median age 8y [range 2y 7mo–33y]; SD 6y 5mo) with pathogenic FOXP1 variants (14 truncating, three missense, three splice site, one in-frame deletion, eight cytogenic deletions; 28 out of 29 were de novo variants) were studied. All had atypical speech, with 21 being verbal and eight minimally verbal. All verbal patients had dysarthric and apraxic features, with phonological deficits in most (14 out of 16). Language scores were low overall. In the 21 individuals who carried truncating or splice site variants and small deletions, expressive abilities were relatively preserved compared with comprehension. Interpretation FOXP1-related disorder is characterized by a complex speech and language phenotype with prominent dysarthria, broader motor planning and programming deficits, and linguistic-based phonological errors. Diagnosis of the speech phenotype associated with FOXP1-related dysfunction will inform early targeted therapy.

    Additional information

    figure S1 table S1
  • Carrion Castillo, A., Estruch, S. B., Maassen, B., Franke, B., Francks, C., & Fisher, S. E. (2021). Whole-genome sequencing identifies functional noncoding variation in SEMA3C that cosegregates with dyslexia in a multigenerational family. Human Genetics, 140, 1183-1200. doi:10.1007/s00439-021-02289-w.

    Abstract

    Dyslexia is a common heritable developmental disorder involving impaired reading abilities. Its genetic underpinnings are thought to be complex and heterogeneous, involving common and rare genetic variation. Multigenerational families segregating apparent monogenic forms of language-related disorders can provide useful entrypoints into biological pathways. In the present study, we performed a genome-wide linkage scan in a three-generational family in which dyslexia affects 14 of its 30 members and seems to be transmitted with an autosomal dominant pattern of inheritance. We identified a locus on chromosome 7q21.11 which cosegregated with dyslexia status, with the exception of two cases of phenocopy (LOD = 2.83). Whole-genome sequencing of key individuals enabled the assessment of coding and noncoding variation in the family. Two rare single-nucleotide variants (rs144517871 and rs143835534) within the first intron of the SEMA3C gene cosegregated with the 7q21.11 risk haplotype. In silico characterization of these two variants predicted effects on gene regulation, which we functionally validated for rs144517871 in human cell lines using luciferase reporter assays. SEMA3C encodes a secreted protein that acts as a guidance cue in several processes, including cortical neuronal migration and cellular polarization. We hypothesize that these intronic variants could have a cis-regulatory effect on SEMA3C expression, making a contribution to dyslexia susceptibility in this family.
  • Den Hoed, J., Devaraju, K., & Fisher, S. E. (2021). Molecular networks of the FOXP2 transcription factor in the brain. EMBO Reports, 22(8): e52803. doi:10.15252/embr.202152803.

    Abstract

    The discovery of the FOXP2 transcription factor, and its implication in a rare severe human speech and language disorder, has led to two decades of empirical studies focused on uncovering its roles in the brain using a range of in vitro and in vivo methods. Here, we discuss what we have learned about the regulation of FOXP2, its downstream effectors, and its modes of action as a transcription factor in brain development and function, providing an integrated overview of what is currently known about the critical molecular networks.
  • Den Hoed, J., De Boer, E., Voisin, N., Dingemans, A. J. M., Guex, N., Wiel, L., Nellaker, C., Amudhavalli, S. M., Banka, S., Bena, F. S., Ben-Zeev, B., Bonagura, V. R., Bruel, A.-L., Brunet, T., Brunner, H. G., Chew, H. B., Chrast, J., Cimbalistienė, L., Coon, H., The DDD study, Délot, E. C. and 77 moreDen Hoed, J., De Boer, E., Voisin, N., Dingemans, A. J. M., Guex, N., Wiel, L., Nellaker, C., Amudhavalli, S. M., Banka, S., Bena, F. S., Ben-Zeev, B., Bonagura, V. R., Bruel, A.-L., Brunet, T., Brunner, H. G., Chew, H. B., Chrast, J., Cimbalistienė, L., Coon, H., The DDD study, Délot, E. C., Démurger, F., Denommé-Pichon, A.-S., Depienne, C., Donnai, D., Dyment, D. A., Elpeleg, O., Faivre, L., Gilissen, C., Granger, L., Haber, B., Hachiya, Y., Hamzavi Abedi, Y., Hanebeck, J., Hehir-Kwa, J. Y., Horist, B., Itai, T., Jackson, A., Jewell, R., Jones, K. L., Joss, S., Kashii, H., Kato, M., Kattentidt-Mouravieva, A. A., Kok, F., Kotzaeridou, U., Krishnamurthy, V., Kučinskas, V., Kuechler, A., Lavillaureix, A., Liu, P., Manwaring, L., Matsumoto, N., Mazel, B., McWalter, K., Meiner, V., Mikati, M. A., Miyatake, S., Mizuguchi, T., Moey, L. H., Mohammed, S., Mor-Shaked, H., Mountford, H., Newbury-Ecob, R., Odent, S., Orec, L., Osmond, M., Palculict, T. B., Parker, M., Petersen, A., Pfundt, R., Preikšaitienė, E., Radtke, K., Ranza, E., Rosenfeld, J. A., Santiago-Sim, T., Schwager, C., Sinnema, M., Snijders Blok, L., Spillmann, R. C., Stegmann, A. P. A., Thiffault, I., Tran, L., Vaknin-Dembinsky, A., Vedovato-dos-Santos, J. H., Vergano, S. A., Vilain, E., Vitobello, A., Wagner, M., Waheeb, A., Willing, M., Zuccarelli, B., Kini, U., Newbury, D. F., Kleefstra, T., Reymond, A., Fisher, S. E., & Vissers, L. E. L. M. (2021). Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction. The American Journal of Human Genetics, 108(2), 346-356. doi:10.1016/j.ajhg.2021.01.007.

    Abstract

    Whereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene, SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carrying SATB1 variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression and a severe phenotype. Contrastingly, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay and encode truncated proteins, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability.
  • Gialluisi, A., Andlauer, T. F. M., Mirza-Schreiber, N., Moll, K., Becker, J., Hoffmann, P., Ludwig, K. U., Czamara, D., St Pourcain, B., Honbolygó, F., Tóth, D., Csépe, V., Huguet, H., Chaix, Y., Iannuzzi, S., Demonet, J.-F., Morris, A. P., Hulslander, J., Willcutt, E. G., DeFries, J. C. and 29 moreGialluisi, A., Andlauer, T. F. M., Mirza-Schreiber, N., Moll, K., Becker, J., Hoffmann, P., Ludwig, K. U., Czamara, D., St Pourcain, B., Honbolygó, F., Tóth, D., Csépe, V., Huguet, H., Chaix, Y., Iannuzzi, S., Demonet, J.-F., Morris, A. P., Hulslander, J., Willcutt, E. G., DeFries, J. C., Olson, R. K., Smith, S. D., Pennington, B. F., Vaessen, A., Maurer, U., Lyytinen, H., Peyrard-Janvid, M., Leppänen, P. H. T., Brandeis, D., Bonte, M., Stein, J. F., Talcott, J. B., Fauchereau, F., Wilcke, A., Kirsten, H., Müller, B., Francks, C., Bourgeron, T., Monaco, A. P., Ramus, F., Landerl, K., Kere, J., Scerri, T. S., Paracchini, S., Fisher, S. E., Schumacher, J., Nöthen, M. M., Müller-Myhsok, B., & Schulte-Körne, G. (2021). Genome-wide association study reveals new insights into the heritability and genetic correlates of developmental dyslexia. Molecular Psychiatry, 26, 3004-3017. doi:10.1038/s41380-020-00898-x.

    Abstract

    Developmental dyslexia (DD) is a learning disorder affecting the ability to read, with a heritability of 40–60%. A notable part of this heritability remains unexplained, and large genetic studies are warranted to identify new susceptibility genes and clarify the genetic bases of dyslexia. We carried out a genome-wide association study (GWAS) on 2274 dyslexia cases and 6272 controls, testing associations at the single variant, gene, and pathway level, and estimating heritability using single-nucleotide polymorphism (SNP) data. We also calculated polygenic scores (PGSs) based on large-scale GWAS data for different neuropsychiatric disorders and cortical brain measures, educational attainment, and fluid intelligence, testing them for association with dyslexia status in our sample. We observed statistically significant (p  < 2.8 × 10−6) enrichment of associations at the gene level, for LOC388780 (20p13; uncharacterized gene), and for VEPH1 (3q25), a gene implicated in brain development. We estimated an SNP-based heritability of 20–25% for DD, and observed significant associations of dyslexia risk with PGSs for attention deficit hyperactivity disorder (at pT = 0.05 in the training GWAS: OR = 1.23[1.16; 1.30] per standard deviation increase; p  = 8 × 10−13), bipolar disorder (1.53[1.44; 1.63]; p = 1 × 10−43), schizophrenia (1.36[1.28; 1.45]; p = 4 × 10−22), psychiatric cross-disorder susceptibility (1.23[1.16; 1.30]; p = 3 × 10−12), cortical thickness of the transverse temporal gyrus (0.90[0.86; 0.96]; p = 5 × 10−4), educational attainment (0.86[0.82; 0.91]; p = 2 × 10−7), and intelligence (0.72[0.68; 0.76]; p = 9 × 10−29). This study suggests an important contribution of common genetic variants to dyslexia risk, and novel genomic overlaps with psychiatric conditions like bipolar disorder, schizophrenia, and cross-disorder susceptibility. Moreover, it revealed the presence of shared genetic foundations with a neural correlate previously implicated in dyslexia by neuroimaging evidence.
  • Jansen, N. A., Braden, R. O., Srivastava, S., Otness, E. F., Lesca, G., Rossi, M., Nizon, M., Bernier, R. A., Quelin, C., Van Haeringen, A., Kleefstra, T., Wong, M. M. K., Whalen, S., Fisher, S. E., Morgan, A. T., & Van Bon, B. W. (2021). Clinical delineation of SETBP1 haploinsufficiency disorder. European Journal of Human Genetics, 29, 1198 -1205. doi:10.1038/s41431-021-00888-9.

    Abstract

    SETBP1 haploinsufficiency disorder (MIM#616078) is caused by haploinsufficiency of SETBP1 on chromosome 18q12.3, but there has not yet been any systematic evaluation of the major features of this monogenic syndrome, assessing penetrance and expressivity. We describe the first comprehensive study to delineate the associated clinical phenotype, with findings from 34 individuals, including 24 novel cases, all of whom have a SETBP1 loss-of-function variant or single (coding) gene deletion, confirmed by molecular diagnostics. The most commonly reported clinical features included mild motor developmental delay, speech impairment, intellectual disability, hypotonia, vision impairment, attention/concentration deficits, and hyperactivity. Although there is a mild overlap in certain facial features, the disorder does not lead to a distinctive recognizable facial gestalt. As well as providing insight into the clinical spectrum of SETBP1 haploinsufficiency disorder, this reports puts forward care recommendations for patient management.

    Additional information

    supplementary table
  • Kong, X., Postema, M., Schijven, D., Carrion Castillo, A., Pepe, A., Crivello, F., Joliot, M., Mazoyer, B., Fisher, S. E., & Francks, C. (2021). Large-scale phenomic and genomic analysis of brain asymmetrical skew. Cerebral Cortex, 31(9), 4151-4168. doi:10.1093/cercor/bhab075.

    Abstract

    The human cerebral hemispheres show a left–right asymmetrical torque pattern, which has been claimed to be absent in chimpanzees. The functional significance and developmental mechanisms are unknown. Here, we carried out the largest-ever analysis of global brain shape asymmetry in magnetic resonance imaging data. Three population datasets were used, UK Biobank (N = 39 678), Human Connectome Project (N = 1113), and BIL&GIN (N = 453). At the population level, there was an anterior and dorsal skew of the right hemisphere, relative to the left. Both skews were associated independently with handedness, and various regional gray and white matter metrics oppositely in the two hemispheres, as well as other variables related to cognitive functions, sociodemographic factors, and physical and mental health. The two skews showed single nucleotide polymorphisms-based heritabilities of 4–13%, but also substantial polygenicity in causal mixture model analysis, and no individually significant loci were found in genome-wide association studies for either skew. There was evidence for a significant genetic correlation between horizontal brain skew and autism, which requires future replication. These results provide the first large-scale description of population-average brain skews and their inter-individual variations, their replicable associations with handedness, and insights into biological and other factors which associate with human brain asymmetry.
  • Morgan, A., Braden, R., Wong, M. M. K., Colin, E., Amor, D., Liégeois, F., Srivastava, S., Vogel, A., Bizaoui, V., Ranguin, K., Fisher, S. E., & Van Bon, B. W. (2021). Speech and language deficits are central to SETBP1 haploinsufficiency disorder. European Journal of Human Genetics, 29, 1216-1225. doi:10.1038/s41431-021-00894-x.

    Abstract

    Expressive communication impairment is associated with haploinsufficiency of SETBP1, as reported in small case series. Heterozygous pathogenic loss-of-function (LoF) variants in SETBP1 have also been identified in independent cohorts ascertained for childhood apraxia of speech (CAS), warranting further investigation of the roles of this gene in speech development. Thirty-one participants (12 males, aged 0; 8–23; 2 years, 28 with pathogenic SETBP1 LoF variants, 3 with 18q12.3 deletions) were assessed for speech, language and literacy abilities. Broader development was examined with standardised motor, social and daily life skills assessments. Gross and fine motor deficits (94%) and intellectual impairments (68%) were common. Protracted and aberrant speech development was consistently seen, regardless of motor or intellectual ability. We expand the linguistic phenotype associated with SETBP1 LoF syndrome (SETBP1 haploinsufficiency disorder), revealing a striking speech presentation that implicates both motor (CAS, dysarthria) and language (phonological errors) systems, with CAS (80%) being the most common diagnosis. In contrast to past reports, the understanding of language was rarely better preserved than language expression (29%). Language was typically low, to moderately impaired, with commensurate expression and comprehension ability. Children were sociable with a strong desire to communicate. Minimally verbal children (32%) augmented speech with sign language, gestures or digital devices. Overall, relative to general development, spoken language and literacy were poorer than social, daily living, motor and adaptive behaviour skills. Our findings show that poor communication is a central feature of SETBP1 haploinsufficiency disorder, confirming this gene as a strong candidate for speech and language disorders.
  • Postema, M., Hoogman, M., Ambrosino, S., Asherson, P., Banaschewski, T., Bandeira, C. E., Baranov, A., Bau, C. H. D., Baumeister, S., Baur-Streubel, R., Bellgrove, M. A., Biederman, J., Bralten, J., Brandeis, D., Brem, S., Buitelaar, J. K., Busatto, G. F., Castellanos, F. X., Cercignani, M., Chaim-Avancini, T. M. and 85 morePostema, M., Hoogman, M., Ambrosino, S., Asherson, P., Banaschewski, T., Bandeira, C. E., Baranov, A., Bau, C. H. D., Baumeister, S., Baur-Streubel, R., Bellgrove, M. A., Biederman, J., Bralten, J., Brandeis, D., Brem, S., Buitelaar, J. K., Busatto, G. F., Castellanos, F. X., Cercignani, M., Chaim-Avancini, T. M., Chantiluke, K. C., Christakou, A., Coghill, D., Conzelmann, A., Cubillo, A. I., Cupertino, R. B., De Zeeuw, P., Doyle, A. E., Durston, S., Earl, E. A., Epstein, J. N., Ethofer, T., Fair, D. A., Fallgatter, A. J., Faraone, S. V., Frodl, T., Gabel, M. C., Gogberashvili, T., Grevet, E. H., Haavik, J., Harrison, N. A., Hartman, C. A., Heslenfeld, D. J., Hoekstra, P. J., Hohmann, S., Høvik, M. F., Jernigan, T. L., Kardatzki, B., Karkashadze, G., Kelly, C., Kohls, G., Konrad, K., Kuntsi, J., Lazaro, L., Lera-Miguel, S., Lesch, K.-P., Louza, M. R., Lundervold, A. J., Malpas, C. B., Mattos, P., McCarthy, H., Namazova-Baranova, L., Nicolau, R., Nigg, J. T., Novotny, S. E., Oberwelland Weiss, E., O'Gorman Tuura, R. L., Oosterlaan, J., Oranje, B., Paloyelis, Y., Pauli, P., Picon, F. A., Plessen, K. J., Ramos-Quiroga, J. A., Reif, A., Reneman, L., Rosa, P. G. P., Rubia, K., Schrantee, A., Schweren, L. J. S., Seitz, J., Shaw, P., Silk, T. J., Skokauskas, N., Soliva Vila, J. C., Stevens, M. C., Sudre, G., Tamm, L., Tovar-Moll, F., Van Erp, T. G. M., Vance, A., Vilarroya, O., Vives-Gilabert, Y., Von Polier, G. G., Walitza, S., Yoncheva, Y. N., Zanetti, M. V., Ziegler, G. C., Glahn, D. C., Jahanshad, N., Medland, S. E., ENIGMA ADHD Working Group, Thompson, P. M., Fisher, S. E., Franke, B., & Francks, C. (2021). Analysis of structural brain asymmetries in Attention-Deficit/Hyperactivity Disorder in 39 datasets. Journal of Child Psychology and Psychiatry, 62(10), 1202-1219. doi:10.1111/jcpp.13396.

    Abstract

    Objective: Some studies have suggested alterations of structural brain asymmetry in attention-deficit/hyperactivity disorder (ADHD), but findings have been contradictory and based on small samples. Here we performed the largest-ever analysis of brain left-right asymmetry in ADHD, using 39 datasets of the ENIGMA consortium. Methods: We analyzed asymmetry of subcortical and cerebral cortical structures in up to 1,933 people with ADHD and 1,829 unaffected controls. Asymmetry Indexes (AIs) were calculated per participant for each bilaterally paired measure, and linear mixed effects modelling was applied separately in children, adolescents, adults, and the total sample, to test exhaustively for potential associations of ADHD with structural brain asymmetries. Results: There was no evidence for altered caudate nucleus asymmetry in ADHD, in contrast to prior literature. In children, there was less rightward asymmetry of the total hemispheric surface area compared to controls (t=2.1, P=0.04). Lower rightward asymmetry of medial orbitofrontal cortex surface area in ADHD (t=2.7, P=0.01) was similar to a recent finding for autism spectrum disorder. There were also some differences in cortical thickness asymmetry across age groups. In adults with ADHD, globus pallidus asymmetry was altered compared to those without ADHD. However, all effects were small (Cohen’s d from -0.18 to 0.18) and would not survive study-wide correction for multiple testing. Conclusion: Prior studies of altered structural brain asymmetry in ADHD were likely under-powered to detect the small effects reported here. Altered structural asymmetry is unlikely to provide a useful biomarker for ADHD, but may provide neurobiological insights into the trait.

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  • Sha, Z., Pepe, A., Schijven, D., Carrion Castillo, A., Roe, J. M., Westerhausen, R., Joliot, M., Fisher, S. E., Crivello, F., & Francks, C. (2021). Handedness and its genetic influences are associated with structural asymmetries of the cerebral cortex in 31,864 individuals. Proceedings of the National Academy of Sciences of the United States of America, 118(47): e2113095118. doi:10.1073/pnas.2113095118.

    Abstract

    Roughly 10% of the human population is left-handed, and this rate is increased in some brain-related disorders. The neuroanatomical correlates of hand preference have remained equivocal. We resampled structural brain image data from 28,802 right-handers and 3,062 left-handers (UK Biobank population dataset) to a symmetrical surface template, and mapped asymmetries for each of 8,681 vertices across the cerebral cortex in each individual. Left-handers compared to right-handers showed average differences of surface area asymmetry within the fusiform cortex, the anterior insula, the anterior middle cingulate cortex, and the precentral cortex. Meta-analyzed functional imaging data implicated these regions in executive functions and language. Polygenic disposition to left-handedness was associated with two of these regional asymmetries, and 18 loci previously linked with left-handedness by genome-wide screening showed associations with one or more of these asymmetries. Implicated genes included six encoding microtubule-related proteins: TUBB, TUBA1B, TUBB3, TUBB4A, MAP2, and NME7—mutations in the latter can cause left to right reversal of the visceral organs. There were also two cortical regions where average thickness asymmetry was altered in left-handedness: on the postcentral gyrus and the inferior occipital cortex, functionally annotated with hand sensorimotor and visual roles. These cortical thickness asymmetries were not heritable. Heritable surface area asymmetries of language-related regions may link the etiologies of hand preference and language, whereas nonheritable asymmetries of sensorimotor cortex may manifest as consequences of hand preference.
  • Sha, Z., Schijven, D., Carrion Castillo, A., Joliot, M., Mazoyer, B., Fisher, S. E., Crivello, F., & Francks, C. (2021). The genetic architecture of structural left–right asymmetry of the human brain. Nature Human Behaviour, 5, 1226-1236. doi:10.1038/s41562-021-01069-w.

    Abstract

    Left–right hemispheric asymmetry is an important aspect of healthy brain organization for many functions including language, and it can be altered in cognitive and psychiatric disorders. No mechanism has yet been identified for establishing the human brain’s left–right axis. We performed multivariate genome-wide association scanning of cortical regional surface area and thickness asymmetries, and subcortical volume asymmetries, using data from 32,256 participants from the UK Biobank. There were 21 significant loci associated with different aspects of brain asymmetry, with functional enrichment involving microtubule-related genes and embryonic brain expression. These findings are consistent with a known role of the cytoskeleton in left–right axis determination in other organs of invertebrates and frogs. Genetic variants associated with brain asymmetry overlapped with those associated with autism, educational attainment and schizophrenia. Comparably large datasets will likely be required in future studies, to replicate and further clarify the associations of microtubule-related genes with variation in brain asymmetry, behavioural and psychiatric traits.
  • Shapland, C. Y., Verhoef, E., Smith, G. D., Fisher, S. E., Verhulst, B., Dale, P. S., & St Pourcain, B. (2021). Multivariate genome-wide covariance analyses of literacy, language and working memory skills reveal distinct etiologies. npj Science of Learning, 6: 23. doi:10.1038/s41539-021-00101-y.

    Abstract

    Several abilities outside literacy proper are associated with reading and spelling, both phenotypically and genetically, though our knowledge of multivariate genomic covariance structures is incomplete. Here, we introduce structural models describing genetic and residual influences between traits to study multivariate links across measures of literacy, phonological awareness, oral language, and phonological working memory (PWM) in unrelated UK youth (8-13 years, N=6,453). We find that all phenotypes share a large proportion of underlying genetic variation, although especially oral language and PWM reveal substantial differences in their genetic variance composition with substantial trait-specific genetic influences. Multivariate genetic and residual trait covariance showed concordant patterns, except for marked differences between oral language and literacy/phonological awareness, where strong genetic links contrasted near-zero residual overlap. These findings suggest differences in etiological mechanisms, acting beyond a pleiotropic set of genetic variants, and implicate variation in trait modifiability even among phenotypes that have high genetic correlations.

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  • Smeets, C. J. L. M., Ma, K. Y., Fisher, S. E., & Verbeek, D. S. (2021). Cerebellar developmental deficits underlie neurodegenerative disorder spinocerebellar ataxia type 23. Brain Pathology, 31(2), 239-252. doi:10.1111/bpa.12905.

    Abstract

    Spinocerebellar ataxia type 23 (SCA23) is a late‐onset neurodegenerative disorder characterized by slowly progressive gait and limb ataxia, for which there is no therapy available. It is caused by pathogenic variants in PDYN, which encodes prodynorphin (PDYN). PDYN is processed into the opioid peptides α‐neoendorphin and dynorphins (Dyn) A and B; inhibitory neurotransmitters that function in pain signaling, stress‐induced responses and addiction. Variants causing SCA23 mostly affect Dyn A, leading to loss of secondary structure and increased peptide stability. PDYNR212W mice express human PDYN containing the SCA23 variant p.R212W. These mice show progressive motor deficits from 3 months of age, climbing fiber (CF) deficits from 3 months of age, and Purkinje cell (PC) loss from 12 months of age. A mouse model for SCA1 showed similar CF deficits, and a recent study found additional developmental abnormalities, namely increased GABAergic interneuron connectivity and non‐cell autonomous disruption of PC function. As SCA23 mice show a similar pathology to SCA1 mice in adulthood, we hypothesized that SCA23 may also follow SCA1 pathology during development. Examining PDYNR212W cerebella during development, we uncovered developmental deficits from 2 weeks of age, namely a reduced number of GABAergic synapses on PC soma, possibly leading to the observed delay in early phase CF elimination between 2 and 3 weeks of age. Furthermore, CFs did not reach terminal height, leaving proximal PC dendrites open to be occupied by parallel fibers (PFs). The observed increase in vGlut1 protein—a marker for PF‐PC synapses—indicates that PFs indeed take over CF territory and have increased connectivity with PCs. Additionally, we detected altered expression of several critical Ca2+ channel subunits, potentially contributing to altered Ca2+ transients in PDYNR212W cerebella. These findings indicate that developmental abnormalities contribute to the SCA23 pathology and uncover a developmental role for PDYN in the cerebellum.
  • Snijders Blok, L., Vino, A., Den Hoed, J., Underhill, H. R., Monteil, D., Li, H., Reynoso Santos, F. J., Chung, W. K., Amaral, M. D., Schnur, R. E., Santiago-Sim, T., Si, Y., Brunner, H. G., Kleefstra, T., & Fisher, S. E. (2021). Heterozygous variants that disturb the transcriptional repressor activity of FOXP4 cause a developmental disorder with speech/language delays and multiple congenital abnormalities. Genetics in Medicine, 23, 534-542. doi:10.1038/s41436-020-01016-6.

    Abstract

    Heterozygous pathogenic variants in various FOXP genes cause specific developmental disorders. The phenotype associated with heterozygous variants in FOXP4 has not been previously described. We assembled a cohort of eight individuals with heterozygous and mostly de novo variants in FOXP4: seven individuals with six different missense variants and one individual with a frameshift variant. We collected clinical data to delineate the phenotypic spectrum, and used in silico analyses and functional cell-based assays to assess pathogenicity of the variants. We collected clinical data for six individuals: five individuals with a missense variant in the forkhead box DNA-binding domain of FOXP4, and one individual with a truncating variant. Overlapping features included speech and language delays, growth abnormalities, congenital diaphragmatic hernia, cervical spine abnormalities, and ptosis. Luciferase assays showed loss-of-function effects for all these variants, and aberrant subcellular localization patterns were seen in a subset. The remaining two missense variants were located outside the functional domains of FOXP4, and showed transcriptional repressor capacities and localization patterns similar to the wild-type protein. Collectively, our findings show that heterozygous loss-of-function variants in FOXP4 are associated with an autosomal dominant neurodevelopmental disorder with speech/language delays, growth defects, and variable congenital abnormalities.
  • Snijders Blok, L., Goosen, Y. M., Haaften, L., Hulst, K., Fisher, S. E., Brunner, H. G., Egger, J. I. M., & Kleefstra, T. (2021). Speech‐language profiles in the context of cognitive and adaptive functioning inSATB2‐associated syndrome. Genes, Brain and Behavior, 20(7): e12761. doi:10.1111/gbb.12761.

    Abstract

    SATB2-associated syndrome (SAS) is a neurodevelopmental disorder caused by heterozygous pathogenic variants in the SATB2 gene, and is typically characterized by intellectual disability and severely impaired communication skills. The goal of this study was to contribute to the understanding of speech and language impairments in SAS, in the context of general developmental skills and cognitive and adaptive functioning. We performed detailed oral motor, speech and language profiling in combination with neuropsychological assessments in 23 individuals with a molecularly confirmed SAS diagnosis: 11 primarily verbal individuals and 12 primarily nonverbal individuals, independent of their ages. All individuals had severe receptive language delays. For all verbal individuals, we were able to define underlying speech conditions. While childhood apraxia of speech was most prevalent, oral motor problems appeared frequent as well and were more present in the nonverbal group than in the verbal group. For seven individuals, age-appropriate Wechsler indices could be derived, showing that the level of intellectual functioning of these individuals varied from moderate–mild ID to mild ID-borderline intellectual functioning. Assessments of adaptive functioning with the Vineland Screener showed relatively high scores on the domain “daily functioning” and relatively low scores on the domain “communication” in most individuals. Altogether, this study provides a detailed delineation of oral motor, speech and language skills and neuropsychological functioning in individuals with SAS, and can provide families and caregivers with information to guide diagnosis, management and treatment approaches.

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  • Sønderby, I. E., Van der Meer, D., Moreau, C., Kaufmann, T., Walters, G. B., Ellegaard, M., Abdellaoui, A., Ames, D., Amunts, K., Andersson, M., Armstrong, N. J., Bernard, M., Blackburn, N. B., Blangero, J., Boomsma, D. I., Brodaty, H., Brouwer, R. M., Bülow, R., Bøen, R., Cahn, W. and 125 moreSønderby, I. E., Van der Meer, D., Moreau, C., Kaufmann, T., Walters, G. B., Ellegaard, M., Abdellaoui, A., Ames, D., Amunts, K., Andersson, M., Armstrong, N. J., Bernard, M., Blackburn, N. B., Blangero, J., Boomsma, D. I., Brodaty, H., Brouwer, R. M., Bülow, R., Bøen, R., Cahn, W., Calhoun, V. D., Caspers, S., Ching, C. R. K., Cichon, S., Ciufolini, S., Crespo-Facorro, B., Curran, J. E., Dale, A. M., Dalvie, S., Dazzan, P., De Geus, E. J. C., De Zubicaray, G. I., De Zwarte, S. M. C., Desrivieres, S., Doherty, J. L., Donohoe, G., Draganski, B., Ehrlich, S., Eising, E., Espeseth, T., Fejgin, K., Fisher, S. E., Fladby, T., Frei, O., Frouin, V., Fukunaga, M., Gareau, T., Ge, T., Glahn, D. C., Grabe, H. J., Groenewold, N. A., Gústafsson, Ó., Haavik, J., Haberg, A. K., Hall, J., Hashimoto, R., Hehir-Kwa, J. Y., Hibar, D. P., Hillegers, M. H. J., Hoffmann, P., Holleran, L., Holmes, A. J., Homuth, G., Hottenga, J.-J., Hulshoff Pol, H. E., Ikeda, M., Jahanshad, N., Jockwitz, C., Johansson, S., Jönsson, E. G., Jørgensen, N. R., Kikuchi, M., Knowles, E. E. M., Kumar, K., Le Hellard, S., Leu, C., Linden, D. E., Liu, J., Lundervold, A., Lundervold, A. J., Maillard, A. M., Martin, N. G., Martin-Brevet, S., Mather, K. A., Mathias, S. R., McMahon, K. L., McRae, A. F., Medland, S. E., Meyer-Lindenberg, A., Moberget, T., Modenato, C., Monereo Sánchez, J., Morris, D. W., Mühleisen, T. W., Murray, R. M., Nielsen, J., Nordvik, J. E., Nyberg, L., Olde Loohuis, L. M., Ophoff, R. A., Owen, M. J., Paus, T., Pausova, Z., Peralta, J. M., Pike, B., Prieto, C., Quinlan, E. B., Reinbold, C. S., Reis Marques, T., Rucker, J. J. H., Sachdev, P. S., Sando, S. B., Schofield, P. R., Schork, A. J., Schumann, G., Shin, J., Shumskaya, E., Silva, A. I., Sisodiya, S. M., Steen, V. M., Stein, D. J., Strike, L. T., Suzuki, I. K., Tamnes, C. K., Teumer, A., Thalamuthu, A., Tordesillas-Gutiérrez, D., Uhlmann, A., Úlfarsson, M. Ö., Van 't Ent, D., Van den Bree, M. B. M., Vanderhaeghen, P., Vassos, E., Wen, W., Wittfeld, K., Wright, M. J., Agartz, I., Djurovic, S., Westlye, L. T., Stefánsson, H., Stefánsson, K., Jacquemont, S., Thompson, P. M., Andreassen, O. A., & the ENIGMA-CNV working group (2021). 1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans. Translational Psychiatry, 11: 182. doi:10.1038/s41398-021-01213-0.

    Abstract

    Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers—the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.

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  • Tilot, A. K., Khramtsova, E. A., Liang, D., Grasby, K. L., Jahanshad, N., Painter, J., Colodro-Conde, L., Bralten, J., Hibar, D. P., Lind, P. A., Liu, S., Brotman, S. M., Thompson, P. M., Medland, S. E., Macciardi, F., Stranger, B. E., Davis, L. K., Fisher, S. E., & Stein, J. L. (2021). The evolutionary history of common genetic variants influencing human cortical surface area. Cerebral Cortex, 31(4), 1873-1887. doi:10.1093/cercor/bhaa327.

    Abstract

    Structural brain changes along the lineage leading to modern Homo sapiens contributed to our distinctive cognitive and social abilities. However, the evolutionarily relevant molecular variants impacting key aspects of neuroanatomy are largely unknown. Here, we integrate evolutionary annotations of the genome at diverse timescales with common variant associations from large-scale neuroimaging genetic screens. We find that alleles with evidence of recent positive polygenic selection over the past 2000–3000 years are associated with increased surface area (SA) of the entire cortex, as well as specific regions, including those involved in spoken language and visual processing. Therefore, polygenic selective pressures impact the structure of specific cortical areas even over relatively recent timescales. Moreover, common sequence variation within human gained enhancers active in the prenatal cortex is associated with postnatal global SA. We show that such variation modulates the function of a regulatory element of the developmentally relevant transcription factor HEY2 in human neural progenitor cells and is associated with structural changes in the inferior frontal cortex. These results indicate that non-coding genomic regions active during prenatal cortical development are involved in the evolution of human brain structure and identify novel regulatory elements and genes impacting modern human brain structure.
  • Verhoef, E., Shapland, C. Y., Fisher, S. E., Dale, P. S., & St Pourcain, B. (2021). The developmental genetic architecture of vocabulary skills during the first three years of life: Capturing emerging associations with later-life reading and cognition. PLoS Genetics, 17(2): e1009144. doi:10.1371/journal.pgen.1009144.

    Abstract

    Individual differences in early-life vocabulary measures are heritable and associated with subsequent reading and cognitive abilities, although the underlying mechanisms are little understood. Here, we (i) investigate the developmental genetic architecture of expressive and receptive vocabulary in early-life and (ii) assess timing of emerging genetic associations with mid-childhood verbal and non-verbal skills. We studied longitudinally assessed early-life vocabulary measures (15–38 months) and later-life verbal and non-verbal skills (7–8 years) in up to 6,524 unrelated children from the population-based Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. We dissected the phenotypic variance of rank-transformed scores into genetic and residual components by fitting multivariate structural equation models to genome-wide genetic-relationship matrices. Our findings show that the genetic architecture of early-life vocabulary involves multiple distinct genetic factors. Two of these genetic factors are developmentally stable and also contribute to genetic variation in mid-childhood skills: One genetic factor emerging with expressive vocabulary at 24 months (path coefficient: 0.32(SE = 0.06)) was also related to later-life reading (path coefficient: 0.25(SE = 0.12)) and verbal intelligence (path coefficient: 0.42(SE = 0.13)), explaining up to 17.9% of the phenotypic variation. A second, independent genetic factor emerging with receptive vocabulary at 38 months (path coefficient: 0.15(SE = 0.07)), was more generally linked to verbal and non-verbal cognitive abilities in mid-childhood (reading path coefficient: 0.57(SE = 0.07); verbal intelligence path coefficient: 0.60(0.10); performance intelligence path coefficient: 0.50(SE = 0.08)), accounting for up to 36.1% of the phenotypic variation and the majority of genetic variance in these later-life traits (≥66.4%). Thus, the genetic foundations of mid-childhood reading and cognitive abilities are diverse. They involve at least two independent genetic factors that emerge at different developmental stages during early language development and may implicate differences in cognitive processes that are already detectable during toddlerhood.

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  • Verhoef, E., Shapland, C. Y., Fisher, S. E., Dale, P. S., & St Pourcain, B. (2021). The developmental origins of genetic factors influencing language and literacy: Associations with early-childhood vocabulary. Journal of Child Psychology and Psychiatry, 62(6), 728-738. doi:10.1111/jcpp.13327.

    Abstract

    Background The heritability of language and literacy skills increases from early‐childhood to adolescence. The underlying mechanisms are little understood and may involve (a) the amplification of genetic influences contributing to early language abilities, and/or (b) the emergence of novel genetic factors (innovation). Here, we investigate the developmental origins of genetic factors influencing mid‐childhood/early‐adolescent language and literacy. We evaluate evidence for the amplification of early‐childhood genetic factors for vocabulary, in addition to genetic innovation processes. Methods Expressive and receptive vocabulary scores at 38 months, thirteen language‐ and literacy‐related abilities and nonverbal cognition (7–13 years) were assessed in unrelated children from the Avon Longitudinal Study of Parents and Children (ALSPAC, Nindividuals ≤ 6,092). We investigated the multivariate genetic architecture underlying early‐childhood expressive and receptive vocabulary, and each of 14 mid‐childhood/early‐adolescent language, literacy or cognitive skills with trivariate structural equation (Cholesky) models as captured by genome‐wide genetic relationship matrices. The individual path coefficients of the resulting structural models were finally meta‐analysed to evaluate evidence for overarching patterns. Results We observed little support for the emergence of novel genetic sources for language, literacy or cognitive abilities during mid‐childhood or early adolescence. Instead, genetic factors of early‐childhood vocabulary, especially those unique to receptive skills, were amplified and represented the majority of genetic variance underlying many of these later complex skills (≤99%). The most predictive early genetic factor accounted for 29.4%(SE = 12.9%) to 45.1%(SE = 7.6%) of the phenotypic variation in verbal intelligence and literacy skills, but also for 25.7%(SE = 6.4%) in performance intelligence, while explaining only a fraction of the phenotypic variation in receptive vocabulary (3.9%(SE = 1.8%)). Conclusions Genetic factors contributing to many complex skills during mid‐childhood and early adolescence, including literacy, verbal cognition and nonverbal cognition, originate developmentally in early‐childhood and are captured by receptive vocabulary. This suggests developmental genetic stability and overarching aetiological mechanisms.

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  • Carrion Castillo, A., Pepe, A., Kong, X., Fisher, S. E., Mazoyer, B., Tzourio-Mazoyer, N., Crivello, F., & Francks, C. (2020). Genetic effects on planum temporale asymmetry and their limited relevance to neurodevelopmental disorders, intelligence or educational attainment. Cortex, 124, 137-153. doi:10.1016/j.cortex.2019.11.006.

    Abstract

    Previous studies have suggested that altered asymmetry of the planum temporale (PT) is associated with neurodevelopmental disorders, including dyslexia, schizophrenia, and autism. Shared genetic factors have been suggested to link PT asymmetry to these disorders. In a dataset of unrelated subjects from the general population (UK Biobank, N= 18,057), we found that PT volume asymmetry had a significant heritability of roughly 14%. In genome-wide association analysis, two loci were significantly associated with PT asymmetry, including a coding polymorphism within the gene ITIH5 that is predicted to affect the protein’s function and to be deleterious (rs41298373, P=2.01×10−15), and a locus that affects the expression of the genes BOK and DTYMK (rs7420166, P=7.54×10-10). DTYMK showed left-right asymmetry of mRNA expression in post mortem PT tissue. Cortex-wide mapping of these SNP effects revealed influences on asymmetry that went somewhat beyond the PT. Using publicly available genome-wide association statistics from large-scale studies, we saw no significant genetic correlations of PT asymmetry with autism spectrum disorder, attention deficit hyperactivity disorder, schizophrenia, educational attainment or intelligence. Of the top two individual loci associated with PT asymmetry, rs41298373 showed a tentative association with intelligence (unadjusted P=0.025), while the locus at BOK/DTYMK showed tentative association with educational attainment (unadjusted Ps<0.05). These findings provide novel insights into the genetic contributions to human brain asymmetry, but do not support a substantial polygenic association of PT asymmetry with cognitive variation and mental disorders, as far as can be discerned with current sample sizes.

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  • Connaughton, D. M., Dai, R., Owen, D. J., Marquez, J., Mann, N., Graham-Paquin, A. L., Nakayama, M., Coyaud, E., Laurent, E. M. N., St-Germain, J. R., Snijders Blok, L., Vino, A., Klämbt, V., Deutsch, K., Wu, C.-H.-W., Kolvenbach, C. M., Kause, F., Ottlewski, I., Schneider, R., Kitzler, T. M. and 79 moreConnaughton, D. M., Dai, R., Owen, D. J., Marquez, J., Mann, N., Graham-Paquin, A. L., Nakayama, M., Coyaud, E., Laurent, E. M. N., St-Germain, J. R., Snijders Blok, L., Vino, A., Klämbt, V., Deutsch, K., Wu, C.-H.-W., Kolvenbach, C. M., Kause, F., Ottlewski, I., Schneider, R., Kitzler, T. M., Majmundar, A. J., Buerger, F., Onuchic-Whitford, A. C., Youying, M., Kolb, A., Salmanullah, D., Chen, E., Van der Ven, A. T., Rao, J., Ityel, H., Seltzsam, S., Rieke, J. M., Chen, J., Vivante, A., Hwang, D.-Y., Kohl, S., Dworschak, G. C., Hermle, T., Alders, M., Bartolomaeus, T., Bauer, S. B., Baum, M. A., Brilstra, E. H., Challman, T. D., Zyskind, J., Costin, C. E., Dipple, K. M., Duijkers, F. A., Ferguson, M., Fitzpatrick, D. R., Fick, R., Glass, I. A., Hulick, P. J., Kline, A. D., Krey, I., Kumar, S., Lu, W., Marco, E. J., Wentzensen, I. M., Mefford, H. C., Platzer, K., Povolotskaya, I. S., Savatt, J. M., Shcherbakova, N. V., Senguttuvan, P., Squire, A. E., Stein, D. R., Thiffault, I., Voinova, V. Y., Somers, M. J. G., Ferguson, M. A., Traum, A. Z., Daouk, G. H., Daga, A., Rodig, N. M., Terhal, P. A., Van Binsbergen, E., Eid, L. A., Tasic, V., Rasouly, H. M., Lim, T. Y., Ahram, D. F., Gharavi, A. G., Reutter, H. M., Rehm, H. L., MacArthur, D. G., Lek, M., Laricchia, K. M., Lifton, R. P., Xu, H., Mane, S. M., Sanna-Cherchi, S., Sharrocks, A. D., Raught, B., Fisher, S. E., Bouchard, M., Khokha, M. K., Shril, S., & Hildebrandt, F. (2020). Mutations of the transcriptional corepressor ZMYM2 cause syndromic urinary tract malformations. The American Journal of Human Genetics, 107(4), 727-742. doi:10.1016/j.ajhg.2020.08.013.

    Abstract

    Congenital anomalies of the kidney and urinary tract (CAKUT) constitute one of the most frequent birth defects and represent the most common cause of chronic kidney disease in the first three decades of life. Despite the discovery of dozens of monogenic causes of CAKUT, most pathogenic pathways remain elusive. We performed whole-exome sequencing (WES) in 551 individuals with CAKUT and identified a heterozygous de novo stop-gain variant in ZMYM2 in two different families with CAKUT. Through collaboration, we identified in total 14 different heterozygous loss-of-function mutations in ZMYM2 in 15 unrelated families. Most mutations occurred de novo, indicating possible interference with reproductive function. Human disease features are replicated in X. tropicalis larvae with morpholino knockdowns, in which expression of truncated ZMYM2 proteins, based on individual mutations, failed to rescue renal and craniofacial defects. Moreover, heterozygous Zmym2-deficient mice recapitulated features of CAKUT with high penetrance. The ZMYM2 protein is a component of a transcriptional corepressor complex recently linked to the silencing of developmentally regulated endogenous retrovirus elements. Using protein-protein interaction assays, we show that ZMYM2 interacts with additional epigenetic silencing complexes, as well as confirming that it binds to FOXP1, a transcription factor that has also been linked to CAKUT. In summary, our findings establish that loss-of-function mutations of ZMYM2, and potentially that of other proteins in its interactome, as causes of human CAKUT, offering new routes for studying the pathogenesis of the disorder.
  • Den Hoed, J., & Fisher, S. E. (2020). Genetic pathways involved in human speech disorders. Current Opinion in Genetics & Development, 65, 103-111. doi:10.1016/j.gde.2020.05.012.
  • Doust, C., Gordon, S. D., Garden, N., Fisher, S. E., Martin, N. G., Bates, T. C., & Luciano, M. (2020). The association of dyslexia and developmental speech and language disorder candidate genes with reading and language abilities in adults. Twin Research and Human Genetics, 23(1), 22-32. doi:10.1017/thg.2020.7.

    Abstract

    Reading and language abilities are critical for educational achievement and success in adulthood. Variation in these traits is highly heritable, but the underlying genetic architecture is largely undiscovered. Genetic studies of reading and language skills traditionally focus on children with developmental disorders; however, much larger unselected adult samples are available, increasing power to identify associations with specific genetic variants of small effect size. We introduce an Australian adult population cohort (41.7–73.2 years of age, N = 1505) in which we obtained data using validated measures of several aspects of reading and language abilities. We performed genetic association analysis for a reading and spelling composite score, nonword reading (assessing phonological processing: a core component in learning to read), phonetic spelling, self-reported reading impairment and nonword repetition (a marker of language ability). Given the limited power in a sample of this size (~80% power to find a minimum effect size of 0.005), we focused on analyzing candidate genes that have been associated with dyslexia and developmental speech and language disorders in prior studies. In gene-based tests, FOXP2, a gene implicated in speech/language disorders, was associated with nonword repetition (p < .001), phonetic spelling (p = .002) and the reading and spelling composite score (p < .001). Gene-set analyses of candidate dyslexia and speech/language disorder genes were not significant. These findings contribute to the assessment of genetic associations in reading and language disorders, crucial for understanding their etiology and informing intervention strategies, and validate the approach of using unselected adult samples for gene discovery in language and reading.

    Additional information

    Supplementary materials
  • Grasby, K. L., Jahanshad, N., Painter, J. N., Colodro-Conde, L., Bralten, J., Hibar, D. P., Lind, P. A., Pizzagalli, F., Ching, C. R. K., McMahon, M. A. B., Shatokhina, N., Zsembik, L. C. P., Thomopoulos, S. I., Zhu, A. H., Strike, L. T., Agartz, I., Alhusaini, S., Almeida, M. A. A., Alnæs, D., Amlien, I. K. and 341 moreGrasby, K. L., Jahanshad, N., Painter, J. N., Colodro-Conde, L., Bralten, J., Hibar, D. P., Lind, P. A., Pizzagalli, F., Ching, C. R. K., McMahon, M. A. B., Shatokhina, N., Zsembik, L. C. P., Thomopoulos, S. I., Zhu, A. H., Strike, L. T., Agartz, I., Alhusaini, S., Almeida, M. A. A., Alnæs, D., Amlien, I. K., Andersson, M., Ard, T., Armstrong, N. J., Ashley-Koch, A., Atkins, J. R., Bernard, M., Brouwer, R. M., Buimer, E. E. L., Bülow, R., Bürger, C., Cannon, D. M., Chakravarty, M., Chen, Q., Cheung, J. W., Couvy-Duchesne, B., Dale, A. M., Dalvie, S., De Araujo, T. K., De Zubicaray, G. I., De Zwarte, S. M. C., Den Braber, A., Doan, N. T., Dohm, K., Ehrlich, S., Engelbrecht, H.-R., Erk, S., Fan, C. C., Fedko, I. O., Foley, S. F., Ford, J. M., Fukunaga, M., Garrett, M. E., Ge, T., Giddaluru, S., Goldman, A. L., Green, M. J., Groenewold, N. A., Grotegerd, D., Gurholt, T. P., Gutman, B. A., Hansell, N. K., Harris, M. A., Harrison, M. B., Haswell, C. C., Hauser, M., Herms, S., Heslenfeld, D. J., Ho, N. F., Hoehn, D., Hoffmann, P., Holleran, L., Hoogman, M., Hottenga, J.-J., Ikeda, M., Janowitz, D., Jansen, I. E., Jia, T., Jockwitz, C., Kanai, R., Karama, S., Kasperaviciute, D., Kaufmann, T., Kelly, S., Kikuchi, M., Klein, M., Knapp, M., Knodt, A. R., Krämer, B., Lam, M., Lancaster, T. M., Lee, P. H., Lett, T. A., Lewis, L. B., Lopes-Cendes, I., Luciano, M., Macciardi, F., Marquand, A. F., Mathias, S. R., Melzer, T. R., Milaneschi, Y., Mirza-Schreiber, N., Moreira, J. C. V., Mühleisen, T. W., Müller-Myhsok, B., Najt, P., Nakahara, S., Nho, K., Olde Loohuis, L. M., Orfanos, D. P., Pearson, J. F., Pitcher, T. L., Pütz, B., Quidé, Y., Ragothaman, A., Rashid, F. M., Reay, W. R., Redlich, R., Reinbold, C. S., Repple, J., Richard, G., Riedel, B. C., Risacher, S. L., Rocha, C. S., Mota, N. R., Salminen, L., Saremi, A., Saykin, A. J., Schlag, F., Schmaal, L., Schofield, P. R., Secolin, R., Shapland, C. Y., Shen, L., Shin, J., Shumskaya, E., Sønderby, I. E., Sprooten, E., Tansey, K. E., Teumer, A., Thalamuthu, A., Tordesillas-Gutiérrez, D., Turner, J. A., Uhlmann, A., Vallerga, C. L., Van der Meer, D., Van Donkelaar, M. M. J., Van Eijk, L., Van Erp, T. G. M., Van Haren, N. E. M., Van Rooij, D., Van Tol, M.-J., Veldink, J. H., Verhoef, E., Walton, E., Wang, M., Wang, Y., Wardlaw, J. M., Wen, W., Westlye, L. T., Whelan, C. D., Witt, S. H., Wittfeld, K., Wolf, C., Wolfers, T., Wu, J. Q., Yasuda, C. L., Zaremba, D., Zhang, Z., Zwiers, M. P., Artiges, E., Assareh, A. A., Ayesa-Arriola, R., Belger, A., Brandt, C. L., Brown, G. G., Cichon, S., Curran, J. E., Davies, G. E., Degenhardt, F., Dennis, M. F., Dietsche, B., Djurovic, S., Doherty, C. P., Espiritu, R., Garijo, D., Gil, Y., Gowland, P. A., Green, R. C., Häusler, A. N., Heindel, W., Ho, B.-C., Hoffmann, W. U., Holsboer, F., Homuth, G., Hosten, N., Jack Jr., C. R., Jang, M., Jansen, A., Kimbrel, N. A., Kolskår, K., Koops, S., Krug, A., Lim, K. O., Luykx, J. J., Mathalon, D. H., Mather, K. A., Mattay, V. S., Matthews, S., Mayoral Van Son, J., McEwen, S. C., Melle, I., Morris, D. W., Mueller, B. A., Nauck, M., Nordvik, J. E., Nöthen, M. M., O’Leary, D. S., Opel, N., Paillère Martinot, M.-L., Pike, G. B., Preda, A., Quinlan, E. B., Rasser, P. E., Ratnakar, V., Reppermund, S., Steen, V. M., Tooney, P. A., Torres, F. R., Veltman, D. J., Voyvodic, J. T., Whelan, R., White, T., Yamamori, H., Adams, H. H. H., Bis, J. C., Debette, S., Decarli, C., Fornage, M., Gudnason, V., Hofer, E., Ikram, M. A., Launer, L., Longstreth, W. T., Lopez, O. L., Mazoyer, B., Mosley, T. H., Roshchupkin, G. V., Satizabal, C. L., Schmidt, R., Seshadri, S., Yang, Q., Alzheimer’s Disease Neuroimaging Initiative, CHARGE Consortium, EPIGEN Consortium, IMAGEN Consortium, SYS Consortium, Parkinson’s Progression Markers Initiative, Alvim, M. K. M., Ames, D., Anderson, T. J., Andreassen, O. A., Arias-Vasquez, A., Bastin, M. E., Baune, B. T., Beckham, J. C., Blangero, J., Boomsma, D. I., Brodaty, H., Brunner, H. G., Buckner, R. L., Buitelaar, J. K., Bustillo, J. R., Cahn, W., Cairns, M. J., Calhoun, V., Carr, V. J., Caseras, X., Caspers, S., Cavalleri, G. L., Cendes, F., Corvin, A., Crespo-Facorro, B., Dalrymple-Alford, J. C., Dannlowski, U., De Geus, E. J. C., Deary, I. J., Delanty, N., Depondt, C., Desrivières, S., Donohoe, G., Espeseth, T., Fernández, G., Fisher, S. E., Flor, H., Forstner, A. J., Francks, C., Franke, B., Glahn, D. C., Gollub, R. L., Grabe, H. J., Gruber, O., Håberg, A. K., Hariri, A. R., Hartman, C. A., Hashimoto, R., Heinz, A., Henskens, F. A., Hillegers, M. H. J., Hoekstra, P. J., Holmes, A. J., Hong, L. E., Hopkins, W. D., Hulshoff Pol, H. E., Jernigan, T. L., Jönsson, E. G., Kahn, R. S., Kennedy, M. A., Kircher, T. T. J., Kochunov, P., Kwok, J. B. J., Le Hellard, S., Loughland, C. M., Martin, N. G., Martinot, J.-L., McDonald, C., McMahon, K. L., Meyer-Lindenberg, A., Michie, P. T., Morey, R. A., Mowry, B., Nyberg, L., Oosterlaan, J., Ophoff, R. A., Pantelis, C., Paus, T., Pausova, Z., Penninx, B. W. J. H., Polderman, T. J. C., Posthuma, D., Rietschel, M., Roffman, J. L., Rowland, L. M., Sachdev, P. S., Sämann, P. G., Schall, U., Schumann, G., Scott, R. J., Sim, K., Sisodiya, S. M., Smoller, J. W., Sommer, I. E., St Pourcain, B., Stein, D. J., Toga, A. W., Trollor, J. N., Van der Wee, N. J. A., van 't Ent, D., Völzke, H., Walter, H., Weber, B., Weinberger, D. R., Wright, M. J., Zhou, J., Stein, J. L., Thompson, P. M., & Medland, S. E. (2020). The genetic architecture of the human cerebral cortex. Science, 367(6484): eaay6690. doi:10.1126/science.aay6690.

    Abstract

    The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson’s disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder.
  • Henson, R. N., Suri, S., Knights, E., Rowe, J. B., Kievit, R. A., Lyall, D. M., Chan, D., Eising, E., & Fisher, S. E. (2020). Effect of apolipoprotein E polymorphism on cognition and brain in the Cambridge Centre for Ageing and Neuroscience cohort. Brain and Neuroscience Advances, 4: 2398212820961704. doi:10.1177/2398212820961704.

    Abstract

    Polymorphisms in the apolipoprotein E (APOE) gene have been associated with individual differences in cognition, brain structure and brain function. For example, the ε4 allele has been associated with cognitive and brain impairment in old age and increased risk of dementia, while the ε2 allele has been claimed to be neuroprotective. According to the ‘antagonistic pleiotropy’ hypothesis, these polymorphisms have different effects across the lifespan, with ε4, for example, postulated to confer benefits on cognitive and brain functions earlier in life. In this stage 2 of the Registered Report – https://osf.io/bufc4, we report the results from the cognitive and brain measures in the Cambridge Centre for Ageing and Neuroscience cohort (www.cam-can.org). We investigated the antagonistic pleiotropy hypothesis by testing for allele-by-age interactions in approximately 600 people across the adult lifespan (18–88 years), on six outcome variables related to cognition, brain structure and brain function (namely, fluid intelligence, verbal memory, hippocampal grey-matter volume, mean diffusion within white matter and resting-state connectivity measured by both functional magnetic resonance imaging and magnetoencephalography). We found no evidence to support the antagonistic pleiotropy hypothesis. Indeed, Bayes factors supported the null hypothesis in all cases, except for the (linear) interaction between age and possession of the ε4 allele on fluid intelligence, for which the evidence for faster decline in older ages was ambiguous. Overall, these pre-registered analyses question the antagonistic pleiotropy of APOE polymorphisms, at least in healthy adults.

    Additional information

    supplementary material
  • Hildebrand, M. S., Jackson, V. E., Scerri, T. S., Van Reyk, O., Coleman, M., Braden, R., Turner, S., Rigbye, K. A., Boys, A., Barton, S., Webster, R., Fahey, M., Saunders, K., Parry-Fielder, B., Paxton, G., Hayman, M., Coman, D., Goel, H., Baxter, A., Ma, A. and 11 moreHildebrand, M. S., Jackson, V. E., Scerri, T. S., Van Reyk, O., Coleman, M., Braden, R., Turner, S., Rigbye, K. A., Boys, A., Barton, S., Webster, R., Fahey, M., Saunders, K., Parry-Fielder, B., Paxton, G., Hayman, M., Coman, D., Goel, H., Baxter, A., Ma, A., Davis, N., Reilly, S., Delatycki, M., Liégeois, F. J., Connelly, A., Gecz, J., Fisher, S. E., Amor, D. J., Scheffer, I. E., Bahlo, M., & Morgan, A. T. (2020). Severe childhood speech disorder: Gene discovery highlights transcriptional dysregulation. Neurology, 94(20), e2148-e2167. doi:10.1212/WNL.0000000000009441.

    Abstract

    Objective Determining the genetic basis of speech disorders provides insight into the neurobiology of human communication. Despite intensive investigation over the past 2 decades, the etiology of most speech disorders in children remains unexplained. To test the hypothesis that speech disorders have a genetic etiology, we performed genetic analysis of children with severe speech disorder, specifically childhood apraxia of speech (CAS). Methods Precise phenotyping together with research genome or exome analysis were performed on children referred with a primary diagnosis of CAS. Gene coexpression and gene set enrichment analyses were conducted on high-confidence gene candidates. Results Thirty-four probands ascertained for CAS were studied. In 11/34 (32%) probands, we identified highly plausible pathogenic single nucleotide (n = 10; CDK13, EBF3, GNAO1, GNB1, DDX3X, MEIS2, POGZ, SETBP1, UPF2, ZNF142) or copy number (n = 1; 5q14.3q21.1 locus) variants in novel genes or loci for CAS. Testing of parental DNA was available for 9 probands and confirmed that the variants had arisen de novo. Eight genes encode proteins critical for regulation of gene transcription, and analyses of transcriptomic data found CAS-implicated genes were highly coexpressed in the developing human brain. Conclusion We identify the likely genetic etiology in 11 patients with CAS and implicate 9 genes for the first time. We find that CAS is often a sporadic monogenic disorder, and highly genetically heterogeneous. Highly penetrant variants implicate shared pathways in broad transcriptional regulation, highlighting the key role of transcriptional regulation in normal speech development. CAS is a distinctive, socially debilitating clinical disorder, and understanding its molecular basis is the first step towards identifying precision medicine approaches.
  • Hofer, E., Roshchupkin, G. V., Adams, H. H. H., Knol, M. J., Lin, H., Li, S., Zare, H., Ahmad, S., Armstrong, N. J., Satizabal, C. L., Bernard, M., Bis, J. C., Gillespie, N. A., Luciano, M., Mishra, A., Scholz, M., Teumer, A., Xia, R., Jian, X., Mosley, T. H. and 79 moreHofer, E., Roshchupkin, G. V., Adams, H. H. H., Knol, M. J., Lin, H., Li, S., Zare, H., Ahmad, S., Armstrong, N. J., Satizabal, C. L., Bernard, M., Bis, J. C., Gillespie, N. A., Luciano, M., Mishra, A., Scholz, M., Teumer, A., Xia, R., Jian, X., Mosley, T. H., Saba, Y., Pirpamer, L., Seiler, S., Becker, J. T., Carmichael, O., Rotter, J. I., Psaty, B. M., Lopez, O. L., Amin, N., Van der Lee, S. J., Yang, Q., Himali, J. J., Maillard, P., Beiser, A. S., DeCarli, C., Karama, S., Lewis, L., Harris, M., Bastin, M. E., Deary, I. J., Witte, A. V., Beyer, F., Loeffler, M., Mather, K. A., Schofield, P. R., Thalamuthu, A., Kwok, J. B., Wright, M. J., Ames, D., Trollor, J., Jiang, J., Brodaty, H., Wen, W., Vernooij, M. W., Hofman, A., Uitterlinden, A. G., Niessen, W. J., Wittfeld, K., Bülow, R., Völker, U., Pausova, Z., Pike, G. B., Maingault, S., Crivello, F., Tzourio, C., Amouyel, P., Mazoyer, B., Neale, M. C., Franz, C. E., Lyons, M. J., Panizzon, M. S., Andreassen, O. A., Dale, A. M., Logue, M., Grasby, K. L., Jahanshad, N., Painter, J. N., Colodro-Conde, L., Bralten, J., Hibar, D. P., Lind, P. A., Pizzagalli, F., Stein, J. L., Thompson, P. M., Medland, S. E., ENIGMA-consortium, Sachdev, P. S., Kremen, W. S., Wardlaw, J. M., Villringer, A., Van Duijn, C. M., Grabe, H. J., Longstreth, W. T., Fornage, M., Paus, T., Debette, S., Ikram, M. A., Schmidt, H., Schmidt, R., & Seshadri, S. (2020). Genetic correlations and genome-wide associations of cortical structure in general population samples of 22,824 adults. Nature Communications, 11: 4796. doi:10.1038/s41467-020-18367-y.
  • Kong, X., Tzourio-Mazoyer, N., Joliot, M., Fedorenko, E., Liu, J., Fisher, S. E., & Francks, C. (2020). Gene expression correlates of the cortical network underlying sentence processing. Neurobiology of Language, 1(1), 77-103. doi:10.1162/nol_a_00004.

    Abstract

    A pivotal question in modern neuroscience is which genes regulate brain circuits that underlie cognitive functions. However, the field is still in its infancy. Here we report an integrated investigation of the high-level language network (i.e., sentence processing network) in the human cerebral cortex, combining regional gene expression profiles, task fMRI, large-scale neuroimaging meta-analysis, and resting-state functional network approaches. We revealed reliable gene expression-functional network correlations using three different network definition strategies, and identified a consensus set of genes related to connectivity within the sentence-processing network. The genes involved showed enrichment for neural development and actin-related functions, as well as association signals with autism, which can involve disrupted language functioning. Our findings help elucidate the molecular basis of the brain’s infrastructure for language. The integrative approach described here will be useful to study other complex cognitive traits.
  • Postema, M., Carrion Castillo, A., Fisher, S. E., Vingerhoets, G., & Francks, C. (2020). The genetics of situs inversus without primary ciliary dyskinesia. Scientific Reports, 10: 3677. doi:10.1038/s41598-020-60589-z.

    Abstract

    Situs inversus (SI), a left-right mirror reversal of the visceral organs, can occur with recessive Primary Ciliary Dyskinesia (PCD). However, most people with SI do not have PCD, and the etiology of their condition remains poorly studied. We sequenced the genomes of 15 people with SI, of which six had PCD, as well as 15 controls. Subjects with non-PCD SI in this sample had an elevated rate of left-handedness (five out of nine), which suggested possible developmental mechanisms linking brain and body laterality. The six SI subjects with PCD all had likely recessive mutations in genes already known to cause PCD. Two non-PCD SI cases also had recessive mutations in known PCD genes, suggesting reduced penetrance for PCD in some SI cases. One non-PCD SI case had recessive mutations in PKD1L1, and another in CFAP52 (also known as WDR16). Both of these genes have previously been linked to SI without PCD. However, five of the nine non-PCD SI cases, including three of the left-handers in this dataset, had no obvious monogenic basis for their condition. Environmental influences, or possible random effects in early development, must be considered.

    Additional information

    Supplementary information
  • Sønderby, I. E., Gústafsson, Ó., Doan, N. T., Hibar, D. P., Martin-Brevet, S., Abdellaoui, A., Ames, D., Amunts, K., Andersson, M., Armstrong, N. J., Bernard, M., Blackburn, N., Blangero, J., Boomsma, D. I., Bralten, J., Brattbak, H.-R., Brodaty, H., Brouwer, R. M., Bülow, R., Calhoun, V. and 133 moreSønderby, I. E., Gústafsson, Ó., Doan, N. T., Hibar, D. P., Martin-Brevet, S., Abdellaoui, A., Ames, D., Amunts, K., Andersson, M., Armstrong, N. J., Bernard, M., Blackburn, N., Blangero, J., Boomsma, D. I., Bralten, J., Brattbak, H.-R., Brodaty, H., Brouwer, R. M., Bülow, R., Calhoun, V., Caspers, S., Cavalleri, G., Chen, C.-H., Cichon, S., Ciufolini, S., Corvin, A., Crespo-Facorro, B., Curran, J. E., Dale, A. M., Dalvie, S., Dazzan, P., De Geus, E. J. C., De Zubicaray, G. I., De Zwarte, S. M. C., Delanty, N., Den Braber, A., Desrivières, S., Donohoe, G., Draganski, B., Ehrlich, S., Espeseth, T., Fisher, S. E., Franke, B., Frouin, V., Fukunaga, M., Gareau, T., Glahn, D. C., Grabe, H., Groenewold, N. A., Haavik, J., Håberg, A., Hashimoto, R., Hehir-Kwa, J. Y., Heinz, A., Hillegers, M. H. J., Hoffmann, P., Holleran, L., Hottenga, J.-J., Hulshoff, H. E., Ikeda, M., Jahanshad, N., Jernigan, T., Jockwitz, C., Johansson, S., Jonsdottir, G. A., Jönsson, E. G., Kahn, R., Kaufmann, T., Kelly, S., Kikuchi, M., Knowles, E. E. M., Kolskår, K. K., Kwok, J. B., Le Hellard, S., Leu, C., Liu, J., Lundervold, A. J., Lundervold, A., Martin, N. G., Mather, K., Mathias, S. R., McCormack, M., McMahon, K. L., McRae, A., Milaneschi, Y., Moreau, C., Morris, D., Mothersill, D., Mühleisen, T. W., Murray, R., Nordvik, J. E., Nyberg, L., Olde Loohuis, L. M., Ophoff, R., Paus, T., Pausova, Z., Penninx, B., Peralta, J. M., Pike, B., Prieto, C., Pudas, S., Quinlan, E., Quintana, D. S., Reinbold, C. S., Reis Marques, T., Reymond, A., Richard, G., Rodriguez-Herreros, B., Roiz-Santiañez, R., Rokicki, J., Rucker, J., Sachdev, P., Sanders, A.-M., Sando, S. B., Schmaal, L., Schofield, P. R., Schork, A. J., Schumann, G., Shin, J., Shumskaya, E., Sisodiya, S., Steen, V. M., Stein, D. J., Steinberg, S., Strike, L., Teumer, A., Thalamuthu, A., Tordesillas-Gutierrez, D., Turner, J., Ueland, T., Uhlmann, A., Ulfarsson, M. O., Van 't Ent, D., Van der Meer, D., Van Haren, N. E. M., Vaskinn, A., Vassos, E., Walters, G. B., Wang, Y., Wen, W., Whelan, C. D., Wittfeld, K., Wright, M., Yamamori, H., Zayats, T., Agartz, I., Westlye, L. T., Jacquemont, S., Djurovic, S., Stefansson, H., Stefansson, K., Thompson, P., & Andreassen, O. A. (2020). Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia. Molecular Psychiatry, 25, 584-602. doi:10.1038/s41380-018-0118-1.

    Abstract

    Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia. We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV. After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes (β = −0.71 to −1.37; P < 0.0005). In an independent sample, consistent results were obtained, with significant effects in the pallidum (β = −0.95, P = 0.0042). The two data sets combined showed significant negative dose-response for the accumbens, caudate, pallidum, putamen and ICV (P = 0.0032, 8.9 × 10−6, 1.7 × 10−9, 3.5 × 10−12 and 1.0 × 10−4, respectively). Full scale IQ was lower in both deletion and duplication carriers compared to non-carriers. This is the first brain MRI study of the impact of the 16p11.2 distal CNV, and we demonstrate a specific effect on subcortical brain structures, suggesting a neuropathological pattern underlying the neurodevelopmental syndromes
  • Thompson, P. M., Jahanshad, N., Ching, C. R. K., Salminen, L. E., Thomopoulos, S. I., Bright, J., Baune, B. T., Bertolín, S., Bralten, J., Bruin, W. B., Bülow, R., Chen, J., Chye, Y., Dannlowski, U., De Kovel, C. G. F., Donohoe, G., Eyler, L. T., Faraone, S. V., Favre, P., Filippi, C. A. and 151 moreThompson, P. M., Jahanshad, N., Ching, C. R. K., Salminen, L. E., Thomopoulos, S. I., Bright, J., Baune, B. T., Bertolín, S., Bralten, J., Bruin, W. B., Bülow, R., Chen, J., Chye, Y., Dannlowski, U., De Kovel, C. G. F., Donohoe, G., Eyler, L. T., Faraone, S. V., Favre, P., Filippi, C. A., Frodl, T., Garijo, D., Gil, Y., Grabe, H. J., Grasby, K. L., Hajek, T., Han, L. K. M., Hatton, S. N., Hilbert, K., Ho, T. C., Holleran, L., Homuth, G., Hosten, N., Houenou, J., Ivanov, I., Jia, T., Kelly, S., Klein, M., Kwon, J. S., Laansma, M. A., Leerssen, J., Lueken, U., Nunes, A., O'Neill, J., Opel, N., Piras, F., Piras, F., Postema, M., Pozzi, E., Shatokhina, N., Soriano-Mas, C., Spalletta, G., Sun, D., Teumer, A., Tilot, A. K., Tozzi, L., Van der Merwe, C., Van Someren, E. J. W., Van Wingen, G. A., Völzke, H., Walton, E., Wang, L., Winkler, A. M., Wittfeld, K., Wright, M. J., Yun, J.-Y., Zhang, G., Zhang-James, Y., Adhikari, B. M., Agartz, I., Aghajani, M., Aleman, A., Althoff, R. R., Altmann, A., Andreassen, O. A., Baron, D. A., Bartnik-Olson, B. L., Bas-Hoogendam, J. M., Baskin-Sommers, A. R., Bearden, C. E., Berner, L. A., Boedhoe, P. S. W., Brouwer, R. M., Buitelaar, J. K., Caeyenberghs, K., Cecil, C. A. M., Cohen, R. A., Cole, J. H., Conrod, P. J., De Brito, S. A., De Zwarte, S. M. C., Dennis, E. L., Desrivieres, S., Dima, D., Ehrlich, S., Esopenko, C., Fairchild, G., Fisher, S. E., Fouche, J.-P., Francks, C., Frangou, S., Franke, B., Garavan, H. P., Glahn, D. C., Groenewold, N. A., Gurholt, T. P., Gutman, B. A., Hahn, T., Harding, I. H., Hernaus, D., Hibar, D. P., Hillary, F. G., Hoogman, M., Hulshoff Pol, H. E., Jalbrzikowski, M., Karkashadze, G. A., Klapwijk, E. T., Knickmeyer, R. C., Kochunov, P., Koerte, I. K., Kong, X., Liew, S.-L., Lin, A. P., Logue, M. W., Luders, E., Macciardi, F., Mackey, S., Mayer, A. R., McDonald, C. R., McMahon, A. B., Medland, S. E., Modinos, G., Morey, R. A., Mueller, S. C., Mukherjee, P., Namazova-Baranova, L., Nir, T. M., Olsen, A., Paschou, P., Pine, D. S., Pizzagalli, F., Rentería, M. E., Rohrer, J. D., Sämann, P. G., Schmaal, L., Schumann, G., Shiroishi, M. S., Sisodiya, S. M., Smit, D. J. A., Sønderby, I. E., Stein, D. J., Stein, J. L., Tahmasian, M., Tate, D. F., Turner, J. A., Van den Heuvel, O. A., Van der Wee, N. J. A., Van der Werf, Y. D., Van Erp, T. G. M., Van Haren, N. E. M., Van Rooij, D., Van Velzen, L. S., Veer, I. M., Veltman, D. J., Villalon-Reina, J. E., Walter, H., Whelan, C. D., Wilde, E. A., Zarei, M., Zelman, V., & Enigma Consortium (2020). ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries. Translational Psychiatry, 10(1): 100. doi:10.1038/s41398-020-0705-1.

    Abstract

    This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of “big data” (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA’s activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors.

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    41398_2020_705_MOESM1_ESM.pdf
  • Thompson, P. A., Bishop, D. V. M., Eising, E., Fisher, S. E., & Newbury, D. F. (2020). Generalized Structured Component Analysis in candidate gene association studies: Applications and limitations [version 2; peer review: 3 approved]. Wellcome Open Research, 4: 142. doi:10.12688/wellcomeopenres.15396.2.

    Abstract

    Background: Generalized Structured Component Analysis (GSCA) is a component-based alternative to traditional covariance-based structural equation modelling. This method has previously been applied to test for association between candidate genes and clinical phenotypes, contrasting with traditional genetic association analyses that adopt univariate testing of many individual single nucleotide polymorphisms (SNPs) with correction for multiple testing. Methods: We first evaluate the ability of the GSCA method to replicate two previous findings from a genetics association study of developmental language disorders. We then present the results of a simulation study to test the validity of the GSCA method under more restrictive data conditions, using smaller sample sizes and larger numbers of SNPs than have previously been investigated. Finally, we compare GSCA performance against univariate association analysis conducted using PLINK v1.9. Results: Results from simulations show that power to detect effects depends not just on sample size, but also on the ratio of SNPs with effect to number of SNPs tested within a gene. Inclusion of many SNPs in a model dilutes true effects. Conclusions: We propose that GSCA is a useful method for replication studies, when candidate SNPs have been identified, but should not be used for exploratory analysis.

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    data via OSF
  • Urbanus, B. H. A., Peter, S., Fisher, S. E., & De Zeeuw, C. I. (2020). Region-specific Foxp2 deletions in cortex, striatum or cerebellum cannot explain vocalization deficits observed in spontaneous global knockouts. Scientific Reports, 10: 21631. doi:10.1038/s41598-020-78531-8.

    Abstract

    FOXP2 has been identified as a gene related to speech in humans, based on rare mutations that yield significant impairments in speech at the level of both motor performance and language comprehension. Disruptions of the murine orthologue Foxp2 in mouse pups have been shown to interfere with production of ultrasonic vocalizations (USVs). However, it remains unclear which structures are responsible for these deficits. Here, we show that conditional knockout mice with selective Foxp2 deletions targeting the cerebral cortex, striatum or cerebellum, three key sites of motor control with robust neural gene expression, do not recapture the profile of pup USV deficits observed in mice with global disruptions of this gene. Moreover, we observed that global Foxp2 knockout pups show substantive reductions in USV production as well as an overproduction of short broadband noise “clicks”, which was not present in the brain region-specific knockouts. These data indicate that deficits of Foxp2 expression in the cortex, striatum or cerebellum cannot solely explain the disrupted vocalization behaviours in global Foxp2 knockouts. Our findings raise the possibility that the impact of Foxp2 disruption on USV is mediated at least in part by effects of this gene on the anatomical prerequisites for vocalizing.
  • Van der Meer, D., Sønderby, I. E., Kaufmann, T., Walters, G. B., Abdellaoui, A., Ames, D., Amunts, K., Andersson, M., Armstrong, N. J., Bernard, M., Blackburn, N. B., Blangero, J., Boomsma, D. I., Brodaty, H., Brouwer, R. M., Bülow, R., Cahn, W., Calhoun, V. D., Caspers, S., Cavalleri, G. L. and 112 moreVan der Meer, D., Sønderby, I. E., Kaufmann, T., Walters, G. B., Abdellaoui, A., Ames, D., Amunts, K., Andersson, M., Armstrong, N. J., Bernard, M., Blackburn, N. B., Blangero, J., Boomsma, D. I., Brodaty, H., Brouwer, R. M., Bülow, R., Cahn, W., Calhoun, V. D., Caspers, S., Cavalleri, G. L., Ching, C. R. K., Cichon, S., Ciufolini, S., Corvin, A., Crespo-Facorro, B., Curran, J. E., Dalvie, S., Dazzan, P., De Geus, E. J. C., De Zubicaray, G. I., De Zwarte, S. M. C., Delanty, N., Den Braber, A., Desrivieres, S., Di Forti, M., Doherty, J. L., Donohoe, G., Ehrlich, S., Eising, E., Espeseth, T., Fisher, S. E., Fladby, T., Frei, O., Frouin, V., Fukunaga, M., Gareau, T., Glahn, D. C., Grabe, H. J., Groenewold, N. A., Gústafsson, Ó., Haavik, J., Haberg, A. K., Hashimoto, R., Hehir-Kwa, J. Y., Hibar, D. P., Hillegers, M. H. J., Hoffmann, P., Holleran, L., Hottenga, J.-J., Hulshoff Pol, H. E., Ikeda, M., Jacquemont, S., Jahanshad, N., Jockwitz, C., Johansson, S., Jönsson, E. G., Kikuchi, M., Knowles, E. E. M., Kwok, J. B., Le Hellard, S., Linden, D. E. J., Liu, J., Lundervold, A., Lundervold, A. J., Martin, N. G., Mather, K. A., Mathias, S. R., McMahon, K. L., McRae, A. F., Medland, S. E., Moberget, T., Moreau, C., Morris, D. W., Mühleisen, T. W., Murray, R. M., Nordvik, J. E., Nyberg, L., Olde Loohuis, L. M., Ophoff, R. A., Owen, M. J., Paus, T., Pausova, Z., Peralta, J. M., Pike, B., Prieto, C., Quinlan, E. B., Reinbold, C. S., Reis Marques, T., Rucker, J. J. H., Sachdev, P. S., Sando, S. B., Schofield, P. R., Schork, A. J., Schumann, G., Shin, J., Shumskaya, E., Silva, A. I., Sisodiya, S. M., Steen, V. M., Stein, D. J., Strike, L. T., Tamnes, C. K., Teumer, A., Thalamuthu, A., Tordesillas-Gutiérrez, D., Uhlmann, A., Úlfarsson, M. Ö., Van 't Ent, D., Van den Bree, M. B. M., Vassos, E., Wen, W., Wittfeld, K., Wright, M. J., Zayats, T., Dale, A. M., Djurovic, S., Agartz, I., Westlye, L. T., Stefánsson, H., Stefánsson, K., Thompson, P. M., & Andreassen, O. A. (2020). Association of copy number variation of the 15q11.2 BP1-BP2 region with cortical and subcortical morphology and cognition. JAMA Psychiatry, 77(4), 420-430. doi:10.1001/jamapsychiatry.2019.3779.

    Abstract

    Importance Recurrent microdeletions and duplications in the genomic region 15q11.2 between breakpoints 1 (BP1) and 2 (BP2) are associated with neurodevelopmental disorders. These structural variants are present in 0.5% to 1.0% of the population, making 15q11.2 BP1-BP2 the site of the most prevalent known pathogenic copy number variation (CNV). It is unknown to what extent this CNV influences brain structure and affects cognitive abilities. Objective To determine the association of the 15q11.2 BP1-BP2 deletion and duplication CNVs with cortical and subcortical brain morphology and cognitive task performance. Design, Setting, and Participants In this genetic association study, T1-weighted brain magnetic resonance imaging were combined with genetic data from the ENIGMA-CNV consortium and the UK Biobank, with a replication cohort from Iceland. In total, 203 deletion carriers, 45 247 noncarriers, and 306 duplication carriers were included. Data were collected from August 2015 to April 2019, and data were analyzed from September 2018 to September 2019. Main Outcomes and Measures The associations of the CNV with global and regional measures of surface area and cortical thickness as well as subcortical volumes were investigated, correcting for age, age2, sex, scanner, and intracranial volume. Additionally, measures of cognitive ability were analyzed in the full UK Biobank cohort. Results Of 45 756 included individuals, the mean (SD) age was 55.8 (18.3) years, and 23 754 (51.9%) were female. Compared with noncarriers, deletion carriers had a lower surface area (Cohen d = −0.41; SE, 0.08; P = 4.9 × 10−8), thicker cortex (Cohen d = 0.36; SE, 0.07; P = 1.3 × 10−7), and a smaller nucleus accumbens (Cohen d = −0.27; SE, 0.07; P = 7.3 × 10−5). There was also a significant negative dose response on cortical thickness (β = −0.24; SE, 0.05; P = 6.8 × 10−7). Regional cortical analyses showed a localization of the effects to the frontal, cingulate, and parietal lobes. Further, cognitive ability was lower for deletion carriers compared with noncarriers on 5 of 7 tasks. Conclusions and Relevance These findings, from the largest CNV neuroimaging study to date, provide evidence that 15q11.2 BP1-BP2 structural variation is associated with brain morphology and cognition, with deletion carriers being particularly affected. The pattern of results fits with known molecular functions of genes in the 15q11.2 BP1-BP2 region and suggests involvement of these genes in neuronal plasticity. These neurobiological effects likely contribute to the association of this CNV with neurodevelopmental disorders.
  • Van der Meer, D., Rokicki, J., Kaufmann, T., Córdova-Palomera, A., Moberget, T., Alnæs, D., Bettella, F., Frei, O., Trung Doan, N., Sønderby, I. E., Smeland, O. B., Agartz, I., Bertolino, A., Bralten, J., Brandt, C. L., Buitelaar, J. K., Djurovic, S., Van Donkelaar, M. M. J., Dørum, E. S., Espeseth, T. and 34 moreVan der Meer, D., Rokicki, J., Kaufmann, T., Córdova-Palomera, A., Moberget, T., Alnæs, D., Bettella, F., Frei, O., Trung Doan, N., Sønderby, I. E., Smeland, O. B., Agartz, I., Bertolino, A., Bralten, J., Brandt, C. L., Buitelaar, J. K., Djurovic, S., Van Donkelaar, M. M. J., Dørum, E. S., Espeseth, T., Faraone, S. V., Fernandez, G., Fisher, S. E., Franke, B., Haatveit, B., Hartman, C., Hoekstra, P. J., Haberg, A. K., Jönsson, E. G., Kolskår, K. K., Le Hellard, S., Lund, M. J., Lundervold, A. J., Lundervold, A., Melle, I., Monereo Sánchez, J., Norbom, L. C., Nordvik, J. E., Nyberg, L., Oosterlaan, J., Papalino, M., Papassotiropoulos, A., Pergola, G., De Quervain, D. J. F., Richard, G., Sanders, A.-M., Selvaggi, P., Shumskaya, E., Steen, V. M., Tønnesen, S., Ulrichsen, K. M., Zwiers, M., Andreassen, O. A., & Westlye, L. T. (2020). Brain scans from 21297 individuals reveal the genetic architecture of hippocampal subfield volumes. Molecular Psychiatry, 25, 3053-3065. doi:10.1038/s41380-018-0262-7.

    Abstract

    The hippocampus is a heterogeneous structure, comprising histologically distinguishable subfields. These subfields are differentially involved in memory consolidation, spatial navigation and pattern separation, complex functions often impaired in individuals with brain disorders characterized by reduced hippocampal volume, including Alzheimer’s disease (AD) and schizophrenia. Given the structural and functional heterogeneity of the hippocampal formation, we sought to characterize the subfields’ genetic architecture. T1-weighted brain scans (n = 21,297, 16 cohorts) were processed with the hippocampal subfields algorithm in FreeSurfer v6.0. We ran a genome-wide association analysis on each subfield, co-varying for whole hippocampal volume. We further calculated the single-nucleotide polymorphism (SNP)-based heritability of 12 subfields, as well as their genetic correlation with each other, with other structural brain features and with AD and schizophrenia. All outcome measures were corrected for age, sex and intracranial volume. We found 15 unique genome-wide significant loci across six subfields, of which eight had not been previously linked to the hippocampus. Top SNPs were mapped to genes associated with neuronal differentiation, locomotor behaviour, schizophrenia and AD. The volumes of all the subfields were estimated to be heritable (h2 from 0.14 to 0.27, all p < 1 × 10–16) and clustered together based on their genetic correlations compared with other structural brain features. There was also evidence of genetic overlap of subicular subfield volumes with schizophrenia. We conclude that hippocampal subfields have partly distinct genetic determinants associated with specific biological processes and traits. Taking into account this specificity may increase our understanding of hippocampal neurobiology and associated pathologies.

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    41380_2018_262_MOESM1_ESM.docx
  • Burenkova, O. V., & Fisher, S. E. (2019). Genetic insights into the neurobiology of speech and language. In E. Grigorenko, Y. Shtyrov, & P. McCardle (Eds.), All About Language: Science, Theory, and Practice. Baltimore, MD: Paul Brookes Publishing, Inc.
  • Carrion Castillo, A., Van der Haegen, L., Tzourio-Mazoyer, N., Kavaklioglu, T., Badillo, S., Chavent, M., Saracco, J., Brysbaert, M., Fisher, S. E., Mazoyer, B., & Francks, C. (2019). Genome sequencing for rightward hemispheric language dominance. Genes, Brain and Behavior, 18(5): e12572. doi:10.1111/gbb.12572.

    Abstract

    Most people have left‐hemisphere dominance for various aspects of language processing, but only roughly 1% of the adult population has atypically reversed, rightward hemispheric language dominance (RHLD). The genetic‐developmental program that underlies leftward language laterality is unknown, as are the causes of atypical variation. We performed an exploratory whole‐genome‐sequencing study, with the hypothesis that strongly penetrant, rare genetic mutations might sometimes be involved in RHLD. This was by analogy with situs inversus of the visceral organs (left‐right mirror reversal of the heart, lungs and so on), which is sometimes due to monogenic mutations. The genomes of 33 subjects with RHLD were sequenced and analyzed with reference to large population‐genetic data sets, as well as 34 subjects (14 left‐handed) with typical language laterality. The sample was powered to detect rare, highly penetrant, monogenic effects if they would be present in at least 10 of the 33 RHLD cases and no controls, but no individual genes had mutations in more than five RHLD cases while being un‐mutated in controls. A hypothesis derived from invertebrate mechanisms of left‐right axis formation led to the detection of an increased mutation load, in RHLD subjects, within genes involved with the actin cytoskeleton. The latter finding offers a first, tentative insight into molecular genetic influences on hemispheric language dominance.

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    gbb12572-sup-0001-AppendixS1.docx
  • Castells-Nobau, A., Eidhof, I., Fenckova, M., Brenman-Suttner, D. B., Scheffer-de Gooyert, J. M., Christine, S., Schellevis, R. L., Van der Laan, K., Quentin, C., Van Ninhuijs, L., Hofmann, F., Ejsmont, R., Fisher, S. E., Kramer, J. M., Sigrist, S. J., Simon, A. F., & Schenck, A. (2019). Conserved regulation of neurodevelopmental processes and behavior by FoxP in Drosophila. PLoS One, 14(2): e211652. doi:10.1371/journal.pone.0211652.

    Abstract

    FOXP proteins form a subfamily of evolutionarily conserved transcription factors involved in the development and functioning of several tissues, including the central nervous system. In humans, mutations in FOXP1 and FOXP2 have been implicated in cognitive deficits including intellectual disability and speech disorders. Drosophila exhibits a single ortholog, called FoxP, but due to a lack of characterized mutants, our understanding of the gene remains poor. Here we show that the dimerization property required for mammalian FOXP function is conserved in Drosophila. In flies, FoxP is enriched in the adult brain, showing strong expression in ~1000 neurons of cholinergic, glutamatergic and GABAergic nature. We generate Drosophila loss-of-function mutants and UAS-FoxP transgenic lines for ectopic expression, and use them to characterize FoxP function in the nervous system. At the cellular level, we demonstrate that Drosophila FoxP is required in larvae for synaptic morphogenesis at axonal terminals of the neuromuscular junction and for dendrite development of dorsal multidendritic sensory neurons. In the developing brain, we find that FoxP plays important roles in α-lobe mushroom body formation. Finally, at a behavioral level, we show that Drosophila FoxP is important for locomotion, habituation learning and social space behavior of adult flies. Our work shows that Drosophila FoxP is important for regulating several neurodevelopmental processes and behaviors that are related to human disease or vertebrate disease model phenotypes. This suggests a high degree of functional conservation with vertebrate FOXP orthologues and established flies as a model system for understanding FOXP related pathologies.
  • Eising, E., Carrion Castillo, A., Vino, A., Strand, E. A., Jakielski, K. J., Scerri, T. S., Hildebrand, M. S., Webster, R., Ma, A., Mazoyer, B., Francks, C., Bahlo, M., Scheffer, I. E., Morgan, A. T., Shriberg, L. D., & Fisher, S. E. (2019). A set of regulatory genes co-expressed in embryonic human brain is implicated in disrupted speech development. Molecular Psychiatry, 24, 1065-1078. doi:10.1038/s41380-018-0020-x.

    Abstract

    Genetic investigations of people with impaired development of spoken language provide windows into key aspects of human biology. Over 15 years after FOXP2 was identified, most speech and language impairments remain unexplained at the molecular level. We sequenced whole genomes of nineteen unrelated individuals diagnosed with childhood apraxia of speech, a rare disorder enriched for causative mutations of large effect. Where DNA was available from unaffected parents, we discovered de novo mutations, implicating genes, including CHD3, SETD1A and WDR5. In other probands, we identified novel loss-of-function variants affecting KAT6A, SETBP1, ZFHX4, TNRC6B and MKL2, regulatory genes with links to neurodevelopment. Several of the new candidates interact with each other or with known speech-related genes. Moreover, they show significant clustering within a single co-expression module of genes highly expressed during early human brain development. This study highlights gene regulatory pathways in the developing brain that may contribute to acquisition of proficient speech.

    Additional information

    Eising_etal_2018sup.pdf
  • Fisher, S. E., & Tilot, A. K. (Eds.). (2019). Bridging senses: Novel insights from synaesthesia [Special Issue]. Philosophical Transactions of the Royal Society of London, Series B: Biological Sciences, 374.
  • Fisher, S. E., & Tilot, A. K. (2019). Bridging senses: Novel insights from synaesthesia. Philosophical Transactions of the Royal Society of London, Series B: Biological Sciences, 374: 20190022. doi:10.1098/rstb.2019.0022.
  • Fisher, S. E. (2019). Human genetics: The evolving story of FOXP2. Current Biology, 29(2), R65-R67. doi:10.1016/j.cub.2018.11.047.

    Abstract

    FOXP2 mutations cause a speech and language disorder, raising interest in potential roles of this gene in human evolution. A new study re-evaluates genomic variation at the human FOXP2 locus but finds no evidence of recent adaptive evolution.
  • Fisher, S. E. (2019). Key issues and future directions: Genes and language. In P. Hagoort (Ed.), Human language: From genes and brain to behavior (pp. 609-620). Cambridge, MA: MIT Press.
  • French, C. A., Vinueza Veloz, M. F., Zhou, K., Peter, S., Fisher, S. E., Costa, R. M., & De Zeeuw, C. I. (2019). Differential effects of Foxp2 disruption in distinct motor circuits. Molecular Psychiatry, 24, 447-462. doi:10.1038/s41380-018-0199-x.

    Abstract

    Disruptions of the FOXP2 gene cause a speech and language disorder involving difficulties in sequencing orofacial movements. FOXP2 is expressed in cortico-striatal and cortico-cerebellar circuits important for fine motor skills, and affected individuals show abnormalities in these brain regions. We selectively disrupted Foxp2 in the cerebellar Purkinje cells, striatum or cortex of mice and assessed the effects on skilled motor behaviour using an operant lever-pressing task. Foxp2 loss in each region impacted behaviour differently, with striatal and Purkinje cell disruptions affecting the variability and the speed of lever-press sequences, respectively. Mice lacking Foxp2 in Purkinje cells showed a prominent phenotype involving slowed lever pressing as well as deficits in skilled locomotion. In vivo recordings from Purkinje cells uncovered an increased simple spike firing rate and decreased modulation of firing during limb movements. This was caused by increased intrinsic excitability rather than changes in excitatory or inhibitory inputs. Our findings show that Foxp2 can modulate different aspects of motor behaviour in distinct brain regions, and uncover an unknown role for Foxp2 in the modulation of Purkinje cell activity that severely impacts skilled movements.
  • Gialluisi, A., Andlauer, T. F. M., Mirza-Schreiber, N., Moll, K., Becker, J., Hoffmann, P., Ludwig, K. U., Czamara, D., St Pourcain, B., Brandler, W., Honbolygó, F., Tóth, D., Csépe, V., Huguet, G., Morris, A. P., Hulslander, J., Willcutt, E. G., DeFries, J. C., Olson, R. K., Smith, S. D. and 25 moreGialluisi, A., Andlauer, T. F. M., Mirza-Schreiber, N., Moll, K., Becker, J., Hoffmann, P., Ludwig, K. U., Czamara, D., St Pourcain, B., Brandler, W., Honbolygó, F., Tóth, D., Csépe, V., Huguet, G., Morris, A. P., Hulslander, J., Willcutt, E. G., DeFries, J. C., Olson, R. K., Smith, S. D., Pennington, B. F., Vaessen, A., Maurer, U., Lyytinen, H., Peyrard-Janvid, M., Leppänen, P. H. T., Brandeis, D., Bonte, M., Stein, J. F., Talcott, J. B., Fauchereau, F., Wilcke, A., Francks, C., Bourgeron, T., Monaco, A. P., Ramus, F., Landerl, K., Kere, J., Scerri, T. S., Paracchini, S., Fisher, S. E., Schumacher, J., Nöthen, M. M., Müller-Myhsok, B., & Schulte-Körne, G. (2019). Genome-wide association scan identifies new variants associated with a cognitive predictor of dyslexia. Translational Psychiatry, 9(1): 77. doi:10.1038/s41398-019-0402-0.

    Abstract

    Developmental dyslexia (DD) is one of the most prevalent learning disorders, with high impact on school and psychosocial development and high comorbidity with conditions like attention-deficit hyperactivity disorder (ADHD), depression, and anxiety. DD is characterized by deficits in different cognitive skills, including word reading, spelling, rapid naming, and phonology. To investigate the genetic basis of DD, we conducted a genome-wide association study (GWAS) of these skills within one of the largest studies available, including nine cohorts of reading-impaired and typically developing children of European ancestry (N = 2562–3468). We observed a genome-wide significant effect (p < 1 × 10−8) on rapid automatized naming of letters (RANlet) for variants on 18q12.2, within MIR924HG (micro-RNA 924 host gene; rs17663182 p = 4.73 × 10−9), and a suggestive association on 8q12.3 within NKAIN3 (encoding a cation transporter; rs16928927, p = 2.25 × 10−8). rs17663182 (18q12.2) also showed genome-wide significant multivariate associations with RAN measures (p = 1.15 × 10−8) and with all the cognitive traits tested (p = 3.07 × 10−8), suggesting (relational) pleiotropic effects of this variant. A polygenic risk score (PRS) analysis revealed significant genetic overlaps of some of the DD-related traits with educational attainment (EDUyears) and ADHD. Reading and spelling abilities were positively associated with EDUyears (p ~ [10−5–10−7]) and negatively associated with ADHD PRS (p ~ [10−8−10−17]). This corroborates a long-standing hypothesis on the partly shared genetic etiology of DD and ADHD, at the genome-wide level. Our findings suggest new candidate DD susceptibility genes and provide new insights into the genetics of dyslexia and its comorbities.
  • Gunz, P., Tilot, A. K., Wittfeld, K., Teumer, A., Shapland, C. Y., Van Erp, T. G. M., Dannemann, M., Vernot, B., Neubauer, S., Guadalupe, T., Fernandez, G., Brunner, H., Enard, W., Fallon, J., Hosten, N., Völker, U., Profico, A., Di Vincenzo, F., Manzi, G., Kelso, J. and 7 moreGunz, P., Tilot, A. K., Wittfeld, K., Teumer, A., Shapland, C. Y., Van Erp, T. G. M., Dannemann, M., Vernot, B., Neubauer, S., Guadalupe, T., Fernandez, G., Brunner, H., Enard, W., Fallon, J., Hosten, N., Völker, U., Profico, A., Di Vincenzo, F., Manzi, G., Kelso, J., St Pourcain, B., Hublin, J.-J., Franke, B., Pääbo, S., Macciardi, F., Grabe, H. J., & Fisher, S. E. (2019). Neandertal introgression sheds light on modern human endocranial globularity. Current Biology, 29(1), 120-127. doi:10.1016/j.cub.2018.10.065.

    Abstract

    One of the features that distinguishes modern humans from our extinct relatives and ancestors is a globular shape of the braincase [1-4]. As the endocranium closely mirrors the outer shape of the brain, these differences might reflect altered neural architecture [4,5]. However, in the absence of fossil brain tissue the underlying neuroanatomical changes as well as their genetic bases remain elusive. To better understand the biological foundations of modern human endocranial shape, we turn to our closest extinct relatives, the Neandertals. Interbreeding between modern humans and Neandertals has resulted in introgressed fragments of Neandertal DNA in the genomes of present-day non- Africans [6,7]. Based on shape analyses of fossil skull endocasts, we derive a measure of endocranial globularity from structural magnetic resonance imaging (MRI) scans of thousands of modern humans, and study the effects of introgressed fragments of Neandertal DNA on this phenotype. We find that Neandertal alleles on chromosomes 1 and 18 are associated with reduced endocranial globularity. These alleles influence expression of two nearby genes, UBR4 and PHLPP1, which are involved in neurogenesis and myelination, respectively. Our findings show how integration of fossil skull data with archaic genomics and neuroimaging can suggest developmental mechanisms that may contribute to the unique modern human endocranial shape.

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    mmc1.pdf mmc2.xlsx
  • Haworth, S., Shapland, C. Y., Hayward, C., Prins, B. P., Felix, J. F., Medina-Gomez, C., Rivadeneira, F., Wang, C., Ahluwalia, T. S., Vrijheid, M., Guxens, M., Sunyer, J., Tachmazidou, I., Walter, K., Iotchkova, V., Jackson, A., Cleal, L., Huffmann, J., Min, J. L., Sass, L. and 15 moreHaworth, S., Shapland, C. Y., Hayward, C., Prins, B. P., Felix, J. F., Medina-Gomez, C., Rivadeneira, F., Wang, C., Ahluwalia, T. S., Vrijheid, M., Guxens, M., Sunyer, J., Tachmazidou, I., Walter, K., Iotchkova, V., Jackson, A., Cleal, L., Huffmann, J., Min, J. L., Sass, L., Timmers, P. R. H. J., UK10K consortium, Davey Smith, G., Fisher, S. E., Wilson, J. F., Cole, T. J., Fernandez-Orth, D., Bønnelykke, K., Bisgaard, H., Pennell, C. E., Jaddoe, V. W. V., Dedoussis, G., Timpson, N. J., Zeggini, E., Vitart, V., & St Pourcain, B. (2019). Low-frequency variation in TP53 has large effects on head circumference and intracranial volume. Nature Communications, 10: 357. doi:10.1038/s41467-018-07863-x.

    Abstract

    Cranial growth and development is a complex process which affects the closely related traits of head circumference (HC) and intracranial volume (ICV). The underlying genetic influences affecting these traits during the transition from childhood to adulthood are little understood, but might include both age-specific genetic influences and low-frequency genetic variation. To understand these influences, we model the developmental genetic architecture of HC, showing this is genetically stable and correlated with genetic determinants of ICV. Investigating up to 46,000 children and adults of European descent, we identify association with final HC and/or final ICV+HC at 9 novel common and low-frequency loci, illustrating that genetic variation from a wide allele frequency spectrum contributes to cranial growth. The largest effects are reported for low-frequency variants within TP53, with 0.5 cm wider heads in increaser-allele carriers versus non-carriers during mid-childhood, suggesting a previously unrecognized role of TP53 transcripts in human cranial development.

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    Supplementary Information
  • Ioumpa, K., Graham, S. A., Clausner, T., Fisher, S. E., Van Lier, R., & Van Leeuwen, T. M. (2019). Enhanced self-reported affect and prosocial behaviour without differential physiological responses in mirror-sensory synaesthesia. Philosophical Transactions of the Royal Society of London, Series B: Biological Sciences, 374: 20190395. doi:10.1098/rstb.2019.0395.

    Abstract

    Mirror-sensory synaesthetes mirror the pain or touch that they observe in other people on their own bodies. This type of synaesthesia has been associated with enhanced empathy. We investigated whether the enhanced empathy of people with mirror-sensory synesthesia influences the experience of situations involving touch or pain and whether it affects their prosocial decision making. Mirror-sensory synaesthetes (N = 18, all female), verified with a touch-interference paradigm, were compared with a similar number of age-matched control individuals (all female). Participants viewed arousing images depicting pain or touch; we recorded subjective valence and arousal ratings, and physiological responses, hypothesizing more extreme reactions in synaesthetes. The subjective impact of positive and negative images was stronger in synaesthetes than in control participants; the stronger the reported synaesthesia, the more extreme the picture ratings. However, there was no evidence for differential physiological or hormonal responses to arousing pictures. Prosocial decision making was assessed with an economic game assessing altruism, in which participants had to divide money between themselves and a second player. Mirror-sensory synaesthetes donated more money than non-synaesthetes, showing enhanced prosocial behaviour, and also scored higher on the Interpersonal Reactivity Index as a measure of empathy. Our study demonstrates the subjective impact of mirror-sensory synaesthesia and its stimulating influence on prosocial behaviour.

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  • Postema, M., Van Rooij, D., Anagnostou, E., Arango, C., Auzias, G., Behrmann, M., Busatto Filho, G., Calderoni, S., Calvo, R., Daly, E., Deruelle, C., Di Martino, A., Dinstein, I., Duran, F. L. S., Durston, S., Ecker, C., Ehrlich, S., Fair, D., Fedor, J., Feng, X. and 38 morePostema, M., Van Rooij, D., Anagnostou, E., Arango, C., Auzias, G., Behrmann, M., Busatto Filho, G., Calderoni, S., Calvo, R., Daly, E., Deruelle, C., Di Martino, A., Dinstein, I., Duran, F. L. S., Durston, S., Ecker, C., Ehrlich, S., Fair, D., Fedor, J., Feng, X., Fitzgerald, J., Floris, D. L., Freitag, C. M., Gallagher, L., Glahn, D. C., Gori, I., Haar, S., Hoekstra, L., Jahanshad, N., Jalbrzikowski, M., Janssen, J., King, J. A., Kong, X., Lazaro, L., Lerch, J. P., Luna, B., Martinho, M. M., McGrath, J., Medland, S. E., Muratori, F., Murphy, C. M., Murphy, D. G. M., O'Hearn, K., Oranje, B., Parellada, M., Puig, O., Retico, A., Rosa, P., Rubia, K., Shook, D., Taylor, M., Tosetti, M., Wallace, G. L., Zhou, F., Thompson, P., Fisher, S. E., Buitelaar, J. K., & Francks, C. (2019). Altered structural brain asymmetry in autism spectrum disorder in a study of 54 datasets. Nature Communications, 10: 4958. doi:10.1038/s41467-019-13005-8.
  • Satizabal, C. L., Adams, H. H. H., Hibar, D. P., White, C. C., Knol, M. J., Stein, J. L., Scholz, M., Sargurupremraj, M., Jahanshad, N., Roshchupkin, G. V., Smith, A. V., Bis, J. C., Jian, X., Luciano, M., Hofer, E., Teumer, A., Van der Lee, S. J., Yang, J., Yanek, L. R., Lee, T. V. and 271 moreSatizabal, C. L., Adams, H. H. H., Hibar, D. P., White, C. C., Knol, M. J., Stein, J. L., Scholz, M., Sargurupremraj, M., Jahanshad, N., Roshchupkin, G. V., Smith, A. V., Bis, J. C., Jian, X., Luciano, M., Hofer, E., Teumer, A., Van der Lee, S. J., Yang, J., Yanek, L. R., Lee, T. V., Li, S., Hu, Y., Koh, J. Y., Eicher, J. D., Desrivières, S., Arias-Vasquez, A., Chauhan, G., Athanasiu, L., Renteria, M. E., Kim, S., Höhn, D., Armstrong, N. J., Chen, Q., Holmes, A. J., Den Braber, A., Kloszewska, I., Andersson, M., Espeseth, T., Grimm, O., Abramovic, L., Alhusaini, S., Milaneschi, Y., Papmeyer, M., Axelsson, T., Ehrlich, S., Roiz-Santiañez, R., Kraemer, B., Håberg, A. K., Jones, H. J., Pike, G. B., Stein, D. J., Stevens, A., Bralten, J., Vernooij, M. W., Harris, T. B., Filippi, I., Witte, A. V., Guadalupe, T., Wittfeld, K., Mosley, T. H., Becker, J. T., Doan, N. T., Hagenaars, S. P., Saba, Y., Cuellar-Partida, G., Amin, N., Hilal, S., Nho, K., Karbalai, N., Arfanakis, K., Becker, D. M., Ames, D., Goldman, A. L., Lee, P. H., Boomsma, D. I., Lovestone, S., Giddaluru, S., Le Hellard, S., Mattheisen, M., Bohlken, M. M., Kasperaviciute, D., Schmaal, L., Lawrie, S. M., Agartz, I., Walton, E., Tordesillas-Gutierrez, D., Davies, G. E., Shin, J., Ipser, J. C., Vinke, L. N., Hoogman, M., Jia, T., Burkhardt, R., Klein, M., Crivello, F., Janowitz, D., Carmichael, O., Haukvik, U. K., Aribisala, B. S., Schmidt, H., Strike, L. T., Cheng, C.-Y., Risacher, S. L., Pütz, B., Fleischman, D. A., Assareh, A. A., Mattay, V. S., Buckner, R. L., Mecocci, P., Dale, A. M., Cichon, S., Boks, M. P., Matarin, M., Penninx, B. W. J. H., Calhoun, V. D., Chakravarty, M. M., Marquand, A., Macare, C., Masouleh, S. K., Oosterlaan, J., Amouyel, P., Hegenscheid, K., Rotter, J. I., Schork, A. J., Liewald, D. C. M., De Zubicaray, G. I., Wong, T. Y., Shen, L., Sämann, P. G., Brodaty, H., Roffman, J. L., De Geus, E. J. C., Tsolaki, M., Erk, S., Van Eijk, K. R., Cavalleri, G. L., Van der Wee, N. J. A., McIntosh, A. M., Gollub, R. L., Bulayeva, K. B., Bernard, M., Richards, J. S., Himali, J. J., Loeffler, M., Rommelse, N., Hoffmann, W., Westlye, L. T., Valdés Hernández, M. C., Hansell, N. K., Van Erp, T. G. M., Wolf, C., Kwok, J. B. J., Vellas, B., Heinz, A., Olde Loohuis, L. M., Delanty, N., Ho, B.-C., Ching, C. R. K., Shumskaya, E., Singh, B., Hofman, A., Van der Meer, D., Homuth, G., Psaty, B. M., Bastin, M., Montgomery, G. W., Foroud, T. M., Reppermund, S., Hottenga, J.-J., Simmons, A., Meyer-Lindenberg, A., Cahn, W., Whelan, C. D., Van Donkelaar, M. M. J., Yang, Q., Hosten, N., Green, R. C., Thalamuthu, A., Mohnke, S., Hulshoff Pol, H. E., Lin, H., Jack Jr., C. R., Schofield, P. R., Mühleisen, T. W., Maillard, P., Potkin, S. G., Wen, W., Fletcher, E., Toga, A. W., Gruber, O., Huentelman, M., Smith, G. D., Launer, L. J., Nyberg, L., Jönsson, E. G., Crespo-Facorro, B., Koen, N., Greve, D., Uitterlinden, A. G., Weinberger, D. R., Steen, V. M., Fedko, I. O., Groenewold, N. A., Niessen, W. J., Toro, R., Tzourio, C., Longstreth Jr., W. T., Ikram, M. K., Smoller, J. W., Van Tol, M.-J., Sussmann, J. E., Paus, T., Lemaître, H., Schroeter, M. L., Mazoyer, B., Andreassen, O. A., Holsboer, F., Depondt, C., Veltman, D. J., Turner, J. A., Pausova, Z., Schumann, G., Van Rooij, D., Djurovic, S., Deary, I. J., McMahon, K. L., Müller-Myhsok, B., Brouwer, R. M., Soininen, H., Pandolfo, M., Wassink, T. H., Cheung, J. W., Wolfers, T., Martinot, J.-L., Zwiers, M. P., Nauck, M., Melle, I., Martin, N. G., Kanai, R., Westman, E., Kahn, R. S., Sisodiya, S. M., White, T., Saremi, A., Van Bokhoven, H., Brunner, H. G., Völzke, H., Wright, M. J., Van 't Ent, D., Nöthen, M. M., Ophoff, R. A., Buitelaar, J. K., Fernández, G., Sachdev, P. S., Rietschel, M., Van Haren, N. E. M., Fisher, S. E., Beiser, A. S., Francks, C., Saykin, A. J., Mather, K. A., Romanczuk-Seiferth, N., Hartman, C. A., DeStefano, A. L., Heslenfeld, D. J., Weiner, M. W., Walter, H., Hoekstra, P. J., Nyquist, P. A., Franke, B., Bennett, D. A., Grabe, H. J., Johnson, A. D., Chen, C., Van Duijn, C. M., Lopez, O. L., Fornage, M., Wardlaw, J. A., Schmidt, R., DeCarli, C., De Jager, P. L., Villringer, A., Debette, S., Gudnason, V., Medland, S. E., Shulman, J. M., Thompson, P. M., Seshadri, S., & Ikram, M. A. (2019). Genetic architecture of subcortical brain structures in 38,854 individuals worldwide. Nature Genetics, 51, 1624-1636. doi:10.1038/s41588-019-0511-y.

    Abstract

    Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.
  • Snijders Blok, L., Kleefstra, T., Venselaar, H., Maas, S., Kroes, H. Y., Lachmeijer, A. M. A., Van Gassen, K. L. I., Firth, H. V., Tomkins, S., Bodek, S., The DDD Study, Õunap, K., Wojcik, M. H., Cunniff, C., Bergstrom, K., Powis, Z., Tang, S., Shinde, D. N., Au, C., Iglesias, A. D., Izumi, K. and 18 moreSnijders Blok, L., Kleefstra, T., Venselaar, H., Maas, S., Kroes, H. Y., Lachmeijer, A. M. A., Van Gassen, K. L. I., Firth, H. V., Tomkins, S., Bodek, S., The DDD Study, Õunap, K., Wojcik, M. H., Cunniff, C., Bergstrom, K., Powis, Z., Tang, S., Shinde, D. N., Au, C., Iglesias, A. D., Izumi, K., Leonard, J., Tayoun, A. A., Baker, S. W., Tartaglia, M., Niceta, M., Dentici, M. L., Okamoto, N., Miyake, N., Matsumoto, N., Vitobello, A., Faivre, L., Philippe, C., Gilissen, C., Wiel, L., Pfundt, R., Derizioti, P., Brunner, H. G., & Fisher, S. E. (2019). De novo variants disturbing the transactivation capacity of POU3F3 cause a characteristic neurodevelopmental disorder. The American Journal of Human Genetics, 105(2), 403-412. doi:10.1016/j.ajhg.2019.06.007.

    Abstract

    POU3F3, also referred to as Brain-1, is a well-known transcription factor involved in the development of the central nervous system, but it has not previously been associated with a neurodevelopmental disorder. Here, we report the identification of 19 individuals with heterozygous POU3F3 disruptions, most of which are de novo variants. All individuals had developmental delays and/or intellectual disability and impairments in speech and language skills. Thirteen individuals had characteristic low-set, prominent, and/or cupped ears. Brain abnormalities were observed in seven of eleven MRI reports. POU3F3 is an intronless gene, insensitive to nonsense-mediated decay, and 13 individuals carried protein-truncating variants. All truncating variants that we tested in cellular models led to aberrant subcellular localization of the encoded protein. Luciferase assays demonstrated negative effects of these alleles on transcriptional activation of a reporter with a FOXP2-derived binding motif. In addition to the loss-of-function variants, five individuals had missense variants that clustered at specific positions within the functional domains, and one small in-frame deletion was identified. Two missense variants showed reduced transactivation capacity in our assays, whereas one variant displayed gain-of-function effects, suggesting a distinct pathophysiological mechanism. In bioluminescence resonance energy transfer (BRET) interaction assays, all the truncated POU3F3 versions that we tested had significantly impaired dimerization capacities, whereas all missense variants showed unaffected dimerization with wild-type POU3F3. Taken together, our identification and functional cell-based analyses of pathogenic variants in POU3F3, coupled with a clinical characterization, implicate disruptions of this gene in a characteristic neurodevelopmental disorder.
  • Tilot, A. K., Vino, A., Kucera, K. S., Carmichael, D. A., Van den Heuvel, L., Den Hoed, J., Sidoroff-Dorso, A. V., Campbell, A., Porteous, D. J., St Pourcain, B., Van Leeuwen, T. M., Ward, J., Rouw, R., Simner, J., & Fisher, S. E. (2019). Investigating genetic links between grapheme-colour synaesthesia and neuropsychiatric traits. Philosophical Transactions of the Royal Society of London, Series B: Biological Sciences, 374: 20190026. doi:10.1098/rstb.2019.0026.

    Abstract

    Synaesthesia is a neurological phenomenon affecting perception, where triggering stimuli (e.g. letters and numbers) elicit unusual secondary sensory experiences (e.g. colours). Family-based studies point to a role for genetic factors in the development of this trait. However, the contributions of common genomic variation to synaesthesia have not yet been investigated. Here, we present the SynGenes cohort, the largest genotyped collection of unrelated people with grapheme–colour synaesthesia (n = 723). Synaesthesia has been associated with a range of other neuropsychological traits, including enhanced memory and mental imagery, as well as greater sensory sensitivity. Motivated by the prior literature on putative trait overlaps, we investigated polygenic scores derived from published genome-wide scans of schizophrenia and autism spectrum disorder (ASD), comparing our SynGenes cohort to 2181 non-synaesthetic controls. We found a very slight association between schizophrenia polygenic scores and synaesthesia (Nagelkerke's R2 = 0.0047, empirical p = 0.0027) and no significant association for scores related to ASD (Nagelkerke's R2 = 0.00092, empirical p = 0.54) or body mass index (R2 = 0.00058, empirical p = 0.60), included as a negative control. As sample sizes for studying common genomic variation continue to increase, genetic investigations of the kind reported here may yield novel insights into the shared biology between synaesthesia and other traits, to complement findings from neuropsychology and brain imaging.

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  • Truong, D. T., Adams, A. K., Paniagua, S., Frijters, J. C., Boada, R., Hill, D. E., Lovett, M. W., Mahone, E. M., Willcutt, E. G., Wolf, M., Defries, J. C., Gialluisi, A., Francks, C., Fisher, S. E., Olson, R. K., Pennington, B. F., Smith, S. D., Bosson-Heenan, J., & Gruen, J. R. (2019). Multivariate genome-wide association study of rapid automatised naming and rapid alternating stimulus in Hispanic American and African–American youth. Journal of Medical Genetics, 56(8), 557-566. doi:10.1136/jmedgenet-2018-105874.

    Abstract

    Background Rapid automatised naming (RAN) and rapid alternating stimulus (RAS) are reliable predictors of reading disability. The underlying biology of reading disability is poorly understood. However, the high correlation among RAN, RAS and reading could be attributable to shared genetic factors that contribute to common biological mechanisms. Objective To identify shared genetic factors that contribute to RAN and RAS performance using a multivariate approach. Methods We conducted a multivariate genome-wide association analysis of RAN Objects, RAN Letters and RAS Letters/Numbers in a sample of 1331 Hispanic American and African–American youth. Follow-up neuroimaging genetic analysis of cortical regions associated with reading ability in an independent sample and epigenetic examination of extant data predicting tissue-specific functionality in the brain were also conducted. Results Genome-wide significant effects were observed at rs1555839 (p=4.03×10−8) and replicated in an independent sample of 318 children of European ancestry. Epigenetic analysis and chromatin state models of the implicated 70 kb region of 10q23.31 support active transcription of the gene RNLS in the brain, which encodes a catecholamine metabolising protein. Chromatin contact maps of adult hippocampal tissue indicate a potential enhancer–promoter interaction regulating RNLS expression. Neuroimaging genetic analysis in an independent, multiethnic sample (n=690) showed that rs1555839 is associated with structural variation in the right inferior parietal lobule. Conclusion This study provides support for a novel trait locus at chromosome 10q23.31 and proposes a potential gene–brain–behaviour relationship for targeted future functional analysis to understand underlying biological mechanisms for reading disability.

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  • Udden, J., Hulten, A., Bendt, K., Mineroff, Z., Kucera, K. S., Vino, A., Fedorenko, E., Hagoort, P., & Fisher, S. E. (2019). Towards robust functional neuroimaging genetics of cognition. Journal of Neuroscience, 39(44), 8778-8787. doi:10.1523/JNEUROSCI.0888-19.2019.

    Abstract

    A commonly held assumption in cognitive neuroscience is that, because measures of human brain function are closer to underlying biology than distal indices of behavior/cognition, they hold more promise for uncovering genetic pathways. Supporting this view is an influential fMRI-based study of sentence reading/listening by Pinel et al. (2012), who reported that common DNA variants in specific candidate genes were associated with altered neural activation in language-related regions of healthy individuals that carried them. In particular, different single-nucleotide polymorphisms (SNPs) of FOXP2 correlated with variation in task-based activation in left inferior frontal and precentral gyri, whereas a SNP at the KIAA0319/TTRAP/THEM2 locus was associated with variable functional asymmetry of the superior temporal sulcus. Here, we directly test each claim using a closely matched neuroimaging genetics approach in independent cohorts comprising 427 participants, four times larger than the original study of 94 participants. Despite demonstrating power to detect associations with substantially smaller effect sizes than those of the original report, we do not replicate any of the reported associations. Moreover, formal Bayesian analyses reveal substantial to strong evidence in support of the null hypothesis (no effect). We highlight key aspects of the original investigation, common to functional neuroimaging genetics studies, which could have yielded elevated false-positive rates. Genetic accounts of individual differences in cognitive functional neuroimaging are likely to be as complex as behavioral/cognitive tests, involving many common genetic variants, each of tiny effect. Reliable identification of true biological signals requires large sample sizes, power calculations, and validation in independent cohorts with equivalent paradigms. SIGNIFICANCE STATEMENT A pervasive idea in neuroscience is that neuroimaging-based measures of brain function, being closer to underlying neurobiology, are more amenable for uncovering links to genetics. This is a core assumption of prominent studies that associate common DNA variants with altered activations in task-based fMRI, despite using samples (10–100 people) that lack power for detecting the tiny effect sizes typical of genetically complex traits. Here, we test central findings from one of the most influential prior studies. Using matching paradigms and substantially larger samples, coupled to power calculations and formal Bayesian statistics, our data strongly refute the original findings. We demonstrate that neuroimaging genetics with task-based fMRI should be subject to the same rigorous standards as studies of other complex traits.
  • Verhoef, E., Demontis, D., Burgess, S., Shapland, C. Y., Dale, P. S., Okbay, A., Neale, B. M., Faraone, S. V., iPSYCH-Broad-PGC ADHD Consortium, Stergiakouli, E., Davey Smith, G., Fisher, S. E., Borglum, A., & St Pourcain, B. (2019). Disentangling polygenic associations between Attention-Deficit/Hyperactivity Disorder, educational attainment, literacy and language. Translational Psychiatry, 9: 35. doi:10.1038/s41398-018-0324-2.

    Abstract

    Interpreting polygenic overlap between ADHD and both literacy-related and language-related impairments is challenging as genetic associations might be influenced by indirectly shared genetic factors. Here, we investigate genetic overlap between polygenic ADHD risk and multiple literacy-related and/or language-related abilities (LRAs), as assessed in UK children (N ≤ 5919), accounting for genetically predictable educational attainment (EA). Genome-wide summary statistics on clinical ADHD and years of schooling were obtained from large consortia (N ≤ 326,041). Our findings show that ADHD-polygenic scores (ADHD-PGS) were inversely associated with LRAs in ALSPAC, most consistently with reading-related abilities, and explained ≤1.6% phenotypic variation. These polygenic links were then dissected into both ADHD effects shared with and independent of EA, using multivariable regressions (MVR). Conditional on EA, polygenic ADHD risk remained associated with multiple reading and/or spelling abilities, phonemic awareness and verbal intelligence, but not listening comprehension and non-word repetition. Using conservative ADHD-instruments (P-threshold < 5 × 10−8), this corresponded, for example, to a 0.35 SD decrease in pooled reading performance per log-odds in ADHD-liability (P = 9.2 × 10−5). Using subthreshold ADHD-instruments (P-threshold < 0.0015), these effects became smaller, with a 0.03 SD decrease per log-odds in ADHD risk (P = 1.4 × 10−6), although the predictive accuracy increased. However, polygenic ADHD-effects shared with EA were of equal strength and at least equal magnitude compared to those independent of EA, for all LRAs studied, and detectable using subthreshold instruments. Thus, ADHD-related polygenic links with LRAs are to a large extent due to shared genetic effects with EA, although there is evidence for an ADHD-specific association profile, independent of EA, that primarily involves literacy-related impairments.

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  • Becker, M., Devanna, P., Fisher, S. E., & Vernes, S. C. (2018). Mapping of Human FOXP2 Enhancers Reveals Complex Regulation. Frontiers in Molecular Neuroscience, 11: 47. doi:10.3389/fnmol.2018.00047.

    Abstract

    Mutations of the FOXP2 gene cause a severe speech and language disorder, providing a molecular window into the neurobiology of language. Individuals with FOXP2 mutations have structural and functional alterations affecting brain circuits that overlap with sites of FOXP2 expression, including regions of the cortex, striatum, and cerebellum. FOXP2 displays complex patterns of expression in the brain, as well as in non-neuronal tissues, suggesting that sophisticated regulatory mechanisms control its spatio-temporal expression. However, to date, little is known about the regulation of FOXP2 or the genomic elements that control its expression. Using chromatin conformation capture (3C), we mapped the human FOXP2 locus to identify putative enhancer regions that engage in long-range interactions with the promoter of this gene. We demonstrate the ability of the identified enhancer regions to drive gene expression. We also show regulation of the FOXP2 promoter and enhancer regions by candidate regulators – FOXP family and TBR1 transcription factors. These data point to regulatory elements that may contribute to the temporal- or tissue-specific expression patterns of human FOXP2. Understanding the upstream regulatory pathways controlling FOXP2 expression will bring new insight into the molecular networks contributing to human language and related disorders.
  • Den Hoed, J., Sollis, E., Venselaar, H., Estruch, S. B., Derizioti, P., & Fisher, S. E. (2018). Functional characterization of TBR1 variants in neurodevelopmental disorder. Scientific Reports, 8: 14279. doi:10.1038/s41598-018-32053-6.

    Abstract

    Recurrent de novo variants in the TBR1 transcription factor are implicated in the etiology of sporadic autism spectrum disorders (ASD). Disruptions include missense variants located in the T-box DNA-binding domain and previous work has demonstrated that they disrupt TBR1 protein function. Recent screens of thousands of simplex families with sporadic ASD cases uncovered additional T-box variants in TBR1 but their etiological relevance is unclear. We performed detailed functional analyses of de novo missense TBR1 variants found in the T-box of ASD cases, assessing many aspects of protein function, including subcellular localization, transcriptional activity and protein-interactions. Only two of the three tested variants severely disrupted TBR1 protein function, despite in silico predictions that all would be deleterious. Furthermore, we characterized a putative interaction with BCL11A, a transcription factor that was recently implicated in a neurodevelopmental syndrome involving developmental delay and language deficits. Our findings enhance understanding of molecular functions of TBR1, as well as highlighting the importance of functional testing of variants that emerge from next-generation sequencing, to decipher their contributions to neurodevelopmental disorders like ASD.

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  • Devanna, P., Chen, X. S., Ho, J., Gajewski, D., Smith, S. D., Gialluisi, A., Francks, C., Fisher, S. E., Newbury, D. F., & Vernes, S. C. (2018). Next-gen sequencing identifies non-coding variation disrupting miRNA binding sites in neurological disorders. Molecular Psychiatry, 23(5), 1375-1384. doi:10.1038/mp.2017.30.

    Abstract

    Understanding the genetic factors underlying neurodevelopmental and neuropsychiatric disorders is a major challenge given their prevalence and potential severity for quality of life. While large-scale genomic screens have made major advances in this area, for many disorders the genetic underpinnings are complex and poorly understood. To date the field has focused predominantly on protein coding variation, but given the importance of tightly controlled gene expression for normal brain development and disorder, variation that affects non-coding regulatory regions of the genome is likely to play an important role in these phenotypes. Herein we show the importance of 3 prime untranslated region (3'UTR) non-coding regulatory variants across neurodevelopmental and neuropsychiatric disorders. We devised a pipeline for identifying and functionally validating putatively pathogenic variants from next generation sequencing (NGS) data. We applied this pipeline to a cohort of children with severe specific language impairment (SLI) and identified a functional, SLI-associated variant affecting gene regulation in cells and post-mortem human brain. This variant and the affected gene (ARHGEF39) represent new putative risk factors for SLI. Furthermore, we identified 3′UTR regulatory variants across autism, schizophrenia and bipolar disorder NGS cohorts demonstrating their impact on neurodevelopmental and neuropsychiatric disorders. Our findings show the importance of investigating non-coding regulatory variants when determining risk factors contributing to neurodevelopmental and neuropsychiatric disorders. In the future, integration of such regulatory variation with protein coding changes will be essential for uncovering the genetic causes of complex neurological disorders and the fundamental mechanisms underlying health and disease

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  • Estruch, S. B., Graham, S. A., Quevedo, M., Vino, A., Dekkers, D. H. W., Deriziotis, P., Sollis, E., Demmers, J., Poot, R. A., & Fisher, S. E. (2018). Proteomic analysis of FOXP proteins reveals interactions between cortical transcription factors associated with neurodevelopmental disorders. Human Molecular Genetics, 27(7), 1212-1227. doi:10.1093/hmg/ddy035.

    Abstract

    FOXP transcription factors play important roles in neurodevelopment, but little is known about how their transcriptional activity is regulated. FOXP proteins cooperatively regulate gene expression by forming homo- and hetero-dimers with each other. Physical associations with other transcription factors might also modulate the functions of FOXP proteins. However, few FOXP-interacting transcription factors have been identified so far. Therefore, we sought to discover additional transcription factors that interact with the brain-expressed FOXP proteins, FOXP1, FOXP2 and FOXP4, through affinity-purifications of protein complexes followed by mass spectrometry. We identified seven novel FOXP-interacting transcription factors (NR2F1, NR2F2, SATB1, SATB2, SOX5, YY1 and ZMYM2), five of which have well-estabslished roles in cortical development. Accordingly, we found that these transcription factors are co-expressed with FoxP2 in the deep layers of the cerebral cortex and also in the Purkinje cells of the cerebellum, suggesting that they may cooperate with the FoxPs to regulate neural gene expression in vivo. Moreover, we demonstrated that etiological mutations of FOXP1 and FOXP2, known to cause neurodevelopmental disorders, severely disrupted the interactions with FOXP-interacting transcription factors. Additionally, we pinpointed specific regions within FOXP2 sequence involved in mediating these interactions. Thus, by expanding the FOXP interactome we have uncovered part of a broader neural transcription factor network involved in cortical development, providing novel molecular insights into the transcriptional architecture underlying brain development and neurodevelopmental disorders
  • Gingras, B., Honing, H., Peretz, I., Trainor, L. J., & Fisher, S. E. (2018). Defining the biological bases of individual differences in musicality. In H. Honing (Ed.), The origins of musicality (pp. 221-250). Cambridge, MA: MIT Press.
  • Kong, X., Mathias, S. R., Guadalupe, T., ENIGMA Laterality Working Group, Glahn, D. C., Franke, B., Crivello, F., Tzourio-Mazoyer, N., Fisher, S. E., Thompson, P. M., & Francks, C. (2018). Mapping Cortical Brain Asymmetry in 17,141 Healthy Individuals Worldwide via the ENIGMA Consortium. Proceedings of the National Academy of Sciences of the United States of America, 115(22), E5154-E5163. doi:10.1073/pnas.1718418115.

    Abstract

    Hemispheric asymmetry is a cardinal feature of human brain organization. Altered brain asymmetry has also been linked to some cognitive and neuropsychiatric disorders. Here the ENIGMA consortium presents the largest ever analysis of cerebral cortical asymmetry and its variability across individuals. Cortical thickness and surface area were assessed in MRI scans of 17,141 healthy individuals from 99 datasets worldwide. Results revealed widespread asymmetries at both hemispheric and regional levels, with a generally thicker cortex but smaller surface area in the left hemisphere relative to the right. Regionally, asymmetries of cortical thickness and/or surface area were found in the inferior frontal gyrus, transverse temporal gyrus, parahippocampal gyrus, and entorhinal cortex. These regions are involved in lateralized functions, including language and visuospatial processing. In addition to population-level asymmetries, variability in brain asymmetry was related to sex, age, and intracranial volume. Interestingly, we did not find significant associations between asymmetries and handedness. Finally, with two independent pedigree datasets (N = 1,443 and 1,113, respectively), we found several asymmetries showing significant, replicable heritability. The structural asymmetries identified, and their variabilities and heritability provide a reference resource for future studies on the genetic basis of brain asymmetry and altered laterality in cognitive, neurological, and psychiatric disorders.

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  • De Kovel, C. G. F., & Fisher, S. E. (2018). Molecular genetic methods. In A. M. B. De Groot, & P. Hagoort (Eds.), Research methods in psycholinguistics and the neurobiology of language: A practical guide (pp. 330-353). Hoboken: Wiley.
  • De Kovel, C. G. F., Lisgo, S. N., Fisher, S. E., & Francks, C. (2018). Subtle left-right asymmetry of gene expression profiles in embryonic and foetal human brains. Scientific Reports, 8: 12606. doi:10.1038/s41598-018-29496-2.

    Abstract

    Left-right laterality is an important aspect of human –and in fact all vertebrate– brain organization for which the genetic basis is poorly understood. Using RNA sequencing data we contrasted gene expression in left- and right-sided samples from several structures of the anterior central nervous systems of post mortem human embryos and foetuses. While few individual genes stood out as significantly lateralized, most structures showed evidence of laterality of their overall transcriptomic profiles. These left-right differences showed overlap with age-dependent changes in expression, indicating lateralized maturation rates, but not consistently in left-right orientation over all structures. Brain asymmetry may therefore originate in multiple locations, or if there is a single origin, it is earlier than 5 weeks post conception, with structure-specific lateralized processes already underway by this age. This pattern is broadly consistent with the weak correlations reported between various aspects of adult brain laterality, such as language dominance and handedness.
  • Kuerbitz, J., Arnett, M., Ehrman, S., Williams, M. T., Voorhees, C. V., Fisher, S. E., Garratt, A. N., Muglia, L. J., Waclaw, R. R., & Campbell, K. (2018). Loss of intercalated cells (ITCs) in the mouse amygdala of Tshz1 mutants correlates with fear, depression and social interaction phenotypes. The Journal of Neuroscience, 38, 1160-1177. doi:10.1523/JNEUROSCI.1412-17.2017.

    Abstract

    The intercalated cells (ITCs) of the amygdala have been shown to be critical regulatory components of amygdalar circuits, which control appropriate fear responses. Despite this, the molecular processes guiding ITC development remain poorly understood. Here we establish the zinc finger transcription factor Tshz1 as a marker of ITCs during their migration from the dorsal lateral ganglionic eminence through maturity. Using germline and conditional knock-out (cKO) mouse models, we show that Tshz1 is required for the proper migration and differentiation of ITCs. In the absence of Tshz1, migrating ITC precursors fail to settle in their stereotypical locations encapsulating the lateral amygdala and BLA. Furthermore, they display reductions in the ITC marker Foxp2 and ectopic persistence of the dorsal lateral ganglionic eminence marker Sp8. Tshz1 mutant ITCs show increased cell death at postnatal time points, leading to a dramatic reduction by 3 weeks of age. In line with this, Foxp2-null mutants also show a loss of ITCs at postnatal time points, suggesting that Foxp2 may function downstream of Tshz1 in the maintenance of ITCs. Behavioral analysis of male Tshz1 cKOs revealed defects in fear extinction as well as an increase in floating during the forced swim test, indicative of a depression-like phenotype. Moreover, Tshz1 cKOs display significantly impaired social interaction (i.e., increased passivity) regardless of partner genetics. Together, these results suggest that Tshz1 plays a critical role in the development of ITCs and that fear, depression-like and social behavioral deficits arise in their absence. SIGNIFICANCE STATEMENT We show here that the zinc finger transcription factor Tshz1 is expressed during development of the intercalated cells (ITCs) within the mouse amygdala. These neurons have previously been shown to play a crucial role in fear extinction. Tshz1 mouse mutants exhibit severely reduced numbers of ITCs as a result of abnormal migration, differentiation, and survival of these neurons. Furthermore, the loss of ITCs in mouse Tshz1 mutants correlates well with defects in fear extinction as well as the appearance of depression-like and abnormal social interaction behaviors reminiscent of depressive disorders observed in human patients with distal 18q deletions, including the Tshz1 locus.
  • Xu, S., Liu, P., Chen, Y., Chen, Y., Zhang, W., Zhao, H., Cao, Y., Wang, F., Jiang, N., Lin, S., Li, B., Zhang, Z., Wei, Z., Fan, Y., Jin, Y., He, L., Zhou, R., Dekker, J. D., Tucker, H. O., Fisher, S. E. and 4 moreXu, S., Liu, P., Chen, Y., Chen, Y., Zhang, W., Zhao, H., Cao, Y., Wang, F., Jiang, N., Lin, S., Li, B., Zhang, Z., Wei, Z., Fan, Y., Jin, Y., He, L., Zhou, R., Dekker, J. D., Tucker, H. O., Fisher, S. E., Yao, Z., Liu, Q., Xia, X., & Guo, X. (2018). Foxp2 regulates anatomical features that may be relevant for vocal behaviors and bipedal locomotion. Proceedings of the National Academy of Sciences of the United States of America, 115(35), 8799-8804. doi:10.1073/pnas.1721820115.

    Abstract

    Fundamental human traits, such as language and bipedalism, are associated with a range of anatomical adaptations in craniofacial shaping and skeletal remodeling. However, it is unclear how such morphological features arose during hominin evolution. FOXP2 is a brain-expressed transcription factor implicated in a rare disorder involving speech apraxia and language impairments. Analysis of its evolutionary history suggests that this gene may have contributed to the emergence of proficient spoken language. In the present study, through analyses of skeleton-specific knockout mice, we identified roles of Foxp2 in skull shaping and bone remodeling. Selective ablation of Foxp2 in cartilage disrupted pup vocalizations in a similar way to that of global Foxp2 mutants, which may be due to pleiotropic effects on craniofacial morphogenesis. Our findings also indicate that Foxp2 helps to regulate strength and length of hind limbs and maintenance of joint cartilage and intervertebral discs, which are all anatomical features that are susceptible to adaptations for bipedal locomotion. In light of the known roles of Foxp2 in brain circuits that are important for motor skills and spoken language, we suggest that this gene may have been well placed to contribute to coevolution of neural and anatomical adaptations related to speech and bipedal locomotion.

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  • Mei, C., Fedorenko, E., Amor, D. J., Boys, A., Hoeflin, C., Carew, P., Burgess, T., Fisher, S. E., & Morgan, A. T. (2018). Deep phenotyping of speech and language skills in individuals with 16p11.2 deletion. European journal of human genetics, 26(5), 676-686. doi:10.1038/s41431-018-0102-x.

    Abstract

    Recurrent deletions of a ~600-kb region of 16p11.2 have been associated with a highly penetrant form of childhood apraxia of speech (CAS). Yet prior findings have been based on a small, potentially biased sample using retrospectively collected data. We examine the prevalence of CAS in a larger cohort of individuals with 16p11.2 deletion using a prospectively designed assessment battery. The broader speech and language phenotype associated with carrying this deletion was also examined. 55 participants with 16p11.2 deletion (47 children, 8 adults) underwent deep phenotyping to test for the presence of CAS and other speech and language diagnoses. Standardized tests of oral motor functioning, speech production, language, and non-verbal IQ were conducted. The majority of children (77%) and half of adults (50%) met criteria for CAS. Other speech outcomes were observed including articulation or phonological errors (i.e., phonetic and cognitive-linguistic errors, respectively), dysarthria (i.e., neuromuscular speech disorder), minimal verbal output, and even typical speech in some. Receptive and expressive language impairment was present in 73% and 70% of children, respectively. Co-occurring neurodevelopmental conditions (e.g., autism) and non-verbal IQ did not correlate with the presence of CAS. Findings indicate that CAS is highly prevalent in children with 16p11.2 deletion with symptoms persisting into adulthood for many. Yet CAS occurs in the context of a broader speech and language profile and other neurobehavioral deficits. Further research will elucidate specific genetic and neural pathways leading to speech and language deficits in individuals with 16p11.2 deletions, resulting in more targeted speech therapies addressing etiological pathways.
  • Morgan, A. T., van Haaften, L., van Hulst, K., Edley, C., Mei, C., Tan, T. Y., Amor, D., Fisher, S. E., & Koolen, D. A. (2018). Early speech development in Koolen de Vries syndrome limited by oral praxis and hypotonia. European journal of human genetics, 26, 75-84. doi:10.1038/s41431-017-0035-9.

    Abstract

    Communication disorder is common in Koolen de Vries syndrome (KdVS), yet its specific symptomatology has not been examined, limiting prognostic counselling and application of targeted therapies. Here we examine the communication phenotype associated with KdVS. Twenty-nine participants (12 males, 4 with KANSL1 variants, 25 with 17q21.31 microdeletion), aged 1.0–27.0 years were assessed for oral-motor, speech, language, literacy, and social functioning. Early history included hypotonia and feeding difficulties. Speech and language development was delayed and atypical from onset of first words (2; 5–3; 5 years of age on average). Speech was characterised by apraxia (100%) and dysarthria (93%), with stuttering in some (17%). Speech therapy and multi-modal communication (e.g., sign-language) was critical in preschool. Receptive and expressive language abilities were typically commensurate (79%), both being severely affected relative to peers. Children were sociable with a desire to communicate, although some (36%) had pragmatic impairments in domains, where higher-level language was required. A common phenotype was identified, including an overriding ‘double hit’ of oral hypotonia and apraxia in infancy and preschool, associated with severely delayed speech development. Remarkably however, speech prognosis was positive; apraxia resolved, and although dysarthria persisted, children were intelligible by mid-to-late childhood. In contrast, language and literacy deficits persisted, and pragmatic deficits were apparent. Children with KdVS require early, intensive, speech motor and language therapy, with targeted literacy and social language interventions as developmentally appropriate. Greater understanding of the linguistic phenotype may help unravel the relevance of KANSL1 to child speech and language development.

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  • St Pourcain, B., Robinson, E. B., Anttila, V., Sullivan, B. B., Maller, J., Golding, J., Skuse, D., Ring, S., Evans, D. M., Zammit, S., Fisher, S. E., Neale, B. M., Anney, R., Ripke, S., Hollegaard, M. V., Werge, T., iPSYCH-SSI-Broad Autism Group, Ronald, A., Grove, J., Hougaard, D. M., Børglum, A. D. and 3 moreSt Pourcain, B., Robinson, E. B., Anttila, V., Sullivan, B. B., Maller, J., Golding, J., Skuse, D., Ring, S., Evans, D. M., Zammit, S., Fisher, S. E., Neale, B. M., Anney, R., Ripke, S., Hollegaard, M. V., Werge, T., iPSYCH-SSI-Broad Autism Group, Ronald, A., Grove, J., Hougaard, D. M., Børglum, A. D., Mortensen, P. B., Daly, M., & Davey Smith, G. (2018). ASD and schizophrenia show distinct developmental profiles in common genetic overlap with population-based social-communication difficulties. Molecular Psychiatry, 23, 263-270. doi:10.1038/mp.2016.198.

    Abstract

    Difficulties in social communication are part of the phenotypic overlap between autism spectrum disorders (ASD) and schizophrenia. Both conditions follow, however, distinct developmental patterns. Symptoms of ASD typically occur during early childhood, whereas most symptoms characteristic of schizophrenia do not appear before early adulthood. We investigated whether overlap in common genetic in fluences between these clinical conditions and impairments in social communication depends on the developmental stage of the assessed trait. Social communication difficulties were measured in typically-developing youth (Avon Longitudinal Study of Parents and Children,N⩽5553, longitudinal assessments at 8, 11, 14 and 17 years) using the Social Communication Disorder Checklist. Data on clinical ASD (PGC-ASD: 5305 cases, 5305 pseudo-controls; iPSYCH-ASD: 7783 cases, 11 359 controls) and schizophrenia (PGC-SCZ2: 34 241 cases, 45 604 controls, 1235 trios) were either obtained through the Psychiatric Genomics Consortium (PGC) or the Danish iPSYCH project. Overlap in genetic in fluences between ASD and social communication difficulties during development decreased with age, both in the PGC-ASD and the iPSYCH-ASD sample. Genetic overlap between schizophrenia and social communication difficulties, by contrast, persisted across age, as observed within two independent PGC-SCZ2 subsamples, and showed an increase in magnitude for traits assessed during later adolescence. ASD- and schizophrenia-related polygenic effects were unrelated to each other and changes in trait-disorder links reflect the heterogeneity of genetic factors in fluencing social communication difficulties during childhood versus later adolescence. Thus, both clinical ASD and schizophrenia share some genetic in fluences with impairments in social communication, but reveal distinct developmental profiles in their genetic links, consistent with the onset of clinical symptoms

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  • St Pourcain, B., Eaves, L. J., Ring, S. M., Fisher, S. E., Medland, S., Evans, D. M., & Smith, G. D. (2018). Developmental changes within the genetic architecture of social communication behaviour: A multivariate study of genetic variance in unrelated individuals. Biological Psychiatry, 83(7), 598-606. doi:10.1016/j.biopsych.2017.09.020.

    Abstract

    Background: Recent analyses of trait-disorder overlap suggest that psychiatric dimensions may relate to distinct sets of genes that exert their maximum influence during different periods of development. This includes analyses of social-communciation difficulties that share, depending on their developmental stage, stronger genetic links with either Autism Spectrum Disorder or schizophrenia. Here we developed a multivariate analysis framework in unrelated individuals to model directly the developmental profile of genetic influences contributing to complex traits, such as social-communication difficulties, during a ~10-year period spanning childhood and adolescence. Methods: Longitudinally assessed quantitative social-communication problems (N ≤ 5,551) were studied in participants from a UK birth cohort (ALSPAC, 8 to 17 years). Using standardised measures, genetic architectures were investigated with novel multivariate genetic-relationship-matrix structural equation models (GSEM) incorporating whole-genome genotyping information. Analogous to twin research, GSEM included Cholesky decomposition, common pathway and independent pathway models. Results: A 2-factor Cholesky decomposition model described the data best. One genetic factor was common to SCDC measures across development, the other accounted for independent variation at 11 years and later, consistent with distinct developmental profiles in trait-disorder overlap. Importantly, genetic factors operating at 8 years explained only ~50% of the genetic variation at 17 years. Conclusion: Using latent factor models, we identified developmental changes in the genetic architecture of social-communication difficulties that enhance the understanding of ASD and schizophrenia-related dimensions. More generally, GSEM present a framework for modelling shared genetic aetiologies between phenotypes and can provide prior information with respect to patterns and continuity of trait-disorder overlap
  • Snijders Blok, L., Rousseau, J., Twist, J., Ehresmann, S., Takaku, M., Venselaar, H., Rodan, L. H., Nowak, C. B., Douglas, J., Swoboda, K. J., Steeves, M. A., Sahai, I., Stumpel, C. T. R. M., Stegmann, A. P. A., Wheeler, P., Willing, M., Fiala, E., Kochhar, A., Gibson, W. T., Cohen, A. S. A. and 59 moreSnijders Blok, L., Rousseau, J., Twist, J., Ehresmann, S., Takaku, M., Venselaar, H., Rodan, L. H., Nowak, C. B., Douglas, J., Swoboda, K. J., Steeves, M. A., Sahai, I., Stumpel, C. T. R. M., Stegmann, A. P. A., Wheeler, P., Willing, M., Fiala, E., Kochhar, A., Gibson, W. T., Cohen, A. S. A., Agbahovbe, R., Innes, A. M., Au, P. Y. B., Rankin, J., Anderson, I. J., Skinner, S. A., Louie, R. J., Warren, H. E., Afenjar, A., Keren, B., Nava, C., Buratti, J., Isapof, A., Rodriguez, D., Lewandowski, R., Propst, J., Van Essen, T., Choi, M., Lee, S., Chae, J. H., Price, S., Schnur, R. E., Douglas, G., Wentzensen, I. M., Zweier, C., Reis, A., Bialer, M. G., Moore, C., Koopmans, M., Brilstra, E. H., Monroe, G. R., Van Gassen, K. L. I., Van Binsbergen, E., Newbury-Ecob, R., Bownass, L., Bader, I., Mayr, J. A., Wortmann, S. B., Jakielski, K. J., Strand, E. A., Kloth, K., Bierhals, T., The DDD study, Roberts, J. D., Petrovich, R. M., Machida, S., Kurumizaka, H., Lelieveld, S., Pfundt, R., Jansen, S., Derizioti, P., Faivre, L., Thevenon, J., Assoum, M., Shriberg, L., Kleefstra, T., Brunner, H. G., Wade, P. A., Fisher, S. E., & Campeau, P. M. (2018). CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language. Nature Communications, 9: 4619. doi:10.1038/s41467-018-06014-6.

    Abstract

    Chromatin remodeling is of crucial importance during brain development. Pathogenic alterations of several chromatin remodeling ATPases have been implicated in neurodevelopmental disorders. We describe an index case with a de novo missense mutation in CHD3, identified during whole genome sequencing of a cohort of children with rare speech disorders. To gain a comprehensive view of features associated with disruption of this gene, we use a genotype-driven approach, collecting and characterizing 35 individuals with de novo CHD3 mutations and overlapping phenotypes. Most mutations cluster within the ATPase/helicase domain of the encoded protein. Modeling their impact on the three-dimensional structure demonstrates disturbance of critical binding and interaction motifs. Experimental assays with six of the identified mutations show that a subset directly affects ATPase activity, and all but one yield alterations in chromatin remodeling. We implicate de novo CHD3 mutations in a syndrome characterized by intellectual disability, macrocephaly, and impaired speech and language.
  • Snijders Blok, L., Hiatt, S. M., Bowling, K. M., Prokop, J. W., Engel, K. L., Cochran, J. N., Bebin, E. M., Bijlsma, E. K., Ruivenkamp, C. A. L., Terhal, P., Simon, M. E. H., Smith, R., Hurst, J. A., The DDD study, MCLaughlin, H., Person, R., Crunk, A., Wangler, M. F., Streff, H., Symonds, J. D., Zuberi, S. M. and 11 moreSnijders Blok, L., Hiatt, S. M., Bowling, K. M., Prokop, J. W., Engel, K. L., Cochran, J. N., Bebin, E. M., Bijlsma, E. K., Ruivenkamp, C. A. L., Terhal, P., Simon, M. E. H., Smith, R., Hurst, J. A., The DDD study, MCLaughlin, H., Person, R., Crunk, A., Wangler, M. F., Streff, H., Symonds, J. D., Zuberi, S. M., Elliott, K. S., Sanders, V. R., Masunga, A., Hopkin, R. J., Dubbs, H. A., Ortiz-Gonzalez, X. R., Pfundt, R., Brunner, H. G., Fisher, S. E., Kleefstra, T., & Cooper, G. M. (2018). De novo mutations in MED13, a component of the Mediator complex, are associated with a novel neurodevelopmental disorder. Human Genetics, 137(5), 375-388. doi:10.1007/s00439-018-1887-y.

    Abstract

    Many genetic causes of developmental delay and/or intellectual disability (DD/ID) are extremely rare, and robust discovery of these requires both large-scale DNA sequencing and data sharing. Here we describe a GeneMatcher collaboration which led to a cohort of 13 affected individuals harboring protein-altering variants, 11 of which are de novo, in MED13; the only inherited variant was transmitted to an affected child from an affected mother. All patients had intellectual disability and/or developmental delays, including speech delays or disorders. Other features that were reported in two or more patients include autism spectrum disorder, attention deficit hyperactivity disorder, optic nerve abnormalities, Duane anomaly, hypotonia, mild congenital heart abnormalities, and dysmorphisms. Six affected individuals had mutations that are predicted to truncate the MED13 protein, six had missense mutations, and one had an in-frame-deletion of one amino acid. Out of the seven non-truncating mutations, six clustered in two specific locations of the MED13 protein: an N-terminal and C-terminal region. The four N-terminal clustering mutations affect two adjacent amino acids that are known to be involved in MED13 ubiquitination and degradation, p.Thr326 and p.Pro327. MED13 is a component of the CDK8-kinase module that can reversibly bind Mediator, a multi-protein complex that is required for Polymerase II transcription initiation. Mutations in several other genes encoding subunits of Mediator have been previously shown to associate with DD/ID, including MED13L, a paralog of MED13. Thus, our findings add MED13 to the group of CDK8-kinase module-associated disease genes
  • Tilot, A. K., Kucera, K. S., Vino, A., Asher, J. E., Baron-Cohen, S., & Fisher, S. E. (2018). Rare variants in axonogenesis genes connect three families with sound–color synesthesia. Proceedings of the National Academy of Sciences of the United States of America, 115(12), 3168-3173. doi:10.1073/pnas.1715492115.

    Abstract

    Synesthesia is a rare nonpathological phenomenon where stimulation of one sense automatically provokes a secondary perception in another. Hypothesized to result from differences in cortical wiring during development, synesthetes show atypical structural and functional neural connectivity, but the underlying molecular mechanisms are unknown. The trait also appears to be more common among people with autism spectrum disorder and savant abilities. Previous linkage studies searching for shared loci of large effect size across multiple families have had limited success. To address the critical lack of candidate genes, we applied whole-exome sequencing to three families with sound–color (auditory–visual) synesthesia affecting multiple relatives across three or more generations. We identified rare genetic variants that fully cosegregate with synesthesia in each family, uncovering 37 genes of interest. Consistent with reports indicating genetic heterogeneity, no variants were shared across families. Gene ontology analyses highlighted six genes—COL4A1, ITGA2, MYO10, ROBO3, SLC9A6, and SLIT2—associated with axonogenesis and expressed during early childhood when synesthetic associations are formed. These results are consistent with neuroimaging-based hypotheses about the role of hyperconnectivity in the etiology of synesthesia and offer a potential entry point into the neurobiology that organizes our sensory experiences.

    Additional information

    Tilot_etal_2018SI.pdf
  • Van Rhijn, J. R., Fisher, S. E., Vernes, S. C., & Nadif Kasri, N. (2018). Foxp2 loss of function increases striatal direct pathway inhibition via increased GABA release. Brain Structure and Function, 223(9), 4211-4226. doi:10.1007/s00429-018-1746-6.

    Abstract

    Heterozygous mutations of the Forkhead-box protein 2 (FOXP2) gene in humans cause childhood apraxia of speech. Loss of Foxp2 in mice is known to affect striatal development and impair motor skills. However, it is unknown if striatal excitatory/inhibitory balance is affected during development and if the imbalance persists into adulthood. We investigated the effect of reduced Foxp2 expression, via a loss-of-function mutation, on striatal medium spiny neurons (MSNs). Our data show that heterozygous loss of Foxp2 decreases excitatory (AMPA receptor-mediated) and increases inhibitory (GABA receptor-mediated) currents in D1 dopamine receptor positive MSNs of juvenile and adult mice. Furthermore, reduced Foxp2 expression increases GAD67 expression, leading to both increased presynaptic content and release of GABA. Finally, pharmacological blockade of inhibitory activity in vivo partially rescues motor skill learning deficits in heterozygous Foxp2 mice. Our results suggest a novel role for Foxp2 in the regulation of striatal direct pathway activity through managing inhibitory drive.

    Additional information

    429_2018_1746_MOESM1_ESM.docx
  • Acuna-Hidalgo, R., Deriziotis, P., Steehouwer, M., Gilissen, C., Graham, S. A., Van Dam, S., Hoover-Fong, J., Telegrafi, A. B., Destree, A., Smigiel, R., Lambie, L. A., Kayserili, H., Altunoglu, U., Lapi, E., Uzielli, M. L., Aracena, M., Nur, B. G., Mihci, E., Moreira, L. M. A., Ferreira, V. B. and 26 moreAcuna-Hidalgo, R., Deriziotis, P., Steehouwer, M., Gilissen, C., Graham, S. A., Van Dam, S., Hoover-Fong, J., Telegrafi, A. B., Destree, A., Smigiel, R., Lambie, L. A., Kayserili, H., Altunoglu, U., Lapi, E., Uzielli, M. L., Aracena, M., Nur, B. G., Mihci, E., Moreira, L. M. A., Ferreira, V. B., Horovitz, D. D. G., Da Rocha, K. M., Jezela-Stanek, A., Brooks, A. S., Reutter, H., Cohen, J. S., Fatemi, A., Smitka, M., Grebe, T. A., Di Donato, N., Deshpande, C., Vandersteen, A., Marques Lourenço, C., Dufke, A., Rossier, E., Andre, G., Baumer, A., Spencer, C., McGaughran, J., Franke, L., Veltman, J. A., De Vries, B. B. A., Schinzel, A., Fisher, S. E., Hoischen, A., & Van Bon, B. W. (2017). Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies. PLoS Genetics, 13: e1006683. doi:10.1371/journal.pgen.1006683.

    Abstract

    Schinzel-Giedion syndrome (SGS) is a rare developmental disorder characterized by multiple malformations, severe neurological alterations and increased risk of malignancy. SGS is caused by de novo germline mutations clustering to a 12bp hotspot in exon 4 of SETBP1. Mutations in this hotspot disrupt a degron, a signal for the regulation of protein degradation, and lead to the accumulation of SETBP1 protein. Overlapping SETBP1 hotspot mutations have been observed recurrently as somatic events in leukemia. We collected clinical information of 47 SGS patients (including 26 novel cases) with germline SETBP1 mutations and of four individuals with a milder phenotype caused by de novo germline mutations adjacent to the SETBP1 hotspot. Different mutations within and around the SETBP1 hotspot have varying effects on SETBP1 stability and protein levels in vitro and in in silico modeling. Substitutions in SETBP1 residue I871 result in a weak increase in protein levels and mutations affecting this residue are significantly more frequent in SGS than in leukemia. On the other hand, substitutions in residue D868 lead to the largest increase in protein levels. Individuals with germline mutations affecting D868 have enhanced cell proliferation in vitro and higher incidence of cancer compared to patients with other germline SETBP1 mutations. Our findings substantiate that, despite their overlap, somatic SETBP1 mutations driving malignancy are more disruptive to the degron than germline SETBP1 mutations causing SGS. Additionally, this suggests that the functional threshold for the development of cancer driven by the disruption of the SETBP1 degron is higher than for the alteration in prenatal development in SGS. Drawing on previous studies of somatic SETBP1 mutations in leukemia, our results reveal a genotype-phenotype correlation in germline SETBP1 mutations spanning a molecular, cellular and clinical phenotype.
  • Carrion Castillo, A., Maassen, B., Franke, B., Heister, A., Naber, M., Van der Leij, A., Francks, C., & Fisher, S. E. (2017). Association analysis of dyslexia candidate genes in a Dutch longitudinal sample. European Journal of Human Genetics, 25(4), 452-460. doi:10.1038/ejhg.2016.194.

    Abstract

    Dyslexia is a common specific learning disability with a substantive genetic component. Several candidate genes have been proposed to be implicated in dyslexia susceptibility, such as DYX1C1, ROBO1, KIAA0319, and DCDC2. Associations with variants in these genes have also been reported with a variety of psychometric measures tapping into the underlying processes that might be impaired in dyslexic people. In this study, we first conducted a literature review to select single nucleotide polymorphisms (SNPs) in dyslexia candidate genes that had been repeatedly implicated across studies. We then assessed the SNPs for association in the richly phenotyped longitudinal data set from the Dutch Dyslexia Program. We tested for association with several quantitative traits, including word and nonword reading fluency, rapid naming, phoneme deletion, and nonword repetition. In this, we took advantage of the longitudinal nature of the sample to examine if associations were stable across four educational time-points (from 7 to 12 years). Two SNPs in the KIAA0319 gene were nominally associated with rapid naming, and these associations were stable across different ages. Genetic association analysis with complex cognitive traits can be enriched through the use of longitudinal information on trait development.
  • Chen, X. S., Reader, R. H., Hoischen, A., Veltman, J. A., Simpson, N. H., Francks, C., Newbury, D. F., & Fisher, S. E. (2017). Next-generation DNA sequencing identifies novel gene variants and pathways involved in specific language impairment. Scientific Reports, 7: 46105. doi:10.1038/srep46105.

    Abstract

    A significant proportion of children have unexplained problems acquiring proficient linguistic skills despite adequate intelligence and opportunity. Developmental language disorders are highly heritable with substantial societal impact. Molecular studies have begun to identify candidate loci, but much of the underlying genetic architecture remains undetermined. We performed whole-exome sequencing of 43 unrelated probands affected by severe specific language impairment, followed by independent validations with Sanger sequencing, and analyses of segregation patterns in parents and siblings, to shed new light on aetiology. By first focusing on a pre-defined set of known candidates from the literature, we identified potentially pathogenic variants in genes already implicated in diverse language-related syndromes, including ERC1, GRIN2A, and SRPX2. Complementary analyses suggested novel putative candidates carrying validated variants which were predicted to have functional effects, such as OXR1, SCN9A and KMT2D. We also searched for potential “multiple-hit” cases; one proband carried a rare AUTS2 variant in combination with a rare inherited haplotype affecting STARD9, while another carried a novel nonsynonymous variant in SEMA6D together with a rare stop-gain in SYNPR. On broadening scope to all rare and novel variants throughout the exomes, we identified biological themes that were enriched for such variants, including microtubule transport and cytoskeletal regulation.
  • Deriziotis, P., & Fisher, S. E. (2017). Speech and Language: Translating the Genome. Trends in Genetics, 33(9), 642-656. doi:10.1016/j.tig.2017.07.002.

    Abstract

    Investigation of the biological basis of human speech and language is being transformed by developments in molecular technologies, including high-throughput genotyping and next-generation sequencing of whole genomes. These advances are shedding new light on the genetic architecture underlying language-related disorders (speech apraxia, specific language impairment, developmental dyslexia) as well as that contributing to variation in relevant skills in the general population. We discuss how state-of-the-art methods are uncovering a range of genetic mechanisms, from rare mutations of large effect to common polymorphisms that increase risk in a subtle way, while converging on neurogenetic pathways that are shared between distinct disorders. We consider the future of the field, highlighting the unusual challenges and opportunities associated with studying genomics of language-related traits.
  • Fisher, S. E. (2017). Evolution of language: Lessons from the genome. Psychonomic Bulletin & Review, 24(1), 34-40. doi: 10.3758/s13423-016-1112-8.

    Abstract

    The post-genomic era is an exciting time for researchers interested in the biology of speech and language. Substantive advances in molecular methodologies have opened up entire vistas of investigation that were not previously possible, or in some cases even imagined. Speculations concerning the origins of human cognitive traits are being transformed into empirically addressable questions, generating specific hypotheses that can be explicitly tested using data collected from both the natural world and experimental settings. In this article, I discuss a number of promising lines of research in this area. For example, the field has begun to identify genes implicated in speech and language skills, including not just disorders but also the normal range of abilities. Such genes provide powerful entry points for gaining insights into neural bases and evolutionary origins, using sophisticated experimental tools from molecular neuroscience and developmental neurobiology. At the same time, sequencing of ancient hominin genomes is giving us an unprecedented view of the molecular genetic changes that have occurred during the evolution of our species. Synthesis of data from these complementary sources offers an opportunity to robustly evaluate alternative accounts of language evolution. Of course, this endeavour remains challenging on many fronts, as I also highlight in the article. Nonetheless, such an integrated approach holds great potential for untangling the complexities of the capacities that make us human.

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