Displaying 1 - 100 of 399
  • Raviv, L., & Kirby, S. (in press). Self domestication and the cultural evolution of language. In The Oxford Handbook of Cultural Evolution. Oxford: Oxford University Press.
  • Barendse, M. T., & Rosseel, Y. (2023). Multilevel SEM with random slopes in discrete data using the pairwise maximum likelihood. British Journal of Mathematical and Statistical Psychology. Advance online publication. doi:10.1111/bmsp.12294.

    Abstract

    Pairwise maximum likelihood (PML) estimation is a promising method for multilevel models with discrete responses. Multilevel models take into account that units within a cluster tend to be more alike than units from different clusters. The pairwise likelihood is then obtained as the product of bivariate likelihoods for all within-cluster pairs of units and items. In this study, we investigate the PML estimation method with computationally intensive multilevel random intercept and random slope structural equation models (SEM) in discrete data. In pursuing this, we first reconsidered the general ‘wide format’ (WF) approach for SEM models and then extend the WF approach with random slopes. In a small simulation study we the determine accuracy and efficiency of the PML estimation method by varying the sample size (250, 500, 1000, 2000), response scales (two-point, four-point), and data-generating model (mediation model with three random slopes, factor model with one and two random slopes). Overall, results show that the PML estimation method is capable of estimating computationally intensive random intercept and random slopes multilevel models in the SEM framework with discrete data and many (six or more) latent variables with satisfactory accuracy and efficiency. However, the condition with 250 clusters combined with a two-point response scale shows more bias.

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    figures
  • Snijders Blok, L., Verseput, J., Rots, D., Venselaar, H., Innes, A. M., Stumpel, C., Õunap, K., Reinson, K., Seaby, E. G., McKee, S., Burton, B., Kim, K., Van Hagen, J. M., Waisfisz, Q., Joset, P., Steindl, K., Rauch, A., Li, D., Zackai, E. H., Sheppard, S. E. and 29 moreSnijders Blok, L., Verseput, J., Rots, D., Venselaar, H., Innes, A. M., Stumpel, C., Õunap, K., Reinson, K., Seaby, E. G., McKee, S., Burton, B., Kim, K., Van Hagen, J. M., Waisfisz, Q., Joset, P., Steindl, K., Rauch, A., Li, D., Zackai, E. H., Sheppard, S. E., Keena, B., Hakonarson, H., Roos, A., Kohlschmidt, N., Cereda, A., Iascone, M., Rebessi, E., Kernohan, K. D., Campeau, P. M., Millan, F., Taylor, J. A., Lochmüller, H., Higgs, M. R., Goula, A., Bernhard, B., Velasco, D. J., Schmanski, A. A., Stark, Z., Gallacher, L., Pais, L., Marcogliese, P. C., Yamamoto, S., Raun, N., Jakub, T. E., Kramer, J. M., Den Hoed, J., Fisher, S. E., Brunner, H. G., & Kleefstra, T. (2023). A clustering of heterozygous missense variants in the crucial chromatin modifier WDR5 defines a new neurodevelopmental disorder. Human Genetics and Genomics Advances, 4(1): 100157. doi:10.1016/j.xhgg.2022.100157.

    Abstract

    WDR5 is a broadly studied, highly conserved key protein involved in a wide array of biological functions. Among these functions, WDR5 is a part of several protein complexes that affect gene regulation via post-translational modification of histones. We collected data from 11 unrelated individuals with six different rare de novo germline missense variants in WDR5; one identical variant was found in five individuals, and another variant in two individuals. All individuals had neurodevelopmental disorders including speech/language delays (N=11), intellectual disability (N=9), epilepsy (N=7) and autism spectrum disorder (N=4). Additional phenotypic features included abnormal growth parameters (N=7), heart anomalies (N=2) and hearing loss (N=2). Three-dimensional protein structures indicate that all the residues affected by these variants are located at the surface of one side of the WDR5 protein. It is predicted that five out of the six amino acid substitutions disrupt interactions of WDR5 with RbBP5 and/or KMT2A/C, as part of the COMPASS (complex proteins associated with Set1) family complexes. Our experimental approaches in Drosophila melanogaster and human cell lines show normal protein expression, localization and protein-protein interactions for all tested variants. These results, together with the clustering of variants in a specific region of WDR5 and the absence of truncating variants so far, suggest that dominant-negative or gain-of-function mechanisms might be at play. All in all, we define a neurodevelopmental disorder associated with missense variants in WDR5 and a broad range of features. This finding highlights the important role of genes encoding COMPASS family proteins in neurodevelopmental disorders.
  • 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
  • Bast, B. J., Oonk, L. C., De Nil, L., Eising, E., Koenraads, S. P., Bouwen, J., & Franken, M.-C. (2022). Ontwikkeling van stotteren: Inleiding tot een praktijkmodel. Stem- Spraak- en Taalpathologie, 27, 1-7. doi:10.21827/32.8310/2022-1.

    Abstract

    Dit artikel is de inleiding op het direct hierna volgende (Oonk e.a. 2022) waar een nieuw praktijkmodel over het ontstaan en ontwikkeling van stotteren wordt voorgesteld.

    In de dagelijkse praktijk van vooral Nederlandstalige logopedisten (-stottertherapeuten) is tot nu toe veel gebruik gemaakt van het klinische werkmodel van Bertens (1994; 2017). Dit model gaat uit van een primaire neuromusculaire timingsstoornis, welke zich niet alleen uit in het spreken, maar ook in algemene zin aanwezig is. Dit model echter, is aan revisie toe. Volgens de recente literatuur is de algemene aard van die timingstoornis niet bewezen, en zijn er veel vroegere (meer primaire) factoren aantoonbaar van belang bij het ontstaan van stotteren, met name in de genetica en in de neurologie. In dit artikel wordt deze literatuur kort samengevat, alsmede worden enkele recente modellen omschreven. Met name regulatie en terugkoppeling krijgen in recente modellen meer aandacht. Er is geen volledigheid nagestreefd, maar dit artikel is meer een tutoriale opmaat voor het hierna te presenteren model.
    (This article serves as an introduction to the accompanying paper, in which a new clinical
    model of the origin and development of stuttering is presented (Oonk e.a., 2022).
    In their clinical practice, Dutch speech language pathologists still tend to use the
    clinical model proposed by Bertens (1994; 2017). This model explains stuttering as de-
    veloping from a primary neuromuscular timing deficit, which manifests itself not only
    in speech, but in more general behaviour as well. In our opinion, this model needs to be
    updated and revised based on current scientific and clinical knowledge. There is littleevidence for the general timing deficit in Bertens’ model and, moreover, several more
    fundamental factors, especially those related to genetics and neural processes, that have
    an important role in the onset of stuttering have been reported. This paper provides a
    review and summary of these recent data, and several newer models are described. An
    important aspect of these models is the importance given to processes of regulation
    and feedback. An exhaustive overview of the existing literature has not been strived for
    but it is hoped that this paper will serve as a useful introduction to the clinical model
    presented in the accompanying paper.)
  • Bignardi, G., Chamberlain, R., Kevenaar, S. T., Tamimy, Z., & Boomsma, D. I. (2022). On the etiology of aesthetic chills: A behavioral genetic study. Scientific Reports, 12: 3247. doi:10.1038/s41598-022-07161-z.

    Abstract

    Aesthetic chills, broadly defined as a somatic marker of peak emotional-hedonic responses, are experienced by individuals across a variety of human cultures. Yet individuals vary widely in the propensity of feeling them. These individual differences have been studied in relation to demographics, personality, and neurobiological and physiological factors, but no study to date has explored the genetic etiological sources of variation. To partition genetic and environmental sources of variation in the propensity of feeling aesthetic chills, we fitted a biometrical genetic model to data from 14127 twins (from 8995 pairs), collected by the Netherlands Twin Register. Both genetic and unique environmental factors accounted for variance in aesthetic chills, with heritability estimated at .36 ([.33, .39] 95% CI). We found females more prone than males to report feeling aesthetic chills. However, a test for genotype x sex interaction did not show evidence that heritability differs between sexes. We thus show that the propensity of feeling aesthetic chills is not shaped by nurture alone, but it also reflects underlying genetic propensities.Competing Interest StatementThe authors have declared no competing interest.

    Additional information

    Link to Preprint on BioRxiv
  • 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.
  • Cambier, N., Miletitch, R., Burraco, A. B., & Raviv, L. (2022). Prosociality in swarm robotics: A model to study self-domestication and language evolution. In A. Ravignani, R. Asano, D. Valente, F. Ferretti, S. Hartmann, M. Hayashi, Y. Jadoul, M. Martins, Y. Oseki, E. D. Rodrigues, O. Vasileva, & S. Wacewicz (Eds.), The evolution of language: Proceedings of the Joint Conference on Language Evolution (JCoLE) (pp. 98-100). Nijmegen: Joint Conference on Language Evolution (JCoLE).
  • Cheung, C.-Y., Yakpo, K., & Coupé, C. (2022). A computational simulation of the genesis and spread of lexical items in situations of abrupt language contact. In A. Ravignani, R. Asano, D. Valente, F. Ferretti, S. Hartmann, M. Hayashi, Y. Jadoul, M. Martins, Y. Oseki, E. D. Rodrigues, O. Vasileva, & S. Wacewicz (Eds.), The evolution of language: Proceedings of the Joint Conference on Language Evolution (JCoLE) (pp. 115-122). Nijmegen: Joint Conference on Language Evolution (JCoLE).

    Abstract

    The current study presents an agent-based model which simulates the innovation and
    competition among lexical items in cases of language contact. It is inspired by relatively
    recent historical cases in which the linguistic ecology and sociohistorical context are highly complex. Pidgin and creole genesis offers an opportunity to obtain linguistic facts, social dynamics, and historical demography in a highly segregated society. This provides a solid ground for researching the interaction of populations with different pre-existing language systems, and how different factors contribute to the genesis of the lexicon of a newly generated mixed language. We take into consideration the population dynamics and structures, as well as a distribution of word frequencies related to language use, in order to study how social factors may affect the developmental trajectory of languages. Focusing on the case of Sranan in Suriname, our study shows that it is possible to account for the
    composition of its core lexicon in relation to different social groups, contact patterns, and
    large population movements.
  • 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.

    Additional information

    supplementary material
  • Den Hoed, J. (2022). Disentangling the molecular landscape of genetic variation of neurodevelopmental and speech disorders. PhD Thesis, Radboud University Nijmegen, Nijmegen.
  • 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.
  • Doust, C., Fontanillas, P., Eising, E., Gordon, S. D., Wang, Z., Alagöz, G., Molz, B., 23andMe Research Team, Quantitative Trait Working Group of the GenLang Consortium, St Pourcain, B., Francks, C., Marioni, R. E., Zhao, J., Paracchini, S., Talcott, J. B., Monaco, A. P., Stein, J. F., Gruen, J. R., Olson, R. K., Willcutt, E. G., DeFries, J. C., Pennington, B. F. and 7 moreDoust, C., Fontanillas, P., Eising, E., Gordon, S. D., Wang, Z., Alagöz, G., Molz, B., 23andMe Research Team, Quantitative Trait Working Group of the GenLang Consortium, St Pourcain, B., Francks, C., Marioni, R. E., Zhao, J., Paracchini, S., Talcott, J. B., Monaco, A. P., Stein, J. F., Gruen, J. R., Olson, R. K., Willcutt, E. G., DeFries, J. C., Pennington, B. F., Smith, S. D., Wright, M. J., Martin, N. G., Auton, A., Bates, T. C., Fisher, S. E., & Luciano, M. (2022). Discovery of 42 genome-wide significant loci associated with dyslexia. Nature Genetics. doi:10.1038/s41588-022-01192-y.

    Abstract

    Reading and writing are crucial life skills but roughly one in ten children are affected by dyslexia, which can persist into adulthood. Family studies of dyslexia suggest heritability up to 70%, yet few convincing genetic markers have been found. Here we performed a genome-wide association study of 51,800 adults self-reporting a dyslexia diagnosis and 1,087,070 controls and identified 42 independent genome-wide significant loci: 15 in genes linked to cognitive ability/educational attainment, and 27 new and potentially more specific to dyslexia. We validated 23 loci (13 new) in independent cohorts of Chinese and European ancestry. Genetic etiology of dyslexia was similar between sexes, and genetic covariance with many traits was found, including ambidexterity, but not neuroanatomical measures of language-related circuitry. Dyslexia polygenic scores explained up to 6% of variance in reading traits, and might in future contribute to earlier identification and remediation of dyslexia.
  • 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. P., 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.
  • Galke, L., & Scherp, A. (2022). Bag-of-words vs. graph vs. sequence in text classification: Questioning the necessity of text-graphs and the surprising strength of a wide MLP. In S. Muresan, P. Nakov, & A. Villavicencio (Eds.), Proceedings of the 60th Annual Meeting of the Association for Computational Linguistics (pp. 4038-4051). Dublin: Association for Computational Linguistics. doi:10.18653/v1/2022.acl-long.279.
  • Galke, L., Cuber, I., Meyer, C., Nölscher, H. F., Sonderecker, A., & Scherp, A. (2022). General cross-architecture distillation of pretrained language models into matrix embedding. In Proceedings of the IEEE Joint Conference on Neural Networks (IJCNN 2022), part of the IEEE World Congress on Computational Intelligence (WCCI 2022). doi:10.1109/IJCNN55064.2022.9892144.

    Abstract

    Large pretrained language models (PreLMs) are rev-olutionizing natural language processing across all benchmarks. However, their sheer size is prohibitive for small laboratories or for deployment on mobile devices. Approaches like pruning and distillation reduce the model size but typically retain the same model architecture. In contrast, we explore distilling PreLMs into a different, more efficient architecture, Continual Multiplication of Words (CMOW), which embeds each word as a matrix and uses matrix multiplication to encode sequences. We extend the CMOW architecture and its CMOW/CBOW-Hybrid variant with a bidirectional component for more expressive power, per-token representations for a general (task-agnostic) distillation during pretraining, and a two-sequence encoding scheme that facilitates downstream tasks on sentence pairs, such as sentence similarity and natural language inference. Our matrix-based bidirectional CMOW/CBOW-Hybrid model is competitive to DistilBERT on question similarity and recognizing textual entailment, but uses only half of the number of parameters and is three times faster in terms of inference speed. We match or exceed the scores of ELMo for all tasks of the GLUE benchmark except for the sentiment analysis task SST-2 and the linguistic acceptability task CoLA. However, compared to previous cross-architecture distillation approaches, we demonstrate a doubling of the scores on detecting linguistic acceptability. This shows that matrix-based embeddings can be used to distill large PreLM into competitive models and motivates further research in this direction.
  • 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
  • Heim, F. (2022). Singing is silver, hearing is gold: Impacts of local FoxP1 knockdowns on auditory perception and gene expression in female zebra finches. PhD Thesis, Leiden University, Leiden.
  • Hoogman, M., Van Rooij, D., Klein, M., Boedhoe, P., Ilioska, I., Li, T., Patel, Y., Postema, M., Zhang-James, Y., Anagnostou, E., Arango, C., Auzias, G., Banaschewski, T., Bau, C. H. D., Behrmann, M., Bellgrove, M. A., Brandeis, D., Brem, S., Busatto, G. F., Calderoni, S. and 60 moreHoogman, M., Van Rooij, D., Klein, M., Boedhoe, P., Ilioska, I., Li, T., Patel, Y., Postema, M., Zhang-James, Y., Anagnostou, E., Arango, C., Auzias, G., Banaschewski, T., Bau, C. H. D., Behrmann, M., Bellgrove, M. A., Brandeis, D., Brem, S., Busatto, G. F., Calderoni, S., Calvo, R., Castellanos, F. X., Coghill, D., Conzelmann, A., Daly, E., Deruelle, C., Dinstein, I., Durston, S., Ecker, C., Ehrlich, S., Epstein, J. N., Fair, D. A., Fitzgerald, J., Freitag, C. M., Frodl, T., Gallagher, L., Grevet, E. H., Haavik, J., Hoekstra, P. J., Janssen, J., Karkashadze, G., King, J. A., Konrad, K., Kuntsi, J., Lazaro, L., Lerch, J. P., Lesch, K.-P., Louza, M. R., Luna, B., Mattos, P., McGrath, J., Muratori, F., Murphy, C., Nigg, J. T., Oberwelland-Weiss, E., O'Gorman Tuura, R. L., O'Hearn, K., Oosterlaan, J., Parellada, M., Pauli, P., Plessen, K. J., Ramos-Quiroga, J. A., Reif, A., Reneman, L., Retico, A., Rosa, P. G. P., Rubia, K., Shaw, P., Silk, T. J., Tamm, L., Vilarroya, O., Walitza, S., Jahanshad, N., Faraone, S. V., Francks, C., Van den Heuvel, O. A., Paus, T., Thompson, P. M., Buitelaar, J. K., & Franke, B. (2022). Consortium neuroscience of attention deficit/hyperactivity disorder and autism spectrum disorder: The ENIGMA adventure. Human Brain Mapping, 43(1), 37-55. doi:10.1002/hbm.25029.

    Abstract

    Abstract Neuroimaging has been extensively used to study brain structure and function in individuals with attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) over the past decades. Two of the main shortcomings of the neuroimaging literature of these disorders are the small sample sizes employed and the heterogeneity of methods used. In 2013 and 2014, the ENIGMA-ADHD and ENIGMA-ASD working groups were respectively, founded with a common goal to address these limitations. Here, we provide a narrative review of the thus far completed and still ongoing projects of these working groups. Due to an implicitly hierarchical psychiatric diagnostic classification system, the fields of ADHD and ASD have developed largely in isolation, despite the considerable overlap in the occurrence of the disorders. The collaboration between the ENIGMA-ADHD and -ASD working groups seeks to bring the neuroimaging efforts of the two disorders closer together. The outcomes of case–control studies of subcortical and cortical structures showed that subcortical volumes are similarly affected in ASD and ADHD, albeit with small effect sizes. Cortical analyses identified unique differences in each disorder, but also considerable overlap between the two, specifically in cortical thickness. Ongoing work is examining alternative research questions, such as brain laterality, prediction of case–control status, and anatomical heterogeneity. In brief, great strides have been made toward fulfilling the aims of the ENIGMA collaborations, while new ideas and follow-up analyses continue that include more imaging modalities (diffusion MRI and resting-state functional MRI), collaborations with other large databases, and samples with dual diagnoses.
  • 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.
  • Laureys, F., De Waelle, S., Barendse, M. T., Lenoir, M., & Deconinck, F. J. (2022). The factor structure of executive function in childhood and adolescence. Intelligence, 90: 101600. doi:10.1016/j.intell.2021.101600.

    Abstract

    Executive functioning (EF) plays a major role in many domains of human behaviour, including self-regulation, academic achievement, and even sports expertise. While a significant proportion of cross-sectional research has focused on the developmental pathways of EF, the existing literature is fractionated due to a wide range of methodologies applied to narrow age ranges, impeding comparison across a broad range of age groups. The current study used a cross-sectional design to investigate the factor structure of EF within late childhood and adolescence. A total of 2166 Flemish children and adolescents completed seven tasks of the Cambridge Brain Sciences test battery. Based on the existing literature, a Confirmatory Factor Analysis was performed, which indicated that a unitary factor model provides the best fit for the youngest age group (7–12 years). For the adolescents (12–18 years), the factor structure consists of four different components, including working memory, shifting, inhibition and planning. With regard to differences between early (12–15 years) and late (15–18 years) adolescents, working memory, inhibition and planning show higher scores for the late adolescents, while there was no difference on shifting. The current study is one of the first to administer the same seven EF tests in a considerably large sample of children and adolescents, and as such contributes to the understanding of the developmental trends in EF. Future studies, especially with longitudinal designs, are encouraged to further increase the knowledge concerning the factor structure of EF, and the development of the different EF components.
  • Lemaitre, H., Le Guen, Y., Tilot, A. K., Stein, J. L., Philippe, C., Mangin, J.-F., Fisher, S. E., & Frouin, V. (2022). Genetic variations within human gained enhancer elements affect human brain sulcal morphology. NeuroImage. Advance online publication. doi:10.1016/j.neuroimage.2022.119773.

    Abstract

    The expansion of the cerebral cortex is one of the most distinctive changes in the evolution of the human brain. Cortical expansion and related increases in cortical folding may have contributed to emergence of our capacities for high-order cognitive abilities. Molecular analysis of humans, archaic hominins, and non-human primates has allowed identification of chromosomal regions showing evolutionary changes at different points of our phylogenetic history. In this study, we assessed the contributions of genomic annotations spanning 30 million years to human sulcal morphology measured via MRI in more than 18,000 participants from the UK Biobank. We found that variation within brain-expressed human gained enhancers, regulatory genetic elements that emerged since our last common ancestor with Old World monkeys, explained more trait heritability than expected for the left and right calloso-marginal posterior fissures and the right central sulcus. Intriguingly, these are sulci that have been previously linked to the evolution of locomotion in primates and later on bipedalism in our hominin ancestors.

    Additional information

    tables
  • Molz, B., Herbik, A., Baseler, H. A., de Best, P. B., Vernon, R. W., Raz, N., Gouws, A. D., Ahmadi, K., Lowndes, R., McLean, R. J., Gottlob, I., Kohl, S., Choritz, L., Maguire, J., Kanowski, M., Käsmann-Kellner, B., Wieland, I., Banin, E., Levin, N., Hoffmann, M. B. and 1 moreMolz, B., Herbik, A., Baseler, H. A., de Best, P. B., Vernon, R. W., Raz, N., Gouws, A. D., Ahmadi, K., Lowndes, R., McLean, R. J., Gottlob, I., Kohl, S., Choritz, L., Maguire, J., Kanowski, M., Käsmann-Kellner, B., Wieland, I., Banin, E., Levin, N., Hoffmann, M. B., & Morland, A. B. (2022). Structural changes to primary visual cortex in the congenital absence of cone input in achromatopsia. NeuroImage: Clinical, 33: 102925. doi:10.1016/j.nicl.2021.102925.

    Abstract

    Autosomal recessive Achromatopsia (ACHM) is a rare inherited disorder associated with dysfunctional cone photoreceptors resulting in a congenital absence of cone input to visual cortex. This might lead to distinct changes in cortical architecture with a negative impact on the success of gene augmentation therapies. To investigate the status of the visual cortex in these patients, we performed a multi-centre study focusing on the cortical structure of regions that normally receive predominantly cone input. Using high-resolution T1-weighted MRI scans and surface-based morphometry, we compared cortical thickness, surface area and grey matter volume in foveal, parafoveal and paracentral representations of primary visual cortex in 15 individuals with ACHM and 42 normally sighted, healthy controls (HC). In ACHM, surface area was reduced in all tested representations, while thickening of the cortex was found highly localized to the most central representation. These results were comparable to more widespread changes in brain structure reported in congenitally blind individuals, suggesting similar developmental processes, i.e., irrespective of the underlying cause and extent of vision loss. The cortical differences we report here could limit the success of treatment of ACHM in adulthood. Interventions earlier in life when cortical structure is not different from normal would likely offer better visual outcomes for those with ACHM.
  • Morison, L., Meffert, E., Stampfer, M., Steiner-Wilke, I., Vollmer, B., Schulze, K., Briggs, T., Braden, R., Vogel, A. P., Thompson-Lake, D., Patel, C., Blair, E., Goel, H., Turner, S., Moog, U., Riess, A., Liegeois, F., Koolen, D. A., Amor, D. J., Kleefstra, T. and 3 moreMorison, L., Meffert, E., Stampfer, M., Steiner-Wilke, I., Vollmer, B., Schulze, K., Briggs, T., Braden, R., Vogel, A. P., Thompson-Lake, D., Patel, C., Blair, E., Goel, H., Turner, S., Moog, U., Riess, A., Liegeois, F., Koolen, D. A., Amor, D. J., Kleefstra, T., Fisher, S. E., Zweier, C., & Morgan, A. T. (2022). In-depth characterisation of a cohort of individuals with missense and loss-of-function variants disrupting FOXP2. Journal of Medical Genetics. Advance online publication. doi:10.1136/jmg-2022-108734.

    Abstract

    Background
    Heterozygous disruptions of FOXP2 were the first identified molecular cause for severe speech disorder; childhood apraxia of speech (CAS), yet few cases have been reported, limiting knowledge of the condition.

    Methods
    Here we phenotyped 29 individuals from 18 families with pathogenic FOXP2-only variants (13 loss-of-function, 5 missense variants; 14 males; aged 2 years to 62 years). Health and development (cognitive, motor, social domains) was examined, including speech and language outcomes with the first cross-linguistic analysis of English and German.

    Results
    Speech disorders were prevalent (24/26, 92%) and CAS was most common (23/26, 89%), with similar speech presentations across English and German. Speech was still impaired in adulthood and some speech sounds (e.g. ‘th’, ‘r’, ‘ch’, ‘j’) were never acquired. Language impairments (22/26, 85%) ranged from mild to severe. Comorbidities included feeding difficulties in infancy (10/27, 37%), fine (14/27, 52%) and gross (14/27, 52%) motor impairment, anxiety (6/28, 21%), depression (7/28, 25%), and sleep disturbance (11/15, 44%). Physical features were common (23/28, 82%) but with no consistent pattern. Cognition ranged from average to mildly impaired, and was incongruent with language ability; for example, seven participants with severe language disorder had average non-verbal cognition.

    Conclusions
    Although we identify increased prevalence of conditions like anxiety, depression and sleep disturbance, we confirm that the consequences of FOXP2 dysfunction remain relatively specific to speech disorder, as compared to other recently identified monogenic conditions associated with CAS. Thus, our findings reinforce that FOXP2 provides a valuable entrypoint for examining the neurobiological bases of speech disorder.
  • Nayak, S., Coleman, P. L., Ladányi, E., Nitin, R., Gustavson, D. E., Fisher, S. E., Magne, C. L., & Gordon, R. L. (2022). The Musical Abilities, Pleiotropy, Language, and Environment (MAPLE) framework for understanding musicality-language links across the lifespan. Neurobiology of Language. Advance online publication. doi:10.1162/nol_a_00079.

    Abstract

    Using individual differences approaches, a growing body of literature finds positive associations between musicality and language-related abilities, complementing prior findings of links between musical training and language skills. Despite these associations, musicality has been often overlooked in mainstream models of individual differences in language acquisition and development. To better understand the biological basis of these individual differences, we propose the Musical Abilities, Pleiotropy, Language, and Environment (MAPLE) framework. This novel integrative framework posits that musical and language-related abilities likely share some common genetic architecture (i.e., genetic pleiotropy) in addition to some degree of overlapping neural endophenotypes, and genetic influences on musically and linguistically enriched environments. Drawing upon recent advances in genomic methodologies for unraveling pleiotropy, we outline testable predictions for future research on language development and how its underlying neurobiological substrates may be supported by genetic pleiotropy with musicality. In support of the MAPLE framework, we review and discuss findings from over seventy behavioral and neural studies, highlighting that musicality is robustly associated with individual differences in a range of speech-language skills required for communication and development. These include speech perception-in-noise, prosodic perception, morphosyntactic skills, phonological skills, reading skills, and aspects of second/foreign language learning. Overall, the current work provides a clear agenda and framework for studying musicality-language links using individual differences approaches, with an emphasis on leveraging advances in the genomics of complex musicality and language traits.
  • Neumann, A., Nolte, I. M., Pappa, I., Ahluwalia, T. S., Pettersson, E., Rodriguez, A., Whitehouse, A., Van Beijsterveldt, C. E. M., Benyamin, B., Hammerschlag, A. R., Helmer, Q., Karhunen, V., Krapohl, E., Lu, Y., Van der Most, P. J., Palviainen, T., St Pourcain, B., Seppälä, I., Suarez, A., Vilor-Tejedor, N. and 41 moreNeumann, A., Nolte, I. M., Pappa, I., Ahluwalia, T. S., Pettersson, E., Rodriguez, A., Whitehouse, A., Van Beijsterveldt, C. E. M., Benyamin, B., Hammerschlag, A. R., Helmer, Q., Karhunen, V., Krapohl, E., Lu, Y., Van der Most, P. J., Palviainen, T., St Pourcain, B., Seppälä, I., Suarez, A., Vilor-Tejedor, N., Tiesler, C. M. T., Wang, C., Wills, A., Zhou, A., Alemany, S., Bisgaard, H., Bønnelykke, K., Davies, G. E., Hakulinen, C., Henders, A. K., Hyppönen, E., Stokholm, J., Bartels, M., Hottenga, J.-J., Heinrich, J., Hewitt, J., Keltikangas-Järvinen, L., Korhonen, T., Kaprio, J., Lahti, J., Lahti-Pulkkinen, M., Lehtimäki, T., Middeldorp, C. M., Najman, J. M., Pennell, C., Power, C., Oldehinkel, A. J., Plomin, R., Räikkönen, K., Raitakari, O. T., Rimfeld, K., Sass, L., Snieder, H., Standl, M., Sunyer, J., Williams, G. M., Bakermans-Kranenburg, M. J., Boomsma, D. I., Van IJzendoorn, M. H., Hartman, C. A., & Tiemeier, H. (2022). A genome-wide association study of total child psychiatric problems scores. PLOS ONE, 17(8): e0273116. doi:10.1371/journal.pone.0273116.

    Abstract

    Substantial genetic correlations have been reported across psychiatric disorders and numerous cross-disorder genetic variants have been detected. To identify the genetic variants underlying general psychopathology in childhood, we performed a genome-wide association study using a total psychiatric problem score. We analyzed 6,844,199 common SNPs in 38,418 school-aged children from 20 population-based cohorts participating in the EAGLE consortium. The SNP heritability of total psychiatric problems was 5.4% (SE = 0.01) and two loci reached genome-wide significance: rs10767094 and rs202005905. We also observed an association of SBF2, a gene associated with neuroticism in previous GWAS, with total psychiatric problems. The genetic effects underlying the total score were shared with common psychiatric disorders only (attention-deficit/hyperactivity disorder, anxiety, depression, insomnia) (rG > 0.49), but not with autism or the less common adult disorders (schizophrenia, bipolar disorder, or eating disorders) (rG < 0.01). Importantly, the total psychiatric problem score also showed at least a moderate genetic correlation with intelligence, educational attainment, wellbeing, smoking, and body fat (rG > 0.29). The results suggest that many common genetic variants are associated with childhood psychiatric symptoms and related phenotypes in general instead of with specific symptoms. Further research is needed to establish causality and pleiotropic mechanisms between related traits.

    Additional information

    Full summary results
  • Niarchou, M., Gustavson, D. E., Sathirapongsasuti, J. F., Anglada-Tort, M., Eising, E., Bell, E., McArthur, E., Straub, P., The 23andMe Research Team, McAuley, J. D., Capra, J. A., Ullén, F., Creanza, N., Mosing, M. A., Hinds, D., Davis, L. K., Jacoby, N., & Gordon, R. L. (2022). Genome-wide association study of musical beat synchronization demonstrates high polygenicity. Nature Human Behaviour, 6(9), 1292-1309. doi:10.1038/s41562-022-01359-x.

    Abstract

    Moving in synchrony to the beat is a fundamental component of musicality. Here we conducted a genome-wide association study to identify common genetic variants associated with beat synchronization in 606,825 individuals. Beat synchronization exhibited a highly polygenic architecture, with 69 loci reaching genome-wide significance (P < 5 × 10−8) and single-nucleotide-polymorphism-based heritability (on the liability scale) of 13%–16%. Heritability was enriched for genes expressed in brain tissues and for fetal and adult brain-specific gene regulatory elements, underscoring the role of central-nervous-system-expressed genes linked to the genetic basis of the trait. We performed validations of the self-report phenotype (through separate experiments) and of the genome-wide association study (polygenic scores for beat synchronization were associated with patients algorithmically classified as musicians in medical records of a separate biobank). Genetic correlations with breathing function, motor function, processing speed and chronotype suggest shared genetic architecture with beat synchronization and provide avenues for new phenotypic and genetic explorations.

    Additional information

    supplementary information
  • 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
  • Postema, A., Van Mierlo, H., Bakker, A. B., & Barendse, M. T. (2022). Study-to-sports spillover among competitive athletes: A field study. International Journal of Sport and Exercise Psychology. Advance online publication. doi:10.1080/1612197X.2022.2058054.

    Abstract

    Combining academics and athletics is challenging but important for the psychological and psychosocial development of those involved. However, little is known about how experiences in academics spill over and relate to athletics. Drawing on the enrichment mechanisms proposed by the Work-Home Resources model, we posit that study crafting behaviours are positively related to volatile personal resources, which, in turn, are related to higher athletic achievement. Via structural equation modelling, we examine a path model among 243 student-athletes, incorporating study crafting behaviours and personal resources (i.e., positive affect and study engagement), and self- and coach-rated athletic achievement measured two weeks later. Results show that optimising the academic environment by crafting challenging study demands relates positively to positive affect and study engagement. In turn, positive affect related positively to self-rated athletic achievement, whereas – unexpectedly – study engagement related negatively to coach-rated athletic achievement. Optimising the academic environment through cognitive crafting and crafting social study resources did not relate to athletic outcomes. We discuss how these findings offer new insights into the interplay between academics and athletics.
  • Price, K. M., Wigg, K. G., Eising, E., Feng, Y., Blokland, K., Wilkinson, M., Kerr, E. N., Guger, S. L., Quantitative Trait Working Group of the GenLang Consortium, Fisher, S. E., Lovett, M. W., Strug, L. J., & Barr, C. L. (2022). Hypothesis-driven genome-wide association studies provide novel insights into genetics of reading disabilities. Translational Psychiatry, 12: 495. doi:10.1038/s41398-022-02250-z.

    Abstract

    Reading Disability (RD) is often characterized by difficulties in the phonology of the language. While the molecular mechanisms underlying it are largely undetermined, loci are being revealed by genome-wide association studies (GWAS). In a previous GWAS for word reading (Price, 2020), we observed that top single-nucleotide polymorphisms (SNPs) were located near to or in genes involved in neuronal migration/axon guidance (NM/AG) or loci implicated in autism spectrum disorder (ASD). A prominent theory of RD etiology posits that it involves disturbed neuronal migration, while potential links between RD-ASD have not been extensively investigated. To improve power to identify associated loci, we up-weighted variants involved in NM/AG or ASD, separately, and performed a new Hypothesis-Driven (HD)–GWAS. The approach was applied to a Toronto RD sample and a meta-analysis of the GenLang Consortium. For the Toronto sample (n = 624), no SNPs reached significance; however, by gene-set analysis, the joint contribution of ASD-related genes passed the threshold (p~1.45 × 10–2, threshold = 2.5 × 10–2). For the GenLang Cohort (n = 26,558), SNPs in DOCK7 and CDH4 showed significant association for the NM/AG hypothesis (sFDR q = 1.02 × 10–2). To make the GenLang dataset more similar to Toronto, we repeated the analysis restricting to samples selected for reading/language deficits (n = 4152). In this GenLang selected subset, we found significant association for a locus intergenic between BTG3-C21orf91 for both hypotheses (sFDR q < 9.00 × 10–4). This study contributes candidate loci to the genetics of word reading. Data also suggest that, although different variants may be involved, alleles implicated in ASD risk may be found in the same genes as those implicated in word reading. This finding is limited to the Toronto sample suggesting that ascertainment influences genetic associations.
  • Raviv, L., Lupyan, G., & Green, S. C. (2022). How variability shapes learning and generalization. Trends in Cognitive Sciences, 26(6), 462-483. doi:10.1016/j.tics.2022.03.007.

    Abstract

    Learning is using past experiences to inform new behaviors and actions. Because all experiences are unique, learning always requires some generalization. An effective way of improving generalization is to expose learners to more variable (and thus often more representative) input. More variability tends to make initial learning more challenging, but eventually leads to more general and robust performance. This core principle has been repeatedly rediscovered and renamed in different domains (e.g., contextual diversity, desirable difficulties, variability of practice). Reviewing this basic result as it has been formulated in different domains allows us to identify key patterns, distinguish between different kinds of variability, discuss the roles of varying task-relevant versus irrelevant dimensions, and examine the effects of introducing variability at different points in training.
  • Raviv, L., Jacobson, S. L., Plotnik, J. M., Bowman, J., Lynch, V., & Benítez-Burraco, A. (2022). Elephants as a new animal model for studying the evolution of language as a result of self-domestication. In A. Ravignani, R. Asano, D. Valente, F. Ferretti, S. Hartmann, M. Hayashi, Y. Jadoul, M. Martins, Y. Oseki, E. D. Rodrigues, O. Vasileva, & S. Wacewicz (Eds.), The evolution of language: Proceedings of the Joint Conference on Language Evolution (JCoLE) (pp. 606-608). Nijmegen: Joint Conference on Language Evolution (JCoLE).
  • Raviv, L., Peckre, L. R., & Boeckx, C. (2022). What is simple is actually quite complex: A critical note on terminology in the domain of language and communication. Journal of Comparative Psychology. Advance online publication. doi:10.1037/com0000328.

    Abstract

    On the surface, the fields of animal communication and human linguistics have arrived at conflicting theories and conclusions with respect to the effect of social complexity on communicative complexity. For example, an increase in group size is argued to have opposite consequences on human versus animal communication systems: although an increase in human community size leads to some types of language simplification, an increase in animal group size leads to an increase in signal complexity. But do human and animal communication systems really show such a fundamental discrepancy? Our key message is that the tension between these two adjacent fields is the result of (a) a focus on different levels of analysis (namely, signal variation or grammar-like rules) and (b) an inconsistent use of terminology (namely, the terms “simple” and “complex”). By disentangling and clarifying these terms with respect to different measures of communicative complexity, we show that although animal and human communication systems indeed show some contradictory effects with respect to signal variability, they actually display essentially the same patterns with respect to grammar-like structure. This is despite the fact that the definitions of complexity and simplicity are actually aligned for signal variability, but diverge for grammatical structure. We conclude by advocating for the use of more objective and descriptive terms instead of terms such as “complexity,” which can be applied uniformly for human and animal communication systems—leading to comparable descriptions of findings across species and promoting a more productive dialogue between fields.
  • 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.
  • Sollis, E., Den Hoed, J., Quevedo, M., Estruch, S. B., Vino, A., Dekkers, D. H. W., Demmers, J. A. A., Poot, R., Derizioti, P., & Fisher, S. E. (2022). Characterisation of the TBR1 interactome: variants associated with neurodevelopmental disorders disrupt novel protein interactions. Human Molecular Genetics. Advance online publication, ddac311. doi:10.1093/hmg/ddac311.

    Abstract

    TBR1 is a neuron-specific transcription factor involved in brain development and implicated in a neurodevelopmental disorder (NDD) combining features of autism spectrum disorder (ASD), intellectual disability (ID) and speech delay. TBR1 has been previously shown to interact with a small number of transcription factors and co-factors also involved in NDDs (including CASK, FOXP1/2/4 and BCL11A), suggesting that the wider TBR1 interactome may have a significant bearing on normal and abnormal brain development. Here we have identified approximately 250 putative TBR1-interaction partners by affinity purification coupled to mass spectrometry. As well as known TBR1-interactors such as CASK, the identified partners include transcription factors and chromatin modifiers, along with ASD- and ID-related proteins. Five interaction candidates were independently validated using bioluminescence resonance energy transfer assays. We went on to test the interaction of these candidates with TBR1 protein variants implicated in cases of NDD. The assays uncovered disturbed interactions for NDD-associated variants and identified two distinct protein-binding domains of TBR1 that have essential roles in protein–protein interaction.
  • 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.
  • 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. M., 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 63 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. M., 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. (2022). Uncovering the genetic architecture of broad antisocial behavior through a genome-wide association study meta-analysis. Molecular Psychiatry. Advance online publication. doi:10.1038/s41380-022-01793-3.

    Abstract

    Despite the substantial heritability of antisocial behavior (ASB), specific genetic variants robustly associated with the trait have not been identified. The present study by the Broad Antisocial Behavior Consortium (BroadABC) meta-analyzed data from 28 discovery samples (N = 85,359) and five independent replication samples (N = 8058) with genotypic data and broad measures of ASB. We identified the first significant genetic associations with broad ASB, involving common intronic variants in the forkhead box protein P2 (FOXP2) gene (lead SNP rs12536335, p = 6.32 × 10−10). Furthermore, we observed intronic variation in Foxp2 and one of its targets (Cntnap2) distinguishing a mouse model of pathological aggression (BALB/cJ strain) from controls (BALB/cByJ strain). Polygenic risk score (PRS) analyses in independent samples revealed that the genetic risk for ASB was associated with several antisocial outcomes across the lifespan, including diagnosis of conduct disorder, official criminal convictions, and trajectories of antisocial development. We found substantial genetic correlations of ASB with mental health (depression rg = 0.63, insomnia rg = 0.47), physical health (overweight rg = 0.19, waist-to-hip ratio rg = 0.32), smoking (rg = 0.54), cognitive ability (intelligence rg = −0.40), educational attainment (years of schooling rg = −0.46) and reproductive traits (age at first birth rg = −0.58, father’s age at death rg = −0.54). Our findings provide a starting point toward identifying critical biosocial risk mechanisms for the development of ASB.
  • Trupp, M. D., Bignardi, G., Chana, K., Specker, E., & Pelowski, M. (2022). Can a brief interaction with online, digital art improve wellbeing? A comparative study of the impact of online art and culture presentations on mood, state-anxiety, subjective wellbeing, and loneliness. Frontiers in Psychology, 13: 782033. doi:10.3389/fpsyg.2022.782033.

    Abstract

    When experienced in-person, engagement with art has been associated—in a growing body of evidence—with positive outcomes in wellbeing and mental health. This represents an exciting new field for psychology, curation, and health interventions, suggesting a widely-accessible, cost-effective, and non-pharmaceutical means of regulating factors such as mood or anxiety. However, can similar impacts be found with online presentations? If so, this would open up positive outcomes to an even-wider population—a trend accelerating due to the current COVID-19 pandemic. Despite its promise, this question, and the underlying mechanisms of art interventions and impacts, has largely not been explored. Participants (N = 84) were asked to engage with one of two online exhibitions from Google Arts and Culture (a Monet painting or a similarly-formatted display of Japanese culinary traditions). With just 1–2 min exposure, both improved negative mood, state-anxiety, loneliness, and wellbeing. Stepdown analysis suggested the changes can be explained primarily via negative mood, while improvements in mood correlated with aesthetic appraisals and cognitive-emotional experience of the exhibition. However, no difference was found between exhibitions. We discuss the findings in terms of applications and targets for future research.

    Additional information

    supplementary materials
  • Vagliano, I., Galke, L., & Scherp, A. (2022). Recommendations for item set completion: On the semantics of item co-occurrence with data sparsity, input size, and input modalities. Information Retrieval Journal, 25(3), 269-305. doi:10.1007/s10791-022-09408-9.

    Abstract

    We address the problem of recommending relevant items to a user in order to "complete" a partial set of items already known. We consider the two scenarios of citation and subject label recommendation, which resemble different semantics of item co-occurrence: relatedness for co-citations and diversity for subject labels. We assess the influence of the completeness of an already known partial item set on the recommender performance. We also investigate data sparsity through a pruning parameter and the influence of using additional metadata. As recommender models, we focus on different autoencoders, which are particularly suited for reconstructing missing items in a set. We extend autoencoders to exploit a multi-modal input of text and structured data. Our experiments on six real-world datasets show that supplying the partial item set as input is helpful when item co-occurrence resembles relatedness, while metadata are effective when co-occurrence implies diversity. This outcome means that the semantics of item co-occurrence is an important factor. The simple item co-occurrence model is a strong baseline for citation recommendation. However, autoencoders have the advantage to enable exploiting additional metadata besides the partial item set as input and achieve comparable performance. For the subject label recommendation task, the title is the most important attribute. Adding more input modalities sometimes even harms the result. In conclusion, it is crucial to consider the semantics of the item co-occurrence for the choice of an appropriate recommendation model and carefully decide which metadata to exploit.
  • 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.
  • Van den Heuvel, O. A., Boedhoe, P. S., Bertolin, S., Bruin, W. B., Francks, C., Ivanov, I., Jahanshad, N., Kong, X., Kwon, J. S., O'Neill, J., Paus, T., Patel, Y., Piras, F., Schmaal, L., Soriano-Mas, C., Spalletta, G., Van Wingen, G. A., Yun, J.-Y., Vriend, C., Simpson, H. B. and 43 moreVan den Heuvel, O. A., Boedhoe, P. S., Bertolin, S., Bruin, W. B., Francks, C., Ivanov, I., Jahanshad, N., Kong, X., Kwon, J. S., O'Neill, J., Paus, T., Patel, Y., Piras, F., Schmaal, L., Soriano-Mas, C., Spalletta, G., Van Wingen, G. A., Yun, J.-Y., Vriend, C., Simpson, H. B., Van Rooij, D., Hoexter, M. Q., Hoogman, M., Buitelaar, J. K., Arnold, P., Beucke, J. C., Benedetti, F., Bollettini, I., Bose, A., Brennan, B. P., De Nadai, A. S., Fitzgerald, K., Gruner, P., Grünblatt, E., Hirano, Y., Huyser, C., James, A., Koch, K., Kvale, G., Lazaro, L., Lochner, C., Marsh, R., Mataix-Cols, D., Morgado, P., Nakamae, T., Nakao, T., Narayanaswamy, J. C., Nurmi, E., Pittenger, C., Reddy, Y. J., Sato, J. R., Soreni, N., Stewart, S. E., Taylor, S. F., Tolin, D., Thomopoulos, S. I., Veltman, D. J., Venkatasubramanian, G., Walitza, S., Wang, Z., Thompson, P. M., Stein, D. J., & ENIGMA-OCD working (2022). An overview of the first 5 years of the ENIGMA obsessive–compulsive disorder working group: The power of worldwide collaboration. Human Brain Mapping, 43(1), 23-36. doi:10.1002/hbm.24972.

    Abstract

    Abstract Neuroimaging has played an important part in advancing our understanding of the neurobiology of obsessive?compulsive disorder (OCD). At the same time, neuroimaging studies of OCD have had notable limitations, including reliance on relatively small samples. International collaborative efforts to increase statistical power by combining samples from across sites have been bolstered by the ENIGMA consortium; this provides specific technical expertise for conducting multi-site analyses, as well as access to a collaborative community of neuroimaging scientists. In this article, we outline the background to, development of, and initial findings from ENIGMA's OCD working group, which currently consists of 47 samples from 34 institutes in 15 countries on 5 continents, with a total sample of 2,323 OCD patients and 2,325 healthy controls. Initial work has focused on studies of cortical thickness and subcortical volumes, structural connectivity, and brain lateralization in children, adolescents and adults with OCD, also including the study on the commonalities and distinctions across different neurodevelopment disorders. Additional work is ongoing, employing machine learning techniques. Findings to date have contributed to the development of neurobiological models of OCD, have provided an important model of global scientific collaboration, and have had a number of clinical implications. Importantly, our work has shed new light on questions about whether structural and functional alterations found in OCD reflect neurodevelopmental changes, effects of the disease process, or medication impacts. We conclude with a summary of ongoing work by ENIGMA-OCD, and a consideration of future directions for neuroimaging research on OCD within and beyond ENIGMA.
  • Vessel, E. A., Ishizu, T., & Bignardi, G. (2022). Neural correlates of visual aesthetic appeal. In M. Skov, & M. Nadal (Eds.), The Routledge international handbook of neuroaesthetics (pp. 103-133). London: Routledge.
  • Vogelezang, S., Bradfield, J. P., the Early Growth Genetics Consortium, Grant, S. F. A., Felix, J. F., & Jaddoe, V. W. V. (2022). Genetics of early-life head circumference and genetic correlations with neurological, psychiatric and cognitive outcomes. BMC Medical Genomics, 15: 124. doi:10.1186/s12920-022-01281-1.

    Abstract

    Background

    Head circumference is associated with intelligence and tracks from childhood into adulthood.
    Methods

    We performed a genome-wide association study meta-analysis and follow-up of head circumference in a total of 29,192 participants between 6 and 30 months of age.
    Results

    Seven loci reached genome-wide significance in the combined discovery and replication analysis of which three loci near ARFGEF2, MYCL1, and TOP1, were novel. We observed positive genetic correlations for early-life head circumference with adult intracranial volume, years of schooling, childhood and adult intelligence, but not with adult psychiatric, neurological, or personality-related phenotypes.
    Conclusions

    The results of this study indicate that the biological processes underlying early-life head circumference overlap largely with those of adult head circumference. The associations of early-life head circumference with cognitive outcomes across the life course are partly explained by genetics.
  • 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.
  • Ahluwalia, T. S., Prins, B. P., Abdollahi, M., Armstrong, N. J., Aslibekyan, S., Bain, L., Jefferis, B., Baumert, J., Beekman, M., Ben-Shlomo, Y., Bis, J. C., Mitchell, B. D., De Geus, E., Delgado, G. E., Marek, D., Eriksson, J., Kajantie, E., Kanoni, S., Kemp, J. P., Lu, C. and 106 moreAhluwalia, T. S., Prins, B. P., Abdollahi, M., Armstrong, N. J., Aslibekyan, S., Bain, L., Jefferis, B., Baumert, J., Beekman, M., Ben-Shlomo, Y., Bis, J. C., Mitchell, B. D., De Geus, E., Delgado, G. E., Marek, D., Eriksson, J., Kajantie, E., Kanoni, S., Kemp, J. P., Lu, C., Marioni, R. E., McLachlan, S., Milaneschi, Y., Nolte, I. M., Petrelis, A. M., Porcu, E., Sabater-Lleal, M., Naderi, E., Seppälä, I., Shah, T., Singhal, G., Standl, M., Teumer, A., Thalamuthu, A., Thiering, E., Trompet, S., Ballantyne, C. M., Benjamin, E. J., Casas, J. P., Toben, C., Dedoussis, G., Deelen, J., Durda, P., Engmann, J., Feitosa, M. F., Grallert, H., Hammarstedt, A., Harris, S. E., Homuth, G., Hottenga, J.-J., Jalkanen, S., Jamshidi, Y., Jawahar, M. C., Jess, T., Kivimaki, M., Kleber, M. E., Lahti, J., Liu, Y., Marques-Vidal, P., Mellström, D., Mooijaart, S. P., Müller-Nurasyid, M., Penninx, B., Revez, J. A., Rossing, P., Räikkönen, K., Sattar, N., Scharnagl, H., Sennblad, B., Silveira, A., St Pourcain, B., Timpson, N. J., Trollor, J., CHARGE Inflammation Working Group, Van Dongen, J., Van Heemst, D., Visvikis-Siest, S., Vollenweider, P., Völker, U., Waldenberger, M., Willemsen, G., Zabaneh, D., Morris, R. W., Arnett, D. K., Baune, B. T., Boomsma, D. I., Chang, Y.-P.-C., Deary, I. J., Deloukas, P., Eriksson, J. G., Evans, D. M., Ferreira, M. A., Gaunt, T., Gudnason, V., Hamsten, A., Heinrich, J., Hingorani, A., Humphries, S. E., Jukema, J. W., Koenig, W., Kumari, M., Kutalik, Z., Lawlor, D. A., Lehtimäki, T., März, W., Mather, K. A., Naitza, S., Nauck, M., Ohlsson, C., Price, J. F., Raitakari, O., Rice, K., Sachdev, P. S., Slagboom, E., Sørensen, T. I. A., Spector, T., Stacey, D., Stathopoulou, M. G., Tanaka, T., Wannamethee, S. G., Whincup, P., Rotter, J. I., Dehghan, A., Boerwinkle, E., Psaty, B. M., Snieder, H., & Alizadeh, B. Z. (2021). Genome-wide association study of circulating interleukin 6 levels identifies novel loci. Human Molecular Genetics, 5(1), 393-409. doi:10.1093/hmg/ddab023.

    Abstract

    Interleukin 6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (Pcombined = 1.8 × 10−11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (Pcombined = 1.5 × 10−10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (Pcombined = 1.2 × 10−122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.
  • 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.
  • Cuellar-Partida, G., Tung, J. Y., Eriksson, N., Albrecht, E., Aliev, F., Andreassen, O. A., Barroso, I., Beckmann, J. S., Boks, M. P., Boomsma, D. I., Boyd, H. A., Breteler, M. M. B., Campbell, H., Chasman, D. I., Cherkas, L. F., Davies, G., De Geus, E. J. C., Deary, I. J., Deloukas, P., Dick, D. M. and 98 moreCuellar-Partida, G., Tung, J. Y., Eriksson, N., Albrecht, E., Aliev, F., Andreassen, O. A., Barroso, I., Beckmann, J. S., Boks, M. P., Boomsma, D. I., Boyd, H. A., Breteler, M. M. B., Campbell, H., Chasman, D. I., Cherkas, L. F., Davies, G., De Geus, E. J. C., Deary, I. J., Deloukas, P., Dick, D. M., Duffy, D. L., Eriksson, J. G., Esko, T., Feenstra, B., Geller, F., Gieger, C., Giegling, I., Gordon, S. D., Han, J., Hansen, T. F., Hartmann, A. M., Hayward, C., Heikkilä, K., Hicks, A. A., Hirschhorn, J. N., Hottenga, J.-J., Huffman, J. E., Hwang, L.-D., Ikram, M. A., Kaprio, J., Kemp, J. P., Khaw, K.-T., Klopp, N., Konte, B., Kutalik, Z., Lahti, J., Li, X., Loos, R. J. F., Luciano, M., Magnusson, S. H., Mangino, M., Marques-Vidal, P., Martin, N. G., McArdle, W. L., McCarthy, M. I., Medina-Gomez, C., Melbye, M., Melville, S. A., Metspalu, A., Milani, L., Mooser, V., Nelis, M., Nyholt, D. R., O'Connell, K. S., Ophoff, R. A., Palmer, C., Palotie, A., Palviainen, T., Pare, G., Paternoster, L., Peltonen, L., Penninx, B. W. J. H., Polasek, O., Pramstaller, P. P., Prokopenko, I., Raikkonen, K., Ripatti, S., Rivadeneira, F., Rudan, I., Rujescu, D., Smit, J. H., Smith, G. D., Smoller, J. W., Soranzo, N., Spector, T. D., St Pourcain, B., Starr, J. M., Stefánsson, H., Steinberg, S., Teder-Laving, M., Thorleifsson, G., Stefansson, K., Timpson, N. J., Uitterlinden, A. G., Van Duijn, C. M., Van Rooij, F. J. A., Vink, J. M., Vollenweider, P., Vuoksimaa, E., Waeber, G., Wareham, N. J., Warrington, N., Waterworth, D., Werge, T., Wichmann, H.-E., Widen, E., Willemsen, G., Wright, A. F., Wright, M. J., Xu, M., Zhao, J. H., Kraft, P., Hinds, D. A., Lindgren, C. M., Magi, R., Neale, B. M., Evans, D. M., & Medland, S. E. (2021). Genome-wide association study identifies 48 common genetic variants associated with handedness. Nature Human Behaviour, 5, 59-70. doi:10.1038/s41562-020-00956-y.

    Abstract

    Handedness has been extensively studied because of its relationship with language and the over-representation of left-handers in some neurodevelopmental disorders. Using data from the UK Biobank, 23andMe and the International Handedness Consortium, we conducted a genome-wide association meta-analysis of handedness (N = 1,766,671). We found 41 loci associated (P < 5 × 10−8) with left-handedness and 7 associated with ambidexterity. Tissue-enrichment analysis implicated the CNS in the aetiology of handedness. Pathways including regulation of microtubules and brain morphology were also highlighted. We found suggestive positive genetic correlations between left-handedness and neuropsychiatric traits, including schizophrenia and bipolar disorder. Furthermore, the genetic correlation between left-handedness and ambidexterity is low (rG = 0.26), which implies that these traits are largely influenced by different genetic mechanisms. Our findings suggest that handedness is highly polygenic and that the genetic variants that predispose to left-handedness may underlie part of the association with some psychiatric disorders.

    Additional information

    supplementary tables
  • 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.
  • Lowndes, R., Molz, B., Warriner, L., Herbik, A., De Best, P. B., Raz, N., Gouws, A., Ahmadi, K., McLean, R. J., Gottlob, I., Kohl, S., Choritz, L., Maguire, J., Kanowski, M., Käsmann-Kellner, B., Wieland, I., Banin, E., Levin, N., Hoffmann, M. B., Morland, A. B. and 1 moreLowndes, R., Molz, B., Warriner, L., Herbik, A., De Best, P. B., Raz, N., Gouws, A., Ahmadi, K., McLean, R. J., Gottlob, I., Kohl, S., Choritz, L., Maguire, J., Kanowski, M., Käsmann-Kellner, B., Wieland, I., Banin, E., Levin, N., Hoffmann, M. B., Morland, A. B., & Baseler, H. A. (2021). Structural differences across multiple visual cortical regions in the absence of cone function in congenital achromatopsia. Frontiers in Neuroscience, 15: 718958. doi:10.3389/fnins.2021.718958.

    Abstract

    Most individuals with congenital achromatopsia (ACHM) carry mutations that affect the retinal phototransduction pathway of cone photoreceptors, fundamental to both high acuity vision and colour perception. As the central fovea is occupied solely by cones, achromats have an absence of retinal input to the visual cortex and a small central area of blindness. Additionally, those with complete ACHM have no colour perception, and colour processing regions of the ventral cortex also lack typical chromatic signals from the cones. This study examined the cortical morphology (grey matter volume, cortical thickness, and cortical surface area) of multiple visual cortical regions in ACHM (n = 15) compared to normally sighted controls (n = 42) to determine the cortical changes that are associated with the retinal characteristics of ACHM. Surface-based morphometry was applied to T1-weighted MRI in atlas-defined early, ventral and dorsal visual regions of interest. Reduced grey matter volume in V1, V2, V3, and V4 was found in ACHM compared to controls, driven by a reduction in cortical surface area as there was no significant reduction in cortical thickness. Cortical surface area (but not thickness) was reduced in a wide range of areas (V1, V2, V3, TO1, V4, and LO1). Reduction in early visual areas with large foveal representations (V1, V2, and V3) suggests that the lack of foveal input to the visual cortex was a major driving factor in morphological changes in ACHM. However, the significant reduction in ventral area V4 coupled with the lack of difference in dorsal areas V3a and V3b suggest that deprivation of chromatic signals to visual cortex in ACHM may also contribute to changes in cortical morphology. This research shows that the congenital lack of cone input to the visual cortex can lead to widespread structural changes across multiple visual areas.

    Additional information

    table S1
  • 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.
  • Pender, R., Fearon, P., St Pourcain, B., Heron, J., & Mandy, W. (2021). Developmental trajectories of autistic social traits in the general population. Psychological Medicine. Advance online publication. doi:10.1017/S0033291721002166.

    Abstract

    Background

    Autistic people show diverse trajectories of autistic traits over time, a phenomenon labelled ‘chronogeneity’. For example, some show a decrease in symptoms, whilst others experience an intensification of difficulties. Autism spectrum disorder (ASD) is a dimensional condition, representing one end of a trait continuum that extends throughout the population. To date, no studies have investigated chronogeneity across the full range of autistic traits. We investigated the nature and clinical significance of autism trait chronogeneity in a large, general population sample.
    Methods

    Autistic social/communication traits (ASTs) were measured in the Avon Longitudinal Study of Parents and Children using the Social and Communication Disorders Checklist (SCDC) at ages 7, 10, 13 and 16 (N = 9744). We used Growth Mixture Modelling (GMM) to identify groups defined by their AST trajectories. Measures of ASD diagnosis, sex, IQ and mental health (internalising and externalising) were used to investigate external validity of the derived trajectory groups.
    Results

    The selected GMM model identified four AST trajectory groups: (i) Persistent High (2.3% of sample), (ii) Persistent Low (83.5%), (iii) Increasing (7.3%) and (iv) Decreasing (6.9%) trajectories. The Increasing group, in which females were a slight majority (53.2%), showed dramatic increases in SCDC scores during adolescence, accompanied by escalating internalising and externalising difficulties. Two-thirds (63.6%) of the Decreasing group were male.
    Conclusions

    Clinicians should note that for some young people autism-trait-like social difficulties first emerge during adolescence accompanied by problems with mood, anxiety, conduct and attention. A converse, majority-male group shows decreasing social difficulties during adolescence.
  • Postema, M. (2021). Left-right asymmetry of the human brain: Associations with neurodevelopmental disorders and genetic factors. PhD Thesis, Radboud University Nijmegen, Nijmegen.
  • 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.

    Additional information

    jcpp13396-sup-0001-supinfo.pdf
  • Raviv, L., De Heer Kloots, M., & Meyer, A. S. (2021). What makes a language easy to learn? A preregistered study on how systematic structure and community size affect language learnability. Cognition, 210: 104620. doi:10.1016/j.cognition.2021.104620.

    Abstract

    Cross-linguistic differences in morphological complexity could have important consequences for language learning. Specifically, it is often assumed that languages with more regular, compositional, and transparent grammars are easier to learn by both children and adults. Moreover, it has been shown that such grammars are more likely to evolve in bigger communities. Together, this suggests that some languages are acquired faster than others, and that this advantage can be traced back to community size and to the degree of systematicity in the language. However, the causal relationship between systematic linguistic structure and language learnability has not been formally tested, despite its potential importance for theories on language evolution, second language learning, and the origin of linguistic diversity. In this pre-registered study, we experimentally tested the effects of community size and systematic structure on adult language learning. We compared the acquisition of different yet comparable artificial languages that were created by big or small groups in a previous communication experiment, which varied in their degree of systematic linguistic structure. We asked (a) whether more structured languages were easier to learn; and (b) whether languages created by the bigger groups were easier to learn. We found that highly systematic languages were learned faster and more accurately by adults, but that the relationship between language learnability and linguistic structure was typically non-linear: high systematicity was advantageous for learning, but learners did not benefit from partly or semi-structured languages. Community size did not affect learnability: languages that evolved in big and small groups were equally learnable, and there was no additional advantage for languages created by bigger groups beyond their degree of systematic structure. Furthermore, our results suggested that predictability is an important advantage of systematic structure: participants who learned more structured languages were better at generalizing these languages to new, unfamiliar meanings, and different participants who learned the same more structured languages were more likely to produce similar labels. That is, systematic structure may allow speakers to converge effortlessly, such that strangers can immediately understand each other.
  • Sha, Z., Schijven, D., & Francks, C. (2021). Patterns of brain asymmetry associated with polygenic risks for autism and schizophrenia implicate language and executive functions but not brain masculinization. Molecular Psychiatry, 26(12), 7652-7660. doi:10.1038/s41380-021-01204-z.

    Abstract

    Autism spectrum disorder (ASD) and schizophrenia have been conceived as partly opposing disorders in terms of systemizing versus empathizing cognitive styles, with resemblances to male versus female average sex differences. Left-right asymmetry of the brain is an important aspect of its organization that shows average differences between the sexes, and can be altered in both ASD and schizophrenia. Here we mapped multivariate associations of polygenic risk scores for ASD and schizophrenia with asymmetries of regional cerebral cortical surface area, thickness and subcortical volume measures in 32,256 participants from the UK Biobank. Polygenic risks for the two disorders were positively correlated (r=0.08, p=7.13×10-50), and both were higher in females compared to males, consistent with biased participation against higher-risk males. Each polygenic risk score was associated with multivariate brain asymmetry after adjusting for sex, ASD r=0.03, p=2.17×10-9, schizophrenia r=0.04, p=2.61×10-11, but the multivariate patterns were mostly distinct for the two polygenic risks, and neither resembled average sex differences. Annotation based on meta-analyzed functional imaging data showed that both polygenic risks were associated with asymmetries of regions important for language and executive functions, consistent with behavioural associations that arose in phenome-wide association analysis. Overall, the results indicate that distinct patterns of subtly altered brain asymmetry may be functionally relevant manifestations of polygenic risks for ASD and schizophrenia, but do not support brain masculinization or feminization in their etiologies.
  • 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.

    Additional information

    supplementary information
  • 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., 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.

    Additional information

    supporting information
  • 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. (2021). Let the genes speak! De novo variants in developmental disorders with speech and language impairment. PhD Thesis, Radboud University Nijmegen, Nijmegen.
  • 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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    figures and notes tables
  • 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.
  • Ip, H. F., Van der Laan, C. M., Krapohl, E. M. L., Brikell, I., Sánchez-Mora, C., Nolte, I. M., St Pourcain, B., Bolhuis, K., Palviainen, T., Zafarmand, H., Colodro-Conde, L., Gordon, S., Zayats, T., Aliev, F., Jiang, C., Wang, C. A., Saunders, G., Karhunen, V., Hammerschlag, A. R., Adkins, D. E. and 129 moreIp, H. F., Van der Laan, C. M., Krapohl, E. M. L., Brikell, I., Sánchez-Mora, C., Nolte, I. M., St Pourcain, B., Bolhuis, K., Palviainen, T., Zafarmand, H., Colodro-Conde, L., Gordon, S., Zayats, T., Aliev, F., Jiang, C., Wang, C. A., Saunders, G., Karhunen, V., Hammerschlag, A. R., Adkins, D. E., Border, R., Peterson, R. E., Prinz, J. A., Thiering, E., Seppälä, I., Vilor-Tejedor, N., Ahluwalia, T. S., Day, F. R., Hottenga, J.-J., Allegrini, A. G., Rimfeld, K., Chen, Q., Lu, Y., Martin, J., Soler Artigas, M., Rovira, P., Bosch, R., Español, G., Ramos Quiroga, J. A., Neumann, A., Ensink, J., Grasby, K., Morosoli, J. J., Tong, X., Marrington, S., Middeldorp, C., Scott, J. G., Vinkhuyzen, A., Shabalin, A. A., Corley, R., Evans, L. M., Sugden, K., Alemany, S., Sass, L., Vinding, R., Ruth, K., Tyrrell, J., Davies, G. E., Ehli, E. A., Hagenbeek, F. A., De Zeeuw, E., Van Beijsterveldt, T. C., Larsson, H., Snieder, H., Verhulst, F. C., Amin, N., Whipp, A. M., Korhonen, T., Vuoksimaa, E., Rose, R. J., Uitterlinden, A. G., Heath, A. C., Madden, P., Haavik, J., Harris, J. R., Helgeland, Ø., Johansson, S., Knudsen, G. P. S., Njolstad, P. R., Lu, Q., Rodriguez, A., Henders, A. K., Mamun, A., Najman, J. M., Brown, S., Hopfer, C., Krauter, K., Reynolds, C., Smolen, A., Stallings, M., Wadsworth, S., Wall, T. L., Silberg, J. L., Miller, A., Keltikangas-Järvinen, L., Hakulinen, C., Pulkki-Råback, L., Havdahl, A., Magnus, P., Raitakari, O. T., Perry, J. R. B., Llop, S., Lopez-Espinosa, M.-J., Bønnelykke, K., Bisgaard, H., Sunyer, J., Lehtimäki, T., Arseneault, L., Standl, M., Heinrich, J., Boden, J., Pearson, J., Horwood, L. J., Kennedy, M., Poulton, R., Eaves, L. J., Maes, H. H., Hewitt, J., Copeland, W. E., Costello, E. J., Williams, G. M., Wray, N., Järvelin, M.-R., McGue, M., Iacono, W., Caspi, A., Moffitt, T. E., Whitehouse, A., Pennell, C. E., Klump, K. L., Burt, S. A., Dick, D. M., Reichborn-Kjennerud, T., Martin, N. G., Medland, S. E., Vrijkotte, T., Kaprio, J., Tiemeier, H., Davey Smith, G., Hartman, C. A., Oldehinkel, A. J., Casas, M., Ribasés, M., Lichtenstein, P., Lundström, S., Plomin, R., Bartels, M., Nivard, M. G., & Boomsma, D. I. (2021). Genetic association study of childhood aggression across raters, instruments, and age. Translational Psychiatry, 11: 413. doi:10.1038/s41398-021-01480-x.
  • Verhoef, E., Grove, J., Shapland, C. Y., Demontis, D., Burgess, S., Rai, D., Børglum, A. D., & St Pourcain, B. (2021). Discordant associations of educational attainment with ASD and ADHD implicate a polygenic form of pleiotropy. Nature Communications, 12: 6534. doi:10.1038/s41467-021-26755-1.

    Abstract

    Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD) are complex co-occurring neurodevelopmental conditions. Their genetic architectures reveal striking similarities but also differences, including strong, discordant polygenic associations with educational attainment (EA). To study genetic mechanisms that present as ASD-related positive and ADHD-related negative genetic correlations with EA, we carry out multivariable regression analyses using genome-wide summary statistics (N = 10,610–766,345). Our results show that EA-related genetic variation is shared across ASD and ADHD architectures, involving identical marker alleles. However, the polygenic association profile with EA, across shared marker alleles, is discordant for ASD versus ADHD risk, indicating independent effects. At the single-variant level, our results suggest either biological pleiotropy or co-localisation of different risk variants, implicating MIR19A/19B microRNA mechanisms. At the polygenic level, they point to a polygenic form of pleiotropy that contributes to the detectable genome-wide correlation between ASD and ADHD and is consistent with effect cancellation across EA-related regions.

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    supplementary information
  • 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.

    Additional information

    supporting information
  • Verhoef, E. (2021). Why do we change how we speak? Multivariate genetic analyses of language and related traits across development and disorder. PhD Thesis, Radboud University Nijmegen, Nijmegen.
  • 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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    supporting information
  • Zhong, S., Wei, L., Zhao, C., Yang, L., Di, Z., Francks, C., & Gong, G. (2021). Interhemispheric relationship of genetic influence on human brain connectivity. Cerebral Cortex, 31(1), 77-88. doi:10.1093/cercor/bhaa207.

    Abstract

    To understand the origins of interhemispheric differences and commonalities/coupling in human brain wiring, it is crucial to determine how homologous interregional connectivities of the left and right hemispheres are genetically determined and related. To address this, in the present study, we analyzed human twin and pedigree samples with high-quality diffusion magnetic resonance imaging tractography and estimated the heritability and genetic correlation of homologous left and right white matter (WM) connections. The results showed that the heritability of WM connectivity was similar and coupled between the 2 hemispheres and that the degree of overlap in genetic factors underlying homologous WM connectivity (i.e., interhemispheric genetic correlation) varied substantially across the human brain: from complete overlap to complete nonoverlap. Particularly, the heritability was significantly stronger and the chance of interhemispheric complete overlap in genetic factors was higher in subcortical WM connections than in cortical WM connections. In addition, the heritability and interhemispheric genetic correlations were stronger for long-range connections than for short-range connections. These findings highlight the determinants of the genetics underlying WM connectivity and its interhemispheric relationships, and provide insight into genetic basis of WM connectivity asymmetries in both healthy and disease states.

    Additional information

    Supplementary data
  • Botvinik-Nezer, R., Holzmeister, F., Camerer, C. F., Dreber, A., Huber, J., Johannesson, M., Kirchler, M., Iwanir, R., Mumford, J. A., Adcock, R. A., Avesani, P., Baczkowski, B., Bajracharya, A., Bakst, L., Ball, S., Barilari, M., Bault, N., Beaton, D., Beitner, J., Benoit, R. G. and 177 moreBotvinik-Nezer, R., Holzmeister, F., Camerer, C. F., Dreber, A., Huber, J., Johannesson, M., Kirchler, M., Iwanir, R., Mumford, J. A., Adcock, R. A., Avesani, P., Baczkowski, B., Bajracharya, A., Bakst, L., Ball, S., Barilari, M., Bault, N., Beaton, D., Beitner, J., Benoit, R. G., Berkers, R., Bhanji, J. P., Biswal, B. B., Bobadilla-Suarez, S., Bortolini, T., Bottenhorn, K. L., Bowring, A., Braem, S., Brooks, H. R., Brudner, E. G., Calderon, C. B., Camilleri, J. A., Castrellon, J. J., Cecchetti, L., Cieslik, E. C., Cole, Z. J., Collignon, O., Cox, R. W., Cunningham, W. A., Czoschke, S., Dadi, K., Davis, C. P., De Luca, A., Delgado, M. R., Demetriou, L., Dennison, J. B., Di, X., Dickie, E. W., Dobryakova, E., Donnat, C. L., Dukart, J., Duncan, N. W., Durnez, J., Eed, A., Eickhoff, S. B., Erhart, A., Fontanesi, L., Fricke, G. M., Fu, S., Galván, A., Gau, R., Genon, S., Glatard, T., Glerean, E., Goeman, J. J., Golowin, S. A. E., González-García, C., Gorgolewski, K. J., Grady, C. L., Green, M. A., Guassi Moreira, J. F., Guest, O., Hakimi, S., Hamilton, J. P., Hancock, R., Handjaras, G., Harry, B. B., Hawco, C., Herholz, P., Herman, G., Heunis, S., Hoffstaedter, F., Hogeveen, J., Holmes, S., Hu, C.-P., Huettel, S. A., Hughes, M. E., Iacovella, V., Iordan, A. D., Isager, P. M., Isik, A. I., Jahn, A., Johnson, M. R., Johnstone, T., Joseph, M. J. E., Juliano, A. C., Kable, J. W., Kassinopoulos, M., Koba, C., Kong, X., Koscik, T. R., Kucukboyaci, N. E., Kuhl, B. A., Kupek, S., Laird, A. R., Lamm, C., Langner, R., Lauharatanahirun, N., Lee, H., Lee, S., Leemans, A., Leo, A., Lesage, E., Li, F., Li, M. Y. C., Lim, P. C., Lintz, E. N., Liphardt, S. W., Losecaat Vermeer, A. B., Love, B. C., Mack, M. L., Malpica, N., Marins, T., Maumet, C., McDonald, K., McGuire, J. T., Melero, H., Méndez Leal, A. S., Meyer, B., Meyer, K. N., Mihai, P. G., Mitsis, G. D., Moll, J., Nielson, D. M., Nilsonne, G., Notter, M. P., Olivetti, E., Onicas, A. I., Papale, P., Patil, K. R., Peelle, J. E., Pérez, A., Pischedda, D., Poline, J.-B., Prystauka, Y., Ray, S., Reuter-Lorenz, P. A., Reynolds, R. C., Ricciardi, E., Rieck, J. R., Rodriguez-Thompson, A. M., Romyn, A., Salo, T., Samanez-Larkin, G. R., Sanz-Morales, E., Schlichting, M. L., Schultz, D. H., Shen, Q., Sheridan, M. A., Silvers, J. A., Skagerlund, K., Smith, A., Smith, D. V., Sokol-Hessner, P., Steinkamp, S. R., Tashjian, S. M., Thirion, B., Thorp, J. N., Tinghög, G., Tisdall, L., Tompson, S. H., Toro-Serey, C., Torre Tresols, J. J., Tozzi, L., Truong, V., Turella, L., van 't Veer, A. E., Verguts, T., Vettel, J. M., Vijayarajah, S., Vo, K., Wall, M. B., Weeda, W. D., Weis, S., White, D. J., Wisniewski, D., Xifra-Porxas, A., Yearling, E. A., Yoon, S., Yuan, R., Yuen, K. S. L., Zhang, L., Zhang, X., Zosky, J. E., Nichols, T. E., Poldrack, R. A., & Schonberg, T. (2020). Variability in the analysis of a single neuroimaging dataset by many teams. Nature, 582, 84-88. doi:10.1038/s41586-020-2314-9.

    Abstract

    Data analysis workflows in many scientific domains have become increasingly complex and flexible. Here we assess the effect of this flexibility on the results of functional magnetic resonance imaging by asking 70 independent teams to analyse the same dataset, testing the same 9 ex-ante hypotheses1. The flexibility of analytical approaches is exemplified by the fact that no two teams chose identical workflows to analyse the data. This flexibility resulted in sizeable variation in the results of hypothesis tests, even for teams whose statistical maps were highly correlated at intermediate stages of the analysis pipeline. Variation in reported results was related to several aspects of analysis methodology. Notably, a meta-analytical approach that aggregated information across teams yielded a significant consensus in activated regions. Furthermore, prediction markets of researchers in the field revealed an overestimation of the likelihood of significant findings, even by researchers with direct knowledge of the dataset2,3,4,5. Our findings show that analytical flexibility can have substantial effects on scientific conclusions, and identify factors that may be related to variability in the analysis of functional magnetic resonance imaging. The results emphasize the importance of validating and sharing complex analysis workflows, and demonstrate the need for performing and reporting multiple analyses of the same data. Potential approaches that could be used to mitigate issues related to analytical variability are discussed.
  • 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.

    Additional information

    Supplementary data
  • 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
  • Francks, C. (2020). Peer Review Report For: Heritability of language laterality assessed by functional transcranial Doppler ultrasound: a twin study [version 2; peer review: 1 approved, 2 approved with reservations] Wellcome Open Research 2020, 4:161. doi:10.21956/wellcomeopenres.17276.r38148.
  • 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.
  • Howe, L. J., Hemani, G., Lesseur, C., Gaborieau, V., Ludwig, K. U., Mangold, E., Brennan, P., Ness, A. R., St Pourcain, B., Smith, G. D., & Lewis, S. J. (2020). Evaluating shared genetic influences on nonsyndromic cleft lip/palate and oropharyngeal neoplasms. Genetic Epidemiology, 44(8), 924-933. doi:10.1002/gepi.22343.

    Abstract

    It has been hypothesised that nonsyndromic cleft lip/palate (nsCL/P) and cancer may share aetiological risk factors. Population studies have found inconsistent evidence for increased incidence of cancer in nsCL/P cases, but several genes (e.g.,CDH1,AXIN2) have been implicated in the aetiologies of both phenotypes. We aimed to evaluate shared genetic aetiology between nsCL/P and oral cavity/oropharyngeal cancers (OC/OPC), which affect similar anatomical regions. Using a primary sample of 5,048 OC/OPC cases and 5,450 controls of European ancestry and a replication sample of 750 cases and 336,319 controls from UK Biobank, we estimate genetic overlap using nsCL/P polygenic risk scores (PRS) with Mendelian randomization analyses performed to evaluate potential causal mechanisms. In the primary sample, we found strong evidence for an association between a nsCL/P PRS and increased odds of OC/OPC (per standard deviation increase in score, odds ratio [OR]: 1.09; 95% confidence interval [CI]: 1.04, 1.13;p = .000053). Although confidence intervals overlapped with the primary estimate, we did not find confirmatory evidence of an association between the PRS and OC/OPC in UK Biobank (OR 1.02; 95% CI: 0.95, 1.10;p = .55). Mendelian randomization analyses provided evidence that major nsCL/P risk variants are unlikely to influence OC/OPC. Our findings suggest possible shared genetic influences on nsCL/P and OC/OPC.

    Additional information

    Supporting information
  • 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.
  • Kong, X., Boedhoe, P. S. W., Abe, Y., Alonso, P., Ameis, S. H., Arnold, P. D., Assogna, F., Baker, J. T., Batistuzzo, M. C., Benedetti, F., Beucke, J. C., Bollettini, I., Bose, A., Brem, S., Brennan, B. P., Buitelaar, J., Calvo, R., Cheng, Y., Cho, K. I. K., Dallaspezia, S. and 71 moreKong, X., Boedhoe, P. S. W., Abe, Y., Alonso, P., Ameis, S. H., Arnold, P. D., Assogna, F., Baker, J. T., Batistuzzo, M. C., Benedetti, F., Beucke, J. C., Bollettini, I., Bose, A., Brem, S., Brennan, B. P., Buitelaar, J., Calvo, R., Cheng, Y., Cho, K. I. K., Dallaspezia, S., Denys, D., Ely, B. A., Feusner, J., Fitzgerald, K. D., Fouche, J.-P., Fridgeirsson, E. A., Glahn, D. C., Gruner, P., Gürsel, D. A., Hauser, T. U., Hirano, Y., Hoexter, M. Q., Hu, H., Huyser, C., James, A., Jaspers-Fayer, F., Kathmann, N., Kaufmann, C., Koch, K., Kuno, M., Kvale, G., Kwon, J. S., Lazaro, L., Liu, Y., Lochner, C., Marques, P., Marsh, R., Martínez-Zalacaín, I., Mataix-Cols, D., Medland, S. E., Menchón, J. M., Minuzzi, L., Moreira, P. S., Morer, A., Morgado, P., Nakagawa, A., Nakamae, T., Nakao, T., Narayanaswamy, J. C., Nurmi, E. L., O'Neill, J., Pariente, J. C., Perriello, C., Piacentini, J., Piras, F., Piras, F., Pittenger, C., Reddy, Y. J., Rus-Oswald, O. G., Sakai, Y., Sato, J. R., Schmaal, L., Simpson, H. B., Soreni, N., Soriano-Mas, C., Spalletta, G., Stern, E. R., Stevens, M. C., Stewart, S. E., Szeszko, P. R., Tolin, D. F., Tsuchiyagaito, A., Van Rooij, D., Van Wingen, G. A., Venkatasubramanian, G., Wang, Z., Yun, J.-Y., ENIGMA-OCD Working Group, Thompson, P. M., Stein, D. J., Van den Heuvel, O. A., & Francks, C. (2020). Mapping cortical and subcortical asymmetry in obsessive-compulsive disorder: Findings from the ENIGMA Consortium. Biological Psychiatry, 87(12), 1022-1034. doi:10.1016/j.biopsych.2019.04.022.

    Abstract

    Objective

    Lateralized dysfunction has been suggested in Obsessive-Compulsive Disorder (OCD). However, it is currently unclear whether OCD is characterized by abnormal patterns of structural brain asymmetry. Here we carried out by far the largest study of brain structural asymmetry in OCD.
    Method

    We studied a collection of 16 pediatric datasets (501 OCD patients and 439 healthy controls), as well as 30 adult datasets (1777 patients and 1654 controls) from the OCD Working Group within the ENIGMA (Enhancing Neuro-Imaging Genetics through Meta-Analysis) consortium. Asymmetries of the volumes of subcortical structures, and of regional cortical thickness and surface area measures, were assessed based on T1-weighted MRI scans, using harmonized image analysis and quality control protocols. We investigated possible alterations of brain asymmetry in OCD patients. We also explored potential associations of asymmetry with specific aspects of the disorder and medication status.
    Results

    In the pediatric datasets, the largest case-control differences were observed for volume asymmetry of the thalamus (more leftward; Cohen’s d = 0.19) and the pallidum (less leftward; d = -0.21). Additional analyses suggested putative links between these asymmetry patterns and medication status, OCD severity, and/or anxiety and depression comorbidities. No significant case-control differences were found in the adult datasets.
    Conclusions

    The results suggest subtle changes of the average asymmetry of subcortical structures in pediatric OCD, which are not detectable in adults with the disorder. These findings may reflect altered neurodevelopmental processes in OCD.
  • Liang, S., Deng, W., Li, X., Wang, Q., Greenshaw, A. J., Guo, W., Kong, X., Li, M., Zhao, L., Meng, Y., Zhang, C., Yu, H., Li, X.-m., Ma, X., & Li, T. (2020). Aberrant posterior cingulate connectivity classify first-episode schizophrenia from controls: A machine learning study. Schizophrenia Research, 220, 187-193. doi:10.1016/j.schres.2020.03.022.

    Abstract

    Background

    Posterior cingulate cortex (PCC) is a key aspect of the default mode network (DMN). Aberrant PCC functional connectivity (FC) is implicated in schizophrenia, but the potential for PCC related changes as biological classifier of schizophrenia has not yet been evaluated.
    Methods

    We conducted a data-driven approach using resting-state functional MRI data to explore differences in PCC-based region- and voxel-wise FC patterns, to distinguish between patients with first-episode schizophrenia (FES) and demographically matched healthy controls (HC). Discriminative PCC FCs were selected via false discovery rate estimation. A gradient boosting classifier was trained and validated based on 100 FES vs. 93 HC. Subsequently, classification models were tested in an independent dataset of 87 FES patients and 80 HC using resting-state data acquired on a different MRI scanner.
    Results

    Patients with FES had reduced connectivity between PCC and frontal areas, left parahippocampal regions, left anterior cingulate cortex, and right inferior parietal lobule, but hyperconnectivity with left lateral temporal regions. Predictive voxel-wise clusters were similar to region-wise selected brain areas functionally connected with PCC in relation to discriminating FES from HC subject categories. Region-wise analysis of FCs yielded a relatively high predictive level for schizophrenia, with an average accuracy of 72.28% in the independent samples, while selected voxel-wise connectivity yielded an accuracy of 68.72%.
    Conclusion

    FES exhibited a pattern of both increased and decreased PCC-based connectivity, but was related to predominant hypoconnectivity between PCC and brain areas associated with DMN, that may be a useful differential feature revealing underpinnings of neuropathophysiology for schizophrenia.
  • 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
  • Schijven, D., Zinkstok, J. R., & Luykx, J. J. (2020). Van genetische bevindingen naar de klinische praktijk van de psychiater: Hoe genetica precisiepsychiatrie mogelijk kan maken. Tijdschrift voor Psychiatrie, 62(9), 776-783.
  • Shin, J., Ma, S., Hofer, E., Patel, Y., Vosberg, D. E., Tilley, S., Roshchupkin, G. V., Sousa, A. M. M., Jian, X., Gottesman, R., Mosley, T. H., Fornage, M., Saba, Y., Pirpamer, L., Schmidt, R., Schmidt, H., Carrion Castillo, A., Crivello, F., Mazoyer, B., Bis, J. C. and 49 moreShin, J., Ma, S., Hofer, E., Patel, Y., Vosberg, D. E., Tilley, S., Roshchupkin, G. V., Sousa, A. M. M., Jian, X., Gottesman, R., Mosley, T. H., Fornage, M., Saba, Y., Pirpamer, L., Schmidt, R., Schmidt, H., Carrion Castillo, A., Crivello, F., Mazoyer, B., Bis, J. C., Li, S., Yang, Q., Luciano, M., Karama, S., Lewis, L., Bastin, M. E., Harris, M. A., Wardlaw, J. M., Deary, I. E., Scholz, M., Loeffler, M., Witte, A. V., Beyer, F., Villringer, A., Armstrong, N. F., Mather, K. A., Ames, D., Jiang, J., Kwok, J. B., Schofield, P. R., Thalamuthu, A., Trollor, J. N., Wright, M. J., Brodaty, H., Wen, W., Sachdev, P. S., Terzikhan, N., Evans, T. E., Adams, H. H. H. H., Ikram, M. A., Frenzel, S., Van der Auwera-Palitschka, S., Wittfeld, K., Bülow, R., Grabe, H. J., Tzourio, C., Mishra, A., Maingault, S., Debette, S., Gillespie, N. A., Franz, C. E., Kremen, W. S., Ding, L., Jahanshad, N., the ENIGMA Consortium, Sestan, N., Pausova, Z., Seshadri, S., Paus, T., & the neuroCHARGE Working Group (2020). Global and regional development of the human cerebral cortex: Molecular acrchitecture and occupational aptitudes. Cerebral Cortex, 30(7), 4121-4139. doi:10.1093/cercor/bhaa035.

    Abstract

    We have carried out meta-analyses of genome-wide association studies (GWAS) (n = 23 784) of the first two principal components (PCs) that group together cortical regions with shared variance in their surface area. PC1 (global) captured variations of most regions, whereas PC2 (visual) was specific to the primary and secondary visual cortices. We identified a total of 18 (PC1) and 17 (PC2) independent loci, which were replicated in another 25 746 individuals. The loci of the global PC1 included those associated previously with intracranial volume and/or general cognitive function, such as MAPT and IGF2BP1. The loci of the visual PC2 included DAAM1, a key player in the planar-cell-polarity pathway. We then tested associations with occupational aptitudes and, as predicted, found that the global PC1 was associated with General Learning Ability, and the visual PC2 was associated with the Form Perception aptitude. These results suggest that interindividual variations in global and regional development of the human cerebral cortex (and its molecular architecture) cascade—albeit in a very limited manner—to behaviors as complex as the choice of one’s occupation.
  • 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.

    Additional information

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