Displaying 1 - 100 of 362
  • 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 64 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., Labate, A., Sisodiya, S. M., Thompson, P. M., McDonald, C. R., Bernasconi, A., Bernasconi, N., & Bernhardt, B. C. (in press). Topographic divergence of atypical cortical asymmetry and atrophy patterns in temporal lobe epilepsy. Brain.

    Abstract

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  • Schlag, F., Allegrini, A. G., Buitelaar, J., Verhoef, E., Van Donkelaar, M. M. J., Plomin, R., Rimfeld, K., Fisher, S. E., & St Pourcain, B. (in press). Polygenic risk for mental disorder reveals distinct association profiles across social behaviour in the general population. Molecular Psychiatry.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Guadalupe, T., Kong, X., Akkermans, S. E. A., Fisher, S. E., & Francks, C. (2021). Relations between hemispheric asymmetries of grey matter and auditory processing of spoken syllables in 281 healthy adults. Brain Structure & Function. Advance online publication. 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
  • 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., 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
  • Postema, M. (2021). Left-right asymmetry of the human brain: Associations with neurodevelopmental disorders and genetic factors. PhD Thesis, Radboud University Nijmegen, Nijmegen.
  • 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. Advance online publication. 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., 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.
  • 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.
  • 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., Vino, A., Den Hoed, J., Underhill, H. R., Monteil, D., Li, H., Reynoso Santos, F. J., Chung, W. K., Amaral, M. D., Schnur, R. E., Santiago-Sim, T., Si, Y., Brunner, H. G., Kleefstra, T., & Fisher, S. E. (2021). Heterozygous variants that disturb the transcriptional repressor activity of FOXP4 cause a developmental disorder with speech/language delays and multiple congenital abnormalities. Genetics in Medicine, 23, 534-542. doi:10.1038/s41436-020-01016-6.

    Abstract

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

    Abstract

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

    Additional information

    supporting information
  • 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 (2021). 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. Advance online publication. 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.
  • 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., 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
  • 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 origins of genetic factors influencing language and literacy: Associations with early-childhood vocabulary. Journal of Child Psychology and Psychiatry, 62(6), 728-738. doi:10.1111/jcpp.13327.

    Abstract

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

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    supporting information
  • 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
  • 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.

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    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.

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    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.

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    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.
  • 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., 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.
  • 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.
  • 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.

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

    Abstract

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

    Additional information

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

    Abstract

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

    Abstract

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

    Abstract

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

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  • Blasi, D. E., Moran, S., Moisik, S. R., Widmer, P., Dediu, D., & Bickel, B. (2019). Human sound systems are shaped by post-Neolithic changes in bite configuration. Science, 363(6432): eaav3218. doi:10.1126/science.aav3218.

    Abstract

    Linguistic diversity, now and in the past, is widely regarded to be independent of biological changes that took place after the emergence of Homo sapiens. We show converging evidence from paleoanthropology, speech biomechanics, ethnography, and historical linguistics that labiodental sounds (such as “f” and “v”) were innovated after the Neolithic. Changes in diet attributable to food-processing technologies modified the human bite from an edge-to-edge configuration to one that preserves adolescent overbite and overjet into adulthood. This change favored the emergence and maintenance of labiodentals. Our findings suggest that language is shaped not only by the contingencies of its history, but also by culturally induced changes in human biology.

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

    Abstract

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

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

    Abstract

    FOXP proteins form a subfamily of evolutionarily conserved transcription factors involved in the development and functioning of several tissues, including the central nervous system. In humans, mutations in FOXP1 and FOXP2 have been implicated in cognitive deficits including intellectual disability and speech disorders. Drosophila exhibits a single ortholog, called FoxP, but due to a lack of characterized mutants, our understanding of the gene remains poor. Here we show that the dimerization property required for mammalian FOXP function is conserved in Drosophila. In flies, FoxP is enriched in the adult brain, showing strong expression in ~1000 neurons of cholinergic, glutamatergic and GABAergic nature. We generate Drosophila loss-of-function mutants and UAS-FoxP transgenic lines for ectopic expression, and use them to characterize FoxP function in the nervous system. At the cellular level, we demonstrate that Drosophila FoxP is required in larvae for synaptic morphogenesis at axonal terminals of the neuromuscular junction and for dendrite development of dorsal multidendritic sensory neurons. In the developing brain, we find that FoxP plays important roles in α-lobe mushroom body formation. Finally, at a behavioral level, we show that Drosophila FoxP is important for locomotion, habituation learning and social space behavior of adult flies. Our work shows that Drosophila FoxP is important for regulating several neurodevelopmental processes and behaviors that are related to human disease or vertebrate disease model phenotypes. This suggests a high degree of functional conservation with vertebrate FOXP orthologues and established flies as a model system for understanding FOXP related pathologies.
  • Dediu, D., & Moisik, S. R. (2019). Pushes and pulls from below: Anatomical variation, articulation and sound change. Glossa: A Journal of General Linguistics, 4(1): 7. doi:10.5334/gjgl.646.

    Abstract

    This paper argues that inter-individual and inter-group variation in language acquisition, perception, processing and production, rooted in our biology, may play a largely neglected role in sound change. We begin by discussing the patterning of these differences, highlighting those related to vocal tract anatomy with a foundation in genetics and development. We use our ArtiVarK database, a large multi-ethnic sample comprising 3D intraoral optical scans, as well as structural, static and real-time MRI scans of vocal tract anatomy and speech articulation, to quantify the articulatory strategies used to produce the North American English /r/ and to statistically show that anatomical factors seem to influence these articulatory strategies. Building on work showing that these alternative articulatory strategies may have indirect coarticulatory effects, we propose two models for how biases due to variation in vocal tract anatomy may affect sound change. The first involves direct overt acoustic effects of such biases that are then reinterpreted by the hearers, while the second is based on indirect coarticulatory phenomena generated by acoustically covert biases that produce overt “at-a-distance” acoustic effects. This view implies that speaker communities might be “poised” for change because they always contain pools of “standing variation” of such biased speakers, and when factors such as the frequency of the biased speakers in the community, their positions in the communicative network or the topology of the network itself change, sound change may rapidly follow as a self-reinforcing network-level phenomenon, akin to a phase transition. Thus, inter-speaker variation in structured and dynamic communicative networks may couple the initiation and actuation of sound change.
  • Dediu, D., Janssen, R., & Moisik, S. R. (2019). Weak biases emerging from vocal tract anatomy shape the repeated transmission of vowels. Nature Human Behaviour, 3, 1107-1115. doi:10.1038/s41562-019-0663-x.

    Abstract

    Linguistic diversity is affected by multiple factors, but it is usually assumed that variation in the anatomy of our speech organs plays no explanatory role. Here we use realistic computer models of the human speech organs to test whether inter-individual and inter-group variation in the shape of the hard palate (the bony roof of the mouth) affects acoustics of speech sounds. Based on 107 midsagittal MRI scans of the hard palate of human participants, we modelled with high accuracy the articulation of a set of five cross-linguistically representative vowels by agents learning to produce speech sounds. We found that different hard palate shapes result in subtle differences in the acoustics and articulatory strategies of the produced vowels, and that these individual-level speech idiosyncrasies are amplified by the repeated transmission of language across generations. Therefore, we suggest that, besides culture and environment, quantitative biological variation can be amplified, also influencing language.
  • Demontis, D., Walters, R. K., Martin, J., Mattheisen, M., Als, T. D., Agerbo, E., Baldursson, G., Belliveau, R., Bybjerg-Grauholm, J., Bækvad-Hansen, M., Cerrato, F., Chambert, K., Churchhouse, C., Dumont, A., Eriksson, N., Gandal, M., Goldstein, J. I., Grasby, K. L., Grove, J., Gudmundsson, O. O. and 61 moreDemontis, D., Walters, R. K., Martin, J., Mattheisen, M., Als, T. D., Agerbo, E., Baldursson, G., Belliveau, R., Bybjerg-Grauholm, J., Bækvad-Hansen, M., Cerrato, F., Chambert, K., Churchhouse, C., Dumont, A., Eriksson, N., Gandal, M., Goldstein, J. I., Grasby, K. L., Grove, J., Gudmundsson, O. O., Hansen, C. S., Hauberg, M. E., Hollegaard, M. V., Howrigan, D. P., Huang, H., Maller, J. B., Martin, A. R., Martin, N. G., Moran, J., Pallesen, J., Palmer, D. S., Pedersen, C. B., Pedersen, M. G., Poterba, T., Poulsen, J. B., Ripke, S., Robinson, E. B., Satterstrom, F. K., Stefansson, H., Stevens, C., Turley, P., Walters, G. B., Won, H., Wright, M. J., ADHD Working Group of the Psychiatric Genomics Consortium (PGC), EArly Genetics and Lifecourse Epidemiology (EAGLE) Consortium, 23andme Research Team, Andreassen, O. A., Asherson, P., Burton, C. L., Boomsma, D. I., Cormand, B., Dalsgaard, S., Franke, B., Gelernter, J., Geschwind, D., Hakonarson, H., Haavik, J., Kranzler, H. R., Kuntsi, J., Langley, K., Lesch, K.-P., Middeldorp, C., Reif, A., Rohde, L. A., Roussos, P., Schachar, R., Sklar, P., Sonuga-Barke, E. J. S., Sullivan, P. F., Thapar, A., Tung, J. Y., Waldman, I. D., Medland, S. E., Stefansson, K., Nordentoft, M., Hougaard, D. M., Werge, T., Mors, O., Mortensen, P. B., Daly, M. J., Faraone, S. V., Børglum, A. D., & Neale, B. (2019). Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder. Nature Genetics, 51, 63-75. doi:10.1038/s41588-018-0269-7.

    Abstract

    Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits.
  • Devanna, P., Dediu, D., & Vernes, S. C. (2019). The Genetics of Language: From complex genes to complex communication. In S.-A. Rueschemeyer, & M. G. Gaskell (Eds.), The Oxford Handbook of Psycholinguistics (2nd ed., pp. 865-898). Oxford: Oxford University Press.

    Abstract

    This chapter discusses the genetic foundations of the human capacity for language. It reviews the molecular structure of the genome and the complex molecular mechanisms that allow genetic information to influence multiple levels of biology. It goes on to describe the active regulation of genes and their formation of complex genetic pathways that in turn control the cellular environment and function. At each of these levels, examples of genes and genetic variants that may influence the human capacity for language are given. Finally, it discusses the value of using animal models to understand the genetic underpinnings of speech and language. From this chapter will emerge the complexity of the genome in action and the multidisciplinary efforts that are currently made to bridge the gap between genetics and language.
  • Eising, E., Carrion Castillo, A., Vino, A., Strand, E. A., Jakielski, K. J., Scerri, T. S., Hildebrand, M. S., Webster, R., Ma, A., Mazoyer, B., Francks, C., Bahlo, M., Scheffer, I. E., Morgan, A. T., Shriberg, L. D., & Fisher, S. E. (2019). A set of regulatory genes co-expressed in embryonic human brain is implicated in disrupted speech development. Molecular Psychiatry, 24, 1065-1078. doi:10.1038/s41380-018-0020-x.

    Abstract

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

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  • Fisher, S. E., & Tilot, A. K. (Eds.). (2019). Bridging senses: Novel insights from synaesthesia [Special Issue]. Philosophical Transactions of the Royal Society of London, Series B: Biological Sciences, 374.
  • Fisher, S. E., & Tilot, A. K. (2019). Bridging senses: Novel insights from synaesthesia. Philosophical Transactions of the Royal Society of London, Series B: Biological Sciences, 374: 20190022. doi:10.1098/rstb.2019.0022.
  • Fisher, S. E. (2019). Key issues and future directions: Genes and language. In P. Hagoort (Ed.), Human language: From genes and brain to behavior (pp. 609-620). Cambridge, MA: MIT Press.
  • Fisher, S. E. (2019). Human genetics: The evolving story of FOXP2. Current Biology, 29(2), R65-R67. doi:10.1016/j.cub.2018.11.047.

    Abstract

    FOXP2 mutations cause a speech and language disorder, raising interest in potential roles of this gene in human evolution. A new study re-evaluates genomic variation at the human FOXP2 locus but finds no evidence of recent adaptive evolution.
  • Francks, C. (2019). In search of the biological roots of typical and atypical human brain asymmetry. Physics of Life Reviews, 30, 22-24. doi:10.1016/j.plrev.2019.07.004.
  • Francks, C. (2019). Peer Review Report For: Negligible heritability of language laterality assessed by functional transcranial Doppler ultrasound: a twin study [version 1; peer review: 1 approved with reservations]. Wellcome Open Research 2019, 4:161. doi:10.21956/wellcomeopenres.16993.r36877.
  • Francks, C. (2019). The genetic bases of brain lateralization. In P. Hagoort (Ed.), Human language: From genes and brain to behavior (pp. 595-608). Cambridge, MA: MIT Press.
  • French, C. A., Vinueza Veloz, M. F., Zhou, K., Peter, S., Fisher, S. E., Costa, R. M., & De Zeeuw, C. I. (2019). Differential effects of Foxp2 disruption in distinct motor circuits. Molecular Psychiatry, 24, 447-462. doi:10.1038/s41380-018-0199-x.

    Abstract

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

    Abstract

    Developmental dyslexia (DD) is one of the most prevalent learning disorders, with high impact on school and psychosocial development and high comorbidity with conditions like attention-deficit hyperactivity disorder (ADHD), depression, and anxiety. DD is characterized by deficits in different cognitive skills, including word reading, spelling, rapid naming, and phonology. To investigate the genetic basis of DD, we conducted a genome-wide association study (GWAS) of these skills within one of the largest studies available, including nine cohorts of reading-impaired and typically developing children of European ancestry (N = 2562–3468). We observed a genome-wide significant effect (p < 1 × 10−8) on rapid automatized naming of letters (RANlet) for variants on 18q12.2, within MIR924HG (micro-RNA 924 host gene; rs17663182 p = 4.73 × 10−9), and a suggestive association on 8q12.3 within NKAIN3 (encoding a cation transporter; rs16928927, p = 2.25 × 10−8). rs17663182 (18q12.2) also showed genome-wide significant multivariate associations with RAN measures (p = 1.15 × 10−8) and with all the cognitive traits tested (p = 3.07 × 10−8), suggesting (relational) pleiotropic effects of this variant. A polygenic risk score (PRS) analysis revealed significant genetic overlaps of some of the DD-related traits with educational attainment (EDUyears) and ADHD. Reading and spelling abilities were positively associated with EDUyears (p ~ [10−5–10−7]) and negatively associated with ADHD PRS (p ~ [10−8−10−17]). This corroborates a long-standing hypothesis on the partly shared genetic etiology of DD and ADHD, at the genome-wide level. Our findings suggest new candidate DD susceptibility genes and provide new insights into the genetics of dyslexia and its comorbities.
  • Grove, J., Ripke, S., Als, T. D., Mattheisen, M., Walters, R., Won, H., Pallesen, J., Agerbo, E., Andreassen, O. A., Anney, R., Belliveau, R., Bettella, F., Buxbaum, J. D., Bybjerg-Grauholm, J., Bækved-Hansen, M., Cerrato, F., Chambert, K., Christensen, J. H., Churchhouse, C., Dellenvall, K. and 55 moreGrove, J., Ripke, S., Als, T. D., Mattheisen, M., Walters, R., Won, H., Pallesen, J., Agerbo, E., Andreassen, O. A., Anney, R., Belliveau, R., Bettella, F., Buxbaum, J. D., Bybjerg-Grauholm, J., Bækved-Hansen, M., Cerrato, F., Chambert, K., Christensen, J. H., Churchhouse, C., Dellenvall, K., Demontis, D., De Rubeis, S., Devlin, B., Djurovic, S., Dumont, A., Goldstein, J., Hansen, C. S., Hauberg, M. E., Hollegaard, M. V., Hope, S., Howrigan, D. P., Huang, H., Hultman, C., Klei, L., Maller, J., Martin, J., Martin, A. R., Moran, J., Nyegaard, M., Nærland, T., Palmer, D. S., Palotie, A., Pedersen, C. B., Pedersen, M. G., Poterba, T., Poulsen, J. B., St Pourcain, B., Qvist, P., Rehnström, K., Reichenberg, A., Reichert, J., Robinson, E. B., Roeder, K., Roussos, P., Saemundsen, E., Sandin, S., Satterstrom, F. K., Smith, G. D., Stefansson, H., Stefansson, K., Steinberg, S., Stevens, C., Sullivan, P. F., Turley, P., Walters, G. B., Xu, X., Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium, BUPGEN, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Me Research Team, Geschwind, D., Nordentoft, M., Hougaard, D. M., Werge, T., Mors, O., Mortensen, P. B., Neale, B. M., Daly, M. J., & Børglum, A. D. (2019). Identification of common genetic risk variants for autism spectrum disorder. Nature Genetics, 51, 431-444. doi:10.1038/s41588-019-0344-8.

    Abstract

    Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls that identified five genome-wide-significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), we identified seven additional loci shared with other traits at equally strict significance levels. Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis, and establish that GWAS performed at scale will be much more productive in the near term in ASD.

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  • Gunz, P., Tilot, A. K., Wittfeld, K., Teumer, A., Shapland, C. Y., Van Erp, T. G. M., Dannemann, M., Vernot, B., Neubauer, S., Guadalupe, T., Fernandez, G., Brunner, H., Enard, W., Fallon, J., Hosten, N., Völker, U., Profico, A., Di Vincenzo, F., Manzi, G., Kelso, J. and 7 moreGunz, P., Tilot, A. K., Wittfeld, K., Teumer, A., Shapland, C. Y., Van Erp, T. G. M., Dannemann, M., Vernot, B., Neubauer, S., Guadalupe, T., Fernandez, G., Brunner, H., Enard, W., Fallon, J., Hosten, N., Völker, U., Profico, A., Di Vincenzo, F., Manzi, G., Kelso, J., St Pourcain, B., Hublin, J.-J., Franke, B., Pääbo, S., Macciardi, F., Grabe, H. J., & Fisher, S. E. (2019). Neandertal introgression sheds light on modern human endocranial globularity. Current Biology, 29(1), 120-127. doi:10.1016/j.cub.2018.10.065.

    Abstract

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

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  • Harneit, A., Braun, U., Geiger, L. S., Zang, Z., Hakobjan, M., Van Donkelaar, M. M. J., Schweiger, J. I., Schwarz, K., Gan, G., Erk, S., Heinz, A., Romanczuk‐Seiferth, N., Witt, S., Rietschel, M., Walter, H., Franke, B., Meyer‐Lindenberg, A., & Tost, H. (2019). MAOA-VNTR genotype affects structural and functional connectivity in distributed brain networks. Human Brain Mapping, 40(18), 5202-5212. doi:10.1002/hbm.24766.

    Abstract

    Previous studies have linked the low expression variant of a variable number of tandem repeat polymorphism in the monoamine oxidase A gene (MAOA‐L) to the risk for impulsivity and aggression, brain developmental abnormalities, altered cortico‐limbic circuit function, and an exaggerated neural serotonergic tone. However, the neurobiological effects of this variant on human brain network architecture are incompletely understood. We studied healthy individuals and used multimodal neuroimaging (sample size range: 219–284 across modalities) and network‐based statistics (NBS) to probe the specificity of MAOA‐L‐related connectomic alterations to cortical‐limbic circuits and the emotion processing domain. We assessed the spatial distribution of affected links across several neuroimaging tasks and data modalities to identify potential alterations in network architecture. Our results revealed a distributed network of node links with a significantly increased connectivity in MAOA‐L carriers compared to the carriers of the high expression (H) variant. The hyperconnectivity phenotype primarily consisted of between‐lobe (“anisocoupled”) network links and showed a pronounced involvement of frontal‐temporal connections. Hyperconnectivity was observed across functional magnetic resonance imaging (fMRI) of implicit emotion processing (pFWE = .037), resting‐state fMRI (pFWE = .022), and diffusion tensor imaging (pFWE = .044) data, while no effects were seen in fMRI data of another cognitive domain, that is, spatial working memory (pFWE = .540). These observations are in line with prior research on the MAOA‐L variant and complement these existing data by novel insights into the specificity and spatial distribution of the neurogenetic effects. Our work highlights the value of multimodal network connectomic approaches for imaging genetics.
  • Haworth, S., Shapland, C. Y., Hayward, C., Prins, B. P., Felix, J. F., Medina-Gomez, C., Rivadeneira, F., Wang, C., Ahluwalia, T. S., Vrijheid, M., Guxens, M., Sunyer, J., Tachmazidou, I., Walter, K., Iotchkova, V., Jackson, A., Cleal, L., Huffmann, J., Min, J. L., Sass, L. and 15 moreHaworth, S., Shapland, C. Y., Hayward, C., Prins, B. P., Felix, J. F., Medina-Gomez, C., Rivadeneira, F., Wang, C., Ahluwalia, T. S., Vrijheid, M., Guxens, M., Sunyer, J., Tachmazidou, I., Walter, K., Iotchkova, V., Jackson, A., Cleal, L., Huffmann, J., Min, J. L., Sass, L., Timmers, P. R. H. J., UK10K consortium, Davey Smith, G., Fisher, S. E., Wilson, J. F., Cole, T. J., Fernandez-Orth, D., Bønnelykke, K., Bisgaard, H., Pennell, C. E., Jaddoe, V. W. V., Dedoussis, G., Timpson, N. J., Zeggini, E., Vitart, V., & St Pourcain, B. (2019). Low-frequency variation in TP53 has large effects on head circumference and intracranial volume. Nature Communications, 10: 357. doi:10.1038/s41467-018-07863-x.

    Abstract

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

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  • Howe, L. J., Richardson, T. G., Arathimos, R., Alvizi, L., Passos-Bueno, M. R., Stanier, P., Nohr, E., Ludwig, K. U., Mangold, E., Knapp, M., Stergiakouli, E., St Pourcain, B., Smith, G. D., Sandy, J., Relton, C. L., Lewis, S. J., Hemani, G., & Sharp, G. C. (2019). Evidence for DNA methylation mediating genetic liability to non-syndromic cleft lip/palate. Epigenomics, 11(2), 133-145. doi:10.2217/epi-2018-0091.

    Abstract

    Aim: To determine if nonsyndromic cleft lip with or without cleft palate (nsCL/P) genetic risk variants influence liability to nsCL/P through gene regulation pathways, such as those involving DNA methylation. Materials & methods: nsCL/P genetic summary data and methylation data from four studies were used in conjunction with Mendelian randomization and joint likelihood mapping to investigate potential mediation of nsCL/P genetic variants. Results & conclusion: Evidence was found at VAX1 (10q25.3), LOC146880 (17q23.3) and NTN1 (17p13.1), that liability to nsCL/P and variation in DNA methylation might be driven by the same genetic variant, suggesting that genetic variation at these loci may increase liability to nsCL/P by influencing DNA methylation. Follow-up analyses using different tissues and gene expression data provided further insight into possible biological mechanisms.

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  • Howe, L., Lawson, D. J., Davies, N. M., St Pourcain, B., Lewis, S. J., Smith, G. D., & Hemani, G. (2019). Genetic evidence for assortative mating on alcohol consumption in the UK Biobank. Nature Communications, 10: 5039. doi:10.1038/s41467-019-12424-x.

    Abstract

    Alcohol use is correlated within spouse-pairs, but it is difficult to disentangle effects of alcohol consumption on mate-selection from social factors or the shared spousal environment. We hypothesised that genetic variants related to alcohol consumption may, via their effect on alcohol behaviour, influence mate selection. Here, we find strong evidence that an individual’s self-reported alcohol consumption and their genotype at rs1229984, a missense variant in ADH1B, are associated with their partner’s self-reported alcohol use. Applying Mendelian randomization, we estimate that a unit increase in an individual’s weekly alcohol consumption increases partner’s alcohol consumption by 0.26 units (95% C.I. 0.15, 0.38; P = 8.20 × 10−6). Furthermore, we find evidence of spousal genotypic concordance for rs1229984, suggesting that spousal concordance for alcohol consumption existed prior to cohabitation. Although the SNP is strongly associated with ancestry, our results suggest some concordance independent of population stratification. Our findings suggest that alcohol behaviour directly influences mate selection.
  • Ioumpa, K., Graham, S. A., Clausner, T., Fisher, S. E., Van Lier, R., & Van Leeuwen, T. M. (2019). Enhanced self-reported affect and prosocial behaviour without differential physiological responses in mirror-sensory synaesthesia. Philosophical Transactions of the Royal Society of London, Series B: Biological Sciences, 374: 20190395. doi:10.1098/rstb.2019.0395.

    Abstract

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

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  • Janssen, R., Moisik, S. R., & Dediu, D. (2019). The effects of larynx height on vowel production are mitigated by the active control of articulators. Journal of Phonetics, 74, 1-17. doi:10.1016/j.wocn.2019.02.002.

    Abstract

    The influence of larynx position on vowel articulation is an important topic in understanding speech production, the present-day distribution of linguistic diversity and the evolution of speech and language in our lineage. We introduce here a realistic computer model of the vocal tract, constructed from actual human MRI data, which can learn, using machine learning techniques, to control the articulators in such a way as to produce speech sounds matching as closely as possible to a given set of target vowels. We systematically control the vertical position of the larynx and we quantify the differences between the target and produced vowels for each such position across multiple replications. We report that, indeed, larynx height does affect the accuracy of reproducing the target vowels and the distinctness of the produced vowel system, that there is a “sweet spot” of larynx positions that are optimal for vowel production, but that nevertheless, even extreme larynx positions do not result in a collapsed or heavily distorted vowel space that would make speech unintelligible. Together with other lines of evidence, our results support the view that the vowel space of human languages is influenced by our larynx position, but that other positions of the larynx may also be fully compatible with speech.

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  • Klingler, E., De la Rossa, A., Fièvre, S., Devaraju, K., Abe, P., & Jabaudon, D. (2019). A translaminar genetic logic for the circuit identity of intracortically projecting neurons. Current Biology, 29(2), 332-339. doi:10.1016/j.cub.2018.11.071.

    Abstract

    Neurons of the neocortex are organized into six radial layers, which have appeared at different times during evolution, with the superficial layers representing a more recent acquisition. Input to the neocortex predominantly reaches superficial layers (SL, i.e., layers (L) 2-4), while output is generated in deep layers (DL, i.e., L5-6) [1]. Intracortical connections, which bridge input and output pathways, are key components of cortical circuits because they allow the propagation and processing of information within the neocortex. Two main types of intracortically projecting neurons (ICPN) can be distinguished by their axonal features: L4 spiny stellate neurons (SSN) with short axons projecting locally within cortical columns [2, 3, 4, 5], and SL and DL long-range projection neurons, including callosally projecting neurons (CPNSL and CPNDL) [5, 6]. Here, we investigate the molecular hallmarks that distinguish SSN, CPNSL, and CPNDL and relate their transcriptional signatures with their output connectivity. Specifically, taking advantage of the presence of CPN in both SL and DL, we identify lamina-independent genetic hallmarks of a constant projection motif (i.e., interhemispheric projection). By performing unbiased transcriptomic comparisons between CPNSL, CPNDL and SSN, we provide specific molecular profiles for each of these populations and show that target identity supersedes laminar position in defining ICPN transcriptional diversity. Together, these findings reveal a projection-based organization of transcriptional programs across cortical layers, which we propose reflects conserved strategy to protect canonical circuit structure (and hence function) across a diverse range of neuroanatomies.

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  • De Kovel, C. G. F., Carrion Castillo, A., & Francks, C. (2019). A large-scale population study of early life factors influencing left-handedness. Scientific Reports, 9: 584. doi:10.1038/s41598-018-37423-8.

    Abstract

    Hand preference is a conspicuous variation in human behaviour, with a worldwide proportion of around 90% of people preferring to use the right hand for many tasks, and 10% the left hand. We used the large cohort of the UK biobank (~500,000 participants) to study possible relations between early life factors and adult hand preference. The probability of being left-handed was affected by the year and location of birth, likely due to cultural effects. In addition, hand preference was affected by birthweight, being part of a multiple birth, season of birth, breastfeeding, and sex, with each effect remaining significant after accounting for all others. Analysis of genome-wide genotype data showed that left-handedness was very weakly heritable, but shared no genetic basis with birthweight. Although on average left-handers and right-handers differed for a number of early life factors, all together these factors had only a minimal predictive value for individual hand preference.

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  • De Kovel, C. G. F., Aftanas, L., Aleman, A., Alexander-Bloch, A. F., Baune, B. T., Brack, I., Bülow, R., Filho, G. B., Carballedo, A., Connolly, C. G., Cullen, K. R., Dannlowski, U., Davey, C. G., Dima, D., Dohm, K., Erwin-Grabner, T., Frodl, T., Fu, C. H., Hall, G. B., Glahn, D. C. and 58 moreDe Kovel, C. G. F., Aftanas, L., Aleman, A., Alexander-Bloch, A. F., Baune, B. T., Brack, I., Bülow, R., Filho, G. B., Carballedo, A., Connolly, C. G., Cullen, K. R., Dannlowski, U., Davey, C. G., Dima, D., Dohm, K., Erwin-Grabner, T., Frodl, T., Fu, C. H., Hall, G. B., Glahn, D. C., Godlewska, B., Gotlib, I. H., Goya-Maldonado, R., Grabe, H. J., Groenewold, N. A., Grotegerd, D., Gruber, O., Harris, M. A., Harrison, B. J., Hatton, S. N., Hickie, I. B., Ho, T. C., Jahanshad, N., Kircher, T., Krämer, B., Krug, A., Lagopoulos, J., Leehr, E. J., Li, M., MacMaster, F. P., MacQueen, G., McIntosh, A. M., McLellan, Q., Medland, S. E., Mueller, B. A., Nenadic, I., Osipov, E., Papmeyer, M., Portella, M. J., Reneman, L., Rosa, P. G., Sacchet, M. D., Schnell, K., Schrantee, A., Sim, K., Simulionyte, E., Sindermann, L., Singh, A., Stein, D. J., Ubani, B. N., der Wee, N. J. V., der Werff, S. J. V., Veer, I. M., Vives-Gilabert, Y., Völzke, H., Walter, H., Walter, M., Schreiner, M. W., Whalley, H., Winter, N., Wittfeld, K., Yang, T. T., Yüksel, D., Zaremba, D., Thompson, P. M., Veltman, D. J., Schmaal, L., & Francks, C. (2019). No alterations of brain structural asymmetry in major depressive disorder: An ENIGMA consortium analysis. American Journal of Psychiatry, 176(12), 1039-1049. doi:10.1176/appi.ajp.2019.18101144.

    Abstract

    Objective: Asymmetry is a subtle but pervasive aspect of the human brain, and it may be altered in several psychiatric conditions. MRI studies have shown subtle differences of brain anatomy between people with major depressive disorder and healthy control subjects, but few studies have specifically examined brain anatomical asymmetry in relation to this disorder, and results from those studies have remained inconclusive. At the functional level, some electroencephalography studies have indicated left fronto-cortical hypoactivity and right parietal hypoactivity in depressive disorders, so aspects of lateralized anatomy may also be affected. The authors used pooled individual-level data from data sets collected around the world to investigate differences in laterality in measures of cortical thickness, cortical surface area, and subcortical volume between individuals with major depression and healthy control subjects. Methods: The authors investigated differences in the laterality of thickness and surface area measures of 34 cerebral cortical regions in 2,256 individuals with major depression and 3,504 control subjects from 31 separate data sets, and they investigated volume asymmetries of eight subcortical structures in 2,540 individuals with major depression and 4,230 control subjects from 32 data sets. T1-weighted MRI data were processed with a single protocol using FreeSurfer and the Desikan-Killiany atlas. The large sample size provided 80% power to detect effects of the order of Cohen’s d=0.1. Results: The largest effect size (Cohen’s d) of major depression diagnosis was 0.085 for the thickness asymmetry of the superior temporal cortex, which was not significant after adjustment for multiple testing. Asymmetry measures were not significantly associated with medication use, acute compared with remitted status, first episode compared with recurrent status, or age at onset. Conclusions: Altered brain macro-anatomical asymmetry may be of little relevance to major depression etiology in most cases.
  • De Kovel, C. G. F., & Francks, C. (2019). The molecular genetics of hand preference revisited. Scientific Reports, 9: 5986. doi:10.1038/s41598-019-42515-0.

    Abstract

    Hand preference is a prominent behavioural trait linked to human brain asymmetry. A handful of genetic variants have been reported to associate with hand preference or quantitative measures related to it. Most of these reports were on the basis of limited sample sizes, by current standards for genetic analysis of complex traits. Here we performed a genome-wide association analysis of hand preference in the large, population-based UK Biobank cohort (N = 331,037). We used gene-set enrichment analysis to investigate whether genes involved in visceral asymmetry are particularly relevant to hand preference, following one previous report. We found no evidence supporting any of the previously suggested variants or genes, nor that genes involved in visceral laterality have a role in hand preference. It remains possible that some of the previously reported genes or pathways are relevant to hand preference as assessed in other ways, or else are relevant within specific disorder populations. However, some or all of the earlier findings are likely to be false positives, and none of them appear relevant to hand preference as defined categorically in the general population. Our analysis did produce a small number of novel, significant associations, including one implicating the microtubule-associated gene MAP2 in handedness.
  • Liang, S., Li, Y., Zhang, Z., Kong, X., Wang, Q., Deng, W., Li, X., Zhao, L., Li, M., Meng, Y., Huang, F., Ma, X., Li, X.-m., Greenshaw, A. J., Shao, J., & Li, T. (2019). Classification of first-episode schizophrenia using multimodal brain features: A combined structural and diffusion imaging study. Schizophrenia Bulletin, 45(3), 591-599. doi:10.1093/schbul/sby091.

    Abstract

    Schizophrenia is a common and complex mental disorder with neuroimaging alterations. Recent neuroanatomical pattern recognition studies attempted to distinguish individuals with schizophrenia by structural magnetic resonance imaging (sMRI) and diffusion tensor imaging (DTI). 1, 2 Applications of cutting-edge machine learning approaches in structural neuroimaging studies have revealed potential pathways to classification of schizophrenia based on regional gray matter volume (GMV) or density or cortical thickness. 3–5 Additionally, cortical folding may have high discriminatory value in correctly identifying symptom severity in schizophrenia. 6 Regional GMV and cortical thickness have also been combined in attempts to differentiate individuals with schizophrenia from healthy controls (HCs). 7 Applications of machine learning algorithms to diffusion imaging data analysis to predict individuals with first-episode schizophrenia (FES) have achieved encouraging accuracy. 8–10 White matter (WM) abnormalities in schizophrenia as estimated by DTI appear to be present in the early stage of the disorder, most likely reflecting the developmental stage of the sample of interest.

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  • Liang, S., Wang, Q., Kong, X., Deng, W., Yang, X., Li, X., Zhang, Z., Zhang, J., Zhang, C., Li, X.-m., Ma, X., Shao, J., Greenshaw, A. J., & Li, T. (2019). White matter abnormalities in major depression bibotypes identified by Diffusion Tensor Imaging. Neuroscience Bulletin, 35(5), 867-876. doi:10.1007/s12264-019-00381-w.

    Abstract

    Identifying data-driven biotypes of major depressive disorder (MDD) has promise for the clarification of diagnostic heterogeneity. However, few studies have focused on white-matter abnormalities for MDD subtyping. This study included 116 patients with MDD and 118 demographically-matched healthy controls assessed by diffusion tensor imaging and neurocognitive evaluation. Hierarchical clustering was applied to the major fiber tracts, in conjunction with tract-based spatial statistics, to reveal white-matter alterations associated with MDD. Clinical and neurocognitive differences were compared between identified subgroups and healthy controls. With fractional anisotropy extracted from 20 fiber tracts, cluster analysis revealed 3 subgroups based on the patterns of abnormalities. Patients in each subgroup versus healthy controls showed a stepwise pattern of white-matter alterations as follows: subgroup 1 (25.9% of patient sample), widespread white-matter disruption; subgroup 2 (43.1% of patient sample), intermediate and more localized abnormalities in aspects of the corpus callosum and left cingulate; and subgroup 3 (31.0% of patient sample), possible mild alterations, but no statistically significant tract disruption after controlling for family-wise error. The neurocognitive impairment in each subgroup accompanied the white-matter alterations: subgroup 1, deficits in sustained attention and delayed memory; subgroup 2, dysfunction in delayed memory; and subgroup 3, no significant deficits. Three subtypes of white-matter abnormality exist in individuals with major depression, those having widespread abnormalities suffering more neurocognitive impairments, which may provide evidence for parsing the heterogeneity of the disorder and help optimize type-specific treatment approaches.

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    12264_2019_381_MOESM1_ESM.pdf
  • Middeldorp, C. M., Felix, J. F., Mahajan, A., EArly Genetics and Lifecourse Epidemiology (EAGLE) Consortium, Early Growth Genetics (EGG) consortium, & McCarthy, M. I. (2019). The Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia: Design, results and future prospects. European Journal of Epidemiology, 34(3), 279-300. doi:10.1007/s10654-019-00502-9.

    Abstract

    The impact of many unfavorable childhood traits or diseases, such as low birth weight and mental disorders, is not limited to childhood and adolescence, as they are also associated with poor outcomes in adulthood, such as cardiovascular disease. Insight into the genetic etiology of childhood and adolescent traits and disorders may therefore provide new perspectives, not only on how to improve wellbeing during childhood, but also how to prevent later adverse outcomes. To achieve the sample sizes required for genetic research, the Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia were established. The majority of the participating cohorts are longitudinal population-based samples, but other cohorts with data on early childhood phenotypes are also involved. Cohorts often have a broad focus and collect(ed) data on various somatic and psychiatric traits as well as environmental factors. Genetic variants have been successfully identified for multiple traits, for example, birth weight, atopic dermatitis, childhood BMI, allergic sensitization, and pubertal growth. Furthermore, the results have shown that genetic factors also partly underlie the association with adult traits. As sample sizes are still increasing, it is expected that future analyses will identify additional variants. This, in combination with the development of innovative statistical methods, will provide detailed insight on the mechanisms underlying the transition from childhood to adult disorders. Both consortia welcome new collaborations. Policies and contact details are available from the corresponding authors of this manuscript and/or the consortium websites.
  • Moisik, S. R., Zhi Yun, D. P., & Dediu, D. (2019). Active adjustment of the cervical spine during pitch production compensates for shape: The ArtiVarK study. In S. Calhoun, P. Escudero, M. Tabain, & P. Warren (Eds.), Proceedings of the 19th International Congress of Phonetic Sciences (ICPhS 20195) (pp. 864-868). Canberra, Australia: Australasian Speech Science and Technology Association Inc.

    Abstract

    The anterior lordosis of the cervical spine is thought to contribute to pitch (fo) production by influencing cricoid rotation as a function of larynx height. This study examines the matter of inter-individual variation in cervical spine shape and whether this has an influence on how fo is produced along increasing or decreasing scales, using the ArtiVarK dataset, which contains real-time MRI pitch production data. We find that the cervical spine actively participates in fo production, but the amount of displacement depends on individual shape. In general, anterior spine motion (tending toward cervical lordosis) occurs for low fo, while posterior movement (tending towards cervical kyphosis) occurs for high fo.
  • Postema, M., Van Rooij, D., Anagnostou, E., Arango, C., Auzias, G., Behrmann, M., Busatto Filho, G., Calderoni, S., Calvo, R., Daly, E., Deruelle, C., Di Martino, A., Dinstein, I., Duran, F. L. S., Durston, S., Ecker, C., Ehrlich, S., Fair, D., Fedor, J., Feng, X. and 38 morePostema, M., Van Rooij, D., Anagnostou, E., Arango, C., Auzias, G., Behrmann, M., Busatto Filho, G., Calderoni, S., Calvo, R., Daly, E., Deruelle, C., Di Martino, A., Dinstein, I., Duran, F. L. S., Durston, S., Ecker, C., Ehrlich, S., Fair, D., Fedor, J., Feng, X., Fitzgerald, J., Floris, D. L., Freitag, C. M., Gallagher, L., Glahn, D. C., Gori, I., Haar, S., Hoekstra, L., Jahanshad, N., Jalbrzikowski, M., Janssen, J., King, J. A., Kong, X., Lazaro, L., Lerch, J. P., Luna, B., Martinho, M. M., McGrath, J., Medland, S. E., Muratori, F., Murphy, C. M., Murphy, D. G. M., O'Hearn, K., Oranje, B., Parellada, M., Puig, O., Retico, A., Rosa, P., Rubia, K., Shook, D., Taylor, M., Tosetti, M., Wallace, G. L., Zhou, F., Thompson, P., Fisher, S. E., Buitelaar, J. K., & Francks, C. (2019). Altered structural brain asymmetry in autism spectrum disorder in a study of 54 datasets. Nature Communications, 10: 4958. doi:10.1038/s41467-019-13005-8.
  • Postema, M., De Marco, M., Colato, E., & Venneri, A. (2019). A study of within-subject reliability of the brain’s default-mode network. Magnetic Resonance Materials in Physics, Biology and Medicine, 32(3), 391-405. doi:10.1007/s10334-018-00732-0.

    Abstract

    Objective Resting-state functional magnetic resonance imaging (fMRI) is promising for Alzheimer’s disease (AD). This study aimed to examine short-term reliability of the default-mode network (DMN), one of the main haemodynamic patterns of the brain. Materials and methods Using a 1.5 T Philips Achieva scanner, two consecutive resting-state fMRI runs were acquired on 69 healthy adults, 62 patients with mild cognitive impairment (MCI) due to AD, and 28 patients with AD dementia. The anterior and posterior DMN and, as control, the visual-processing network (VPN) were computed using two different methodologies: connectivity of predetermined seeds (theory-driven) and dual regression (data-driven). Divergence and convergence in network strength and topography were calculated with paired t tests, global correlation coefficients, voxel-based correlation maps, and indices of reliability. Results No topographical differences were found in any of the networks. High correlations and reliability were found in the posterior DMN of healthy adults and MCI patients. Lower reliability was found in the anterior DMN and in the VPN, and in the posterior DMN of dementia patients. Discussion Strength and topography of the posterior DMN appear relatively stable and reliable over a short-term period of acquisition but with some degree of variability across clinical samples.

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