Displaying 1 - 100 of 328
  • Henson, R. N., Suri, S., Knights, E., Rowe, J. B., Kievit, R. A., Lyall, D. M., Chan, D., Eising, E., & Fisher, S. E. (in press). Effect of APOE polymorphism on cognition and brain in the CamCAN cohort. Brain and Neuroscience Advances.
  • 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. (in press). Greater male than female variability in regional brain structure across the lifespan. Human Brain Mapping.
  • 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.

    Supplementary material

    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.
  • 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. (2020). Genome-wide association study identifies 48 common genetic variants associated with handedness. Nature Human Behaviour. Advance online publication. 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.

    Supplementary material

    supplementary tables
  • 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.

    Supplementary material

    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.

    Supplementary material

    Link to Version 1
  • 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. (2020). Genome-wide association study reveals new insights into the heritability and genetic correlates of developmental dyslexia. Molecular Psychiatry. Advance online publication. 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.
  • 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.
  • 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. Advance online publication. 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.
  • 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. (2020). Consortium neuroscience of attention deficit/hyperactivity disorder and autism spectrum disorder: The ENIGMA adventure. Human Brain Mapping. Advance online publication. 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.
  • 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. Advance online publication. 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.

    Supplementary material

    Supporting information
  • Kong, X., Tzourio-Mazoyer, N., Joliot, M., Fedorenko, E., Liu, J., Fisher, S. E., & Francks, C. (2020). Gene expression correlates of the cortical network underlying sentence processing. Neurobiology of Language. Advance publication. doi:10.1162/nol_a_00004.

    Abstract

    A pivotal question in modern neuroscience is which genes regulate brain circuits that underlie cognitive functions. However, the field is still in its infancy. Here we report an integrated investigation of the high-level language network (i.e., sentence processing network) in the human cerebral cortex, combining regional gene expression profiles, task fMRI, large-scale neuroimaging meta-analysis, and resting-state functional network approaches. We revealed reliable gene expression-functional network correlations using three different network definition strategies, and identified a consensus set of genes related to connectivity within the sentence-processing network. The genes involved showed enrichment for neural development and actin-related functions, as well as association signals with autism, which can involve disrupted language functioning. Our findings help elucidate the molecular basis of the brain’s infrastructure for language. The integrative approach described here will be useful to study other complex cognitive traits.
  • Kong, X., 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. (2020). Mapping brain asymmetry in health and disease through the ENIGMA consortium. Human Brain Mapping. Advance online publication. 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., 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., ENIGMA Laterality Working Group, & Francks, C. (2020). Reproducibility in the absence of selective reporting: An illustration from large‐scale brain asymmetry research. Human Brain Mapping. Advance online publication. 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.
  • 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.

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  • 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.

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  • 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., Sestan, N., Pausova, Z., Seshadri, S., Paus, T., the ENIGMA Consortium, & for 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.

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  • 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. (2020). 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. Advance online publication. 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.
  • 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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  • 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 (2020). An overview of the first 5 years of the ENIGMA obsessive–compulsive disorder working group: The power of worldwide collaboration. Human Brain Mapping. Advance online publication. 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.
  • 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.
  • Verhoef, E., Shapland, C. Y., Fisher, S. E., Dale, P. S., & St Pourcain, B. (2020). The developmental origins of genetic factors influencing language and literacy: Associations with early-childhood vocabulary. Journal of Child Psychology and Psychiatry. Advance online publication. 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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  • Zhong, S., Wei, L., Zhao, C., Yang, L., Di, Z., Francks, C., & Gong, G. (2020). Interhemispheric relationship of genetic influence on human brain connectivity. Cerebral Cortex. Advance online publication. 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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  • 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.

    Supplementary material

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

    Abstract

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

    Supplementary material

    Eising_etal_2018sup.pdf
  • Fisher, S. E. (2019). Human genetics: The evolving story of FOXP2. Current Biology, 29(2), R65-R67. doi:10.1016/j.cub.2018.11.047.

    Abstract

    FOXP2 mutations cause a speech and language disorder, raising interest in potential roles of this gene in human evolution. A new study re-evaluates genomic variation at the human FOXP2 locus but finds no evidence of recent adaptive evolution.
  • Fisher, S. E. (2019). Key issues and future directions: Genes and language. In P. Hagoort (Ed.), Human language: From genes and brain to behavior (pp. 609-620). Cambridge, MA: MIT Press.
  • 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.

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  • 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). 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.
  • 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.

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  • 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.

    Supplementary material

    Supplementary Text and Figures
  • 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., Franontike, B., Pääbo, S., Macciardi, F., Grabe, H. J., & Fisher, S. E. (2019). Neandertal introgression sheds light on modern human endocranial globularity. Current Biology, 29(1), 120-127. doi:10.1016/j.cub.2018.10.065.

    Abstract

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

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    mmc1.pdf mmc2.xlsx
  • 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.

    Supplementary material

    Supplementary material
  • 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.

    Supplementary material

    Research Data via Github
  • 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., 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.
  • 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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  • 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.

    Supplementary material

    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., 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.
  • 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.

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

    Abstract

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

    Abstract

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

    Abstract

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

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

    Abstract

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

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

    Abstract

    A commonly held assumption in cognitive neuroscience is that, because measures of human brain function are closer to underlying biology than distal indices of behavior/cognition, they hold more promise for uncovering genetic pathways. Supporting this view is an influential fMRI-based study of sentence reading/listening by Pinel et al. (2012), who reported that common DNA variants in specific candidate genes were associated with altered neural activation in language-related regions of healthy individuals that carried them. In particular, different single-nucleotide polymorphisms (SNPs) of FOXP2 correlated with variation in task-based activation in left inferior frontal and precentral gyri, whereas a SNP at the KIAA0319/TTRAP/THEM2 locus was associated with variable functional asymmetry of the superior temporal sulcus. Here, we directly test each claim using a closely matched neuroimaging genetics approach in independent cohorts comprising 427 participants, four times larger than the original study of 94 participants. Despite demonstrating power to detect associations with substantially smaller effect sizes than those of the original report, we do not replicate any of the reported associations. Moreover, formal Bayesian analyses reveal substantial to strong evidence in support of the null hypothesis (no effect). We highlight key aspects of the original investigation, common to functional neuroimaging genetics studies, which could have yielded elevated false-positive rates. Genetic accounts of individual differences in cognitive functional neuroimaging are likely to be as complex as behavioral/cognitive tests, involving many common genetic variants, each of tiny effect. Reliable identification of true biological signals requires large sample sizes, power calculations, and validation in independent cohorts with equivalent paradigms. SIGNIFICANCE STATEMENT A pervasive idea in neuroscience is that neuroimaging-based measures of brain function, being closer to underlying neurobiology, are more amenable for uncovering links to genetics. This is a core assumption of prominent studies that associate common DNA variants with altered activations in task-based fMRI, despite using samples (10–100 people) that lack power for detecting the tiny effect sizes typical of genetically complex traits. Here, we test central findings from one of the most influential prior studies. Using matching paradigms and substantially larger samples, coupled to power calculations and formal Bayesian statistics, our data strongly refute the original findings. We demonstrate that neuroimaging genetics with task-based fMRI should be subject to the same rigorous standards as studies of other complex traits.
  • Van Rhijn, J. R. (2019). The role of FoxP2 in striatal circuitry. PhD Thesis, Radboud University Nijmegen, Nijmegen.
  • Verhoef, E., Demontis, D., Burgess, S., Shapland, C. Y., Dale, P. S., Okbay, A., Neale, B. M., Faraone, S. V., iPSYCH-Broad-PGC ADHD Consortium, Stergiakouli, E., Davey Smith, G., Fisher, S. E., Borglum, A., & St Pourcain, B. (2019). Disentangling polygenic associations between Attention-Deficit/Hyperactivity Disorder, educational attainment, literacy and language. Translational Psychiatry, 9: 35. doi:10.1038/s41398-018-0324-2.

    Abstract

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

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    41398_2018_324_MOESM1_ESM.docx
  • Becker, M., Devanna, P., Fisher, S. E., & Vernes, S. C. (2018). Mapping of Human FOXP2 Enhancers Reveals Complex Regulation. Frontiers in Molecular Neuroscience, 11: 47. doi:10.3389/fnmol.2018.00047.

    Abstract

    Mutations of the FOXP2 gene cause a severe speech and language disorder, providing a molecular window into the neurobiology of language. Individuals with FOXP2 mutations have structural and functional alterations affecting brain circuits that overlap with sites of FOXP2 expression, including regions of the cortex, striatum, and cerebellum. FOXP2 displays complex patterns of expression in the brain, as well as in non-neuronal tissues, suggesting that sophisticated regulatory mechanisms control its spatio-temporal expression. However, to date, little is known about the regulation of FOXP2 or the genomic elements that control its expression. Using chromatin conformation capture (3C), we mapped the human FOXP2 locus to identify putative enhancer regions that engage in long-range interactions with the promoter of this gene. We demonstrate the ability of the identified enhancer regions to drive gene expression. We also show regulation of the FOXP2 promoter and enhancer regions by candidate regulators – FOXP family and TBR1 transcription factors. These data point to regulatory elements that may contribute to the temporal- or tissue-specific expression patterns of human FOXP2. Understanding the upstream regulatory pathways controlling FOXP2 expression will bring new insight into the molecular networks contributing to human language and related disorders.
  • Bentz, C., Dediu, D., Verkerk, A., & Jäger, G. (2018). Language family trees reflect geography and demography beyond neutral drift. In C. Cuskley, M. Flaherty, H. Little, L. McCrohon, A. Ravignani, & T. Verhoef (Eds.), Proceedings of the 12th International Conference on the Evolution of Language (EVOLANG XII) (pp. 38-40). Toruń, Poland: NCU Press. doi:10.12775/3991-1.006.
  • Bentz, C., Dediu, D., Verkerk, A., & Jäger, G. (2018). The evolution of language families is shaped by the environment beyond neutral drift. Nature Human Behaviour, 2, 816-821. doi:10.1038/s41562-018-0457-6.

    Abstract

    There are more than 7,000 languages spoken in the world today1. It has been argued that the natural and social environment of languages drives this diversity. However, a fundamental question is how strong are environmental pressures, and does neutral drift suffice as a mechanism to explain diversification? We estimate the phylogenetic signals of geographic dimensions, distance to water, climate and population size on more than 6,000 phylogenetic trees of 46 language families. Phylogenetic signals of environmental factors are generally stronger than expected under the null hypothesis of no relationship with the shape of family trees. Importantly, they are also—in most cases—not compatible with neutral drift models of constant-rate change across the family tree branches. Our results suggest that language diversification is driven by further adaptive and non-adaptive pressures. Language diversity cannot be understood without modelling the pressures that physical, ecological and social factors exert on language users in different environments across the globe.
  • Dediu, D. (2018). Making genealogical language classifications available for phylogenetic analysis: Newick trees, unified identifiers, and branch length. Language Dynamics and Change, 8(1), 1-21. doi:10.1163/22105832-00801001.

    Abstract

    One of the best-known types of non-independence between languages is caused by genealogical relationships due to descent from a common ancestor. These can be represented by (more or less resolved and controversial) language family trees. In theory, one can argue that language families should be built through the strict application of the comparative method of historical linguistics, but in practice this is not always the case, and there are several proposed classifications of languages into language families, each with its own advantages and disadvantages. A major stumbling block shared by most of them is that they are relatively difficult to use with computational methods, and in particular with phylogenetics. This is due to their lack of standardization, coupled with the general non-availability of branch length information, which encapsulates the amount of evolution taking place on the family tree. In this paper I introduce a method (and its implementation in R) that converts the language classifications provided by four widely-used databases (Ethnologue, WALS, AUTOTYP and Glottolog) intothe de facto Newick standard generally used in phylogenetics, aligns the four most used conventions for unique identifiers of linguistic entities (ISO 639-3, WALS, AUTOTYP and Glottocode), and adds branch length information from a variety of sources (the tree's own topology, an externally given numeric constant, or a distance matrix). The R scripts, input data and resulting Newick trees are available under liberal open-source licenses in a GitHub repository (https://github.com/ddediu/lgfam-newick), to encourage and promote the use of phylogenetic methods to investigate linguistic diversity and its temporal dynamics.
  • Dediu, D., & Levinson, S. C. (2018). Neanderthal language revisited: Not only us. Current Opinion in Behavioral Sciences, 21, 49-55. doi:10.1016/j.cobeha.2018.01.001.

    Abstract

    Here we re-evaluate our 2013 paper on the antiquity of language (Dediu and Levinson, 2013) in the light of a surge of new information on human evolution in the last half million years. Although new genetic data suggest the existence of some cognitive differences between Neanderthals and modern humans — fully expected after hundreds of thousands of years of partially separate evolution, overall our claims that Neanderthals were fully articulate beings and that language evolution was gradual are further substantiated by the wealth of new genetic, paleontological and archeological evidence briefly reviewed here.
  • Den Hoed, J., Sollis, E., Venselaar, H., Estruch, S. B., Derizioti, P., & Fisher, S. E. (2018). Functional characterization of TBR1 variants in neurodevelopmental disorder. Scientific Reports, 8: 14279. doi:10.1038/s41598-018-32053-6.

    Abstract

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

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

    Abstract

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

    Supplementary material

    mp201730x1.docx
  • Estruch, S. B. (2018). Characterization of transcription factors in monogenic disorders of speech and language. PhD Thesis, Radboud University Nijmegen, Nijmegen.
  • Estruch, S. B., Graham, S. A., Quevedo, M., Vino, A., Dekkers, D. H. W., Deriziotis, P., Sollis, E., Demmers, J., Poot, R. A., & Fisher, S. E. (2018). Proteomic analysis of FOXP proteins reveals interactions between cortical transcription factors associated with neurodevelopmental disorders. Human Molecular Genetics, 27(7), 1212-1227. doi:10.1093/hmg/ddy035.

    Abstract

    FOXP transcription factors play important roles in neurodevelopment, but little is known about how their transcriptional activity is regulated. FOXP proteins cooperatively regulate gene expression by forming homo- and hetero-dimers with each other. Physical associations with other transcription factors might also modulate the functions of FOXP proteins. However, few FOXP-interacting transcription factors have been identified so far. Therefore, we sought to discover additional transcription factors that interact with the brain-expressed FOXP proteins, FOXP1, FOXP2 and FOXP4, through affinity-purifications of protein complexes followed by mass spectrometry. We identified seven novel FOXP-interacting transcription factors (NR2F1, NR2F2, SATB1, SATB2, SOX5, YY1 and ZMYM2), five of which have well-estabslished roles in cortical development. Accordingly, we found that these transcription factors are co-expressed with FoxP2 in the deep layers of the cerebral cortex and also in the Purkinje cells of the cerebellum, suggesting that they may cooperate with the FoxPs to regulate neural gene expression in vivo. Moreover, we demonstrated that etiological mutations of FOXP1 and FOXP2, known to cause neurodevelopmental disorders, severely disrupted the interactions with FOXP-interacting transcription factors. Additionally, we pinpointed specific regions within FOXP2 sequence involved in mediating these interactions. Thus, by expanding the FOXP interactome we have uncovered part of a broader neural transcription factor network involved in cortical development, providing novel molecular insights into the transcriptional architecture underlying brain development and neurodevelopmental disorders
  • Gingras, B., Honing, H., Peretz, I., Trainor, L. J., & Fisher, S. E. (2018). Defining the biological bases of individual differences in musicality. In H. Honing (Ed.), The origins of musicality (pp. 221-250). Cambridge, MA: MIT Press.
  • Heyne, H. O., Singh, T., Stamberger, H., Jamra, R. A., Caglayan, H., Craiu, D., Guerrini, R., Helbig, K. L., Koeleman, B. P. C., Kosmicki, J. A., Linnankivi, T., May, P., Muhle, H., Møller, R. S., Neubauer, B. A., Palotie, A., Pendziwiat, M., Striano, P., Tang, S., Wu, S. and 9 moreHeyne, H. O., Singh, T., Stamberger, H., Jamra, R. A., Caglayan, H., Craiu, D., Guerrini, R., Helbig, K. L., Koeleman, B. P. C., Kosmicki, J. A., Linnankivi, T., May, P., Muhle, H., Møller, R. S., Neubauer, B. A., Palotie, A., Pendziwiat, M., Striano, P., Tang, S., Wu, S., EuroEPINOMICS RES Consortium, De Kovel, C. G. F., Poduri, A., Weber, Y. G., Weckhuysen, S., Sisodiya, S. M., Daly, M. J., Helbig, I., Lal, D., & Lemke, J. R. (2018). De novo variants in neurodevelopmental disorders with epilepsy. Nature Genetics, 50, 1048-1053. doi:10.1038/s41588-018-0143-7.

    Abstract

    Epilepsy is a frequent feature of neurodevelopmental disorders (NDDs), but little is known about genetic differences between NDDs with and without epilepsy. We analyzed de novo variants (DNVs) in 6,753 parent–offspring trios ascertained to have different NDDs. In the subset of 1,942 individuals with NDDs with epilepsy, we identified 33 genes with a significant excess of DNVs, of which SNAP25 and GABRB2 had previously only limited evidence of disease association. Joint analysis of all individuals with NDDs also implicated CACNA1E as a novel disease-associated gene. Comparing NDDs with and without epilepsy, we found missense DNVs, DNVs in specific genes, age of recruitment, and severity of intellectual disability to be associated with epilepsy. We further demonstrate the extent to which our results affect current genetic testing as well as treatment, emphasizing the benefit of accurate genetic diagnosis in NDDs with epilepsy.
  • Howe, L. J., Lee, M. K., Sharp, G. C., Smith, G. D. W., St Pourcain, B., Shaffer, J. R., Ludwig, K. U., Mangold, E., Marazita, M. L., Feingold, E., Zhurov, A., Stergiakouli, E., Sandy, J., Richmond, S., Weinberg, S. M., Hemani, G., & Lewis, S. J. (2018). Investigating the shared genetics of non-syndromic cleft lip/palate and facial morphology. PLoS Genetics, 14(8): e1007501. doi:10.1371/journal.pgen.1007501.

    Abstract

    There is increasing evidence that genetic risk variants for non-syndromic cleft lip/palate (nsCL/P) are also associated with normal-range variation in facial morphology. However, previous analyses are mostly limited to candidate SNPs and findings have not been consistently replicated. Here, we used polygenic risk scores (PRS) to test for genetic overlap between nsCL/P and seven biologically relevant facial phenotypes. Where evidence was found of genetic overlap, we used bidirectional Mendelian randomization (MR) to test the hypothesis that genetic liability to nsCL/P is causally related to implicated facial phenotypes. Across 5,804 individuals of European ancestry from two studies, we found strong evidence, using PRS, of genetic overlap between nsCL/P and philtrum width; a 1 S.D. increase in nsCL/P PRS was associated with a 0.10 mm decrease in philtrum width (95% C.I. 0.054, 0.146; P = 2x10-5). Follow-up MR analyses supported a causal relationship; genetic variants for nsCL/P homogeneously cause decreased philtrum width. In addition to the primary analysis, we also identified two novel risk loci for philtrum width at 5q22.2 and 7p15.2 in our Genome-wide Association Study (GWAS) of 6,136 individuals. Our results support a liability threshold model of inheritance for nsCL/P, related to abnormalities in development of the philtrum.
  • Janssen, R., Moisik, S. R., & Dediu, D. (2018). Agent model reveals the influence of vocal tract anatomy on speech during ontogeny and glossogeny. In C. Cuskley, M. Flaherty, H. Little, L. McCrohon, A. Ravignani, & T. Verhoef (Eds.), Proceedings of the 12th International Conference on the Evolution of Language (EVOLANG XII) (pp. 171-174). Toruń, Poland: NCU Press. doi:10.12775/3991-1.042.
  • Janssen, R., & Dediu, D. (2018). Genetic biases affecting language: What do computer models and experimental approaches suggest? In T. Poibeau, & A. Villavicencio (Eds.), Language, Cognition and Computational Models (pp. 256-288). Cambridge: Cambridge University Press.

    Abstract

    Computer models of cultural evolution have shown language properties emerging on interacting agents with a brain that lacks dedicated, nativist language modules. Notably, models using Bayesian agents provide a precise specification of (extra-)liguististic factors (e.g., genetic) that shape language through iterated learning (biases on language), and demonstrate that weak biases get expressed more strongly over time (bias amplification). Other models attempt to lessen assumption on agents’ innate predispositions even more, and emphasize self-organization within agents, highlighting glossogenesis (the development of language from a nonlinguistic state). Ultimately however, one also has to recognize that biology and culture are strongly interacting, forming a coevolving system. As such, computer models show that agents might (biologically) evolve to a state predisposed to language adaptability, where (culturally) stable language features might get assimilated into the genome via Baldwinian niche construction. In summary, while many questions about language evolution remain unanswered, it is clear that it is not to be completely understood from a purely biological, cognitivist perspective. Language should be regarded as (partially) emerging on the social interactions between large populations of speakers. In this context, agent models provide a sound approach to investigate the complex dynamics of genetic biasing on language and speech
  • Janssen, R., Moisik, S. R., & Dediu, D. (2018). Modelling human hard palate shape with Bézier curves. PLoS One, 13(2): e0191557. doi:10.1371/journal.pone.0191557.

    Abstract

    People vary at most levels, from the molecular to the cognitive, and the shape of the hard palate (the bony roof of the mouth) is no exception. The patterns of variation in the hard palate are important for the forensic sciences and (palaeo)anthropology, and might also play a role in speech production, both in pathological cases and normal variation. Here we describe a method based on Bézier curves, whose main aim is to generate possible shapes of the hard palate in humans for use in computer simulations of speech production and language evolution. Moreover, our method can also capture existing patterns of variation using few and easy-to-interpret parameters, and fits actual data obtained from MRI traces very well with as little as two or three free parameters. When compared to the widely-used Principal Component Analysis (PCA), our method fits actual data slightly worse for the same number of degrees of freedom. However, it is much better at generating new shapes without requiring a calibration sample, its parameters have clearer interpretations, and their ranges are grounded in geometrical considerations. © 2018 Janssen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
  • Janssen, R. (2018). Let the agents do the talking: On the influence of vocal tract anatomy no speech during ontogeny. PhD Thesis, Radboud University Nijmegen, Nijmegen.
  • Kong, X., Mathias, S. R., Guadalupe, T., ENIGMA Laterality Working Group, Glahn, D. C., Franke, B., Crivello, F., Tzourio-Mazoyer, N., Fisher, S. E., Thompson, P. M., & Francks, C. (2018). Mapping Cortical Brain Asymmetry in 17,141 Healthy Individuals Worldwide via the ENIGMA Consortium. Proceedings of the National Academy of Sciences of the United States of America, 115(22), E5154-E5163. doi:10.1073/pnas.1718418115.

    Abstract

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

    Supplementary material

    pnas.1718418115.sapp.pdf
  • Hu, C.-P., Kong, X., Wagenmakers, E.-J., Ly, A., & Peng, K. (2018). The Bayes factor and its implementation in JASP: A practical primer. Advances in Psychological Science, 26(6), 951-965. doi:10.3724/SP.J.1042.2018.00951.

    Abstract

    Statistical inference plays a critical role in modern scientific research, however, the dominant method for statistical inference in science, null hypothesis significance testing (NHST), is often misunderstood and misused, which leads to unreproducible findings. To address this issue, researchers propose to adopt the Bayes factor as an alternative to NHST. The Bayes factor is a principled Bayesian tool for model selection and hypothesis testing, and can be interpreted as the strength for both the null hypothesis H0 and the alternative hypothesis H1 based on the current data. Compared to NHST, the Bayes factor has the following advantages: it quantifies the evidence that the data provide for both the H0 and the H1, it is not “violently biased” against H0, it allows one to monitor the evidence as the data accumulate, and it does not depend on sampling plans. Importantly, the recently developed open software JASP makes the calculation of Bayes factor accessible for most researchers in psychology, as we demonstrated for the t-test. Given these advantages, adopting the Bayes factor will improve psychological researchers’ statistical inferences. Nevertheless, to make the analysis more reproducible, researchers should keep their data analysis transparent and open.
  • De Kovel, C. G. F., & Fisher, S. E. (2018). Molecular genetic methods. In A. M. B. De Groot, & P. Hagoort (Eds.), Research methods in psycholinguistics and the neurobiology of language: A practical guide (pp. 330-353). Hoboken: Wiley.
  • De Kovel, C. G. F., Lisgo, S. N., Fisher, S. E., & Francks, C. (2018). Subtle left-right asymmetry of gene expression profiles in embryonic and foetal human brains. Scientific Reports, 8: 12606. doi:10.1038/s41598-018-29496-2.

    Abstract

    Left-right laterality is an important aspect of human –and in fact all vertebrate– brain organization for which the genetic basis is poorly understood. Using RNA sequencing data we contrasted gene expression in left- and right-sided samples from several structures of the anterior central nervous systems of post mortem human embryos and foetuses. While few individual genes stood out as significantly lateralized, most structures showed evidence of laterality of their overall transcriptomic profiles. These left-right differences showed overlap with age-dependent changes in expression, indicating lateralized maturation rates, but not consistently in left-right orientation over all structures. Brain asymmetry may therefore originate in multiple locations, or if there is a single origin, it is earlier than 5 weeks post conception, with structure-specific lateralized processes already underway by this age. This pattern is broadly consistent with the weak correlations reported between various aspects of adult brain laterality, such as language dominance and handedness.
  • De Kovel, C. G. F., Lisgo, S. N., & Francks, C. (2018). Transcriptomic analysis of left-right differences in human embryonic forebrain and midbrain. Scientific Data, 5: 180164. doi:10.1038/sdata.2018.164.

    Abstract

    Left-right asymmetry is subtle but pervasive in the human central nervous system. This asymmetry is initiated early during development, but its mechanisms are poorly known. Forebrains and midbrains were dissected from six human embryos at Carnegie stages 15 or 16, one of which was female. The structures were divided into left and right sides, and RNA was isolated. RNA was sequenced with 100 base-pair paired ends using Illumina Hiseq 4000. After quality control, five paired brain sides were available for midbrain and forebrain. A paired analysis between left- and right sides of a given brain structure across the embryos identified left-right differences. The dataset, consisting of Fastq files and a read count table, can be further used to study early development of the human brain
  • Kuerbitz, J., Arnett, M., Ehrman, S., Williams, M. T., Voorhees, C. V., Fisher, S. E., Garratt, A. N., Muglia, L. J., Waclaw, R. R., & Campbell, K. (2018). Loss of intercalated cells (ITCs) in the mouse amygdala of Tshz1 mutants correlates with fear, depression and social interaction phenotypes. The Journal of Neuroscience, 38, 1160-1177. doi:10.1523/JNEUROSCI.1412-17.2017.

    Abstract

    The intercalated cells (ITCs) of the amygdala have been shown to be critical regulatory components of amygdalar circuits, which control appropriate fear responses. Despite this, the molecular processes guiding ITC development remain poorly understood. Here we establish the zinc finger transcription factor Tshz1 as a marker of ITCs during their migration from the dorsal lateral ganglionic eminence through maturity. Using germline and conditional knock-out (cKO) mouse models, we show that Tshz1 is required for the proper migration and differentiation of ITCs. In the absence of Tshz1, migrating ITC precursors fail to settle in their stereotypical locations encapsulating the lateral amygdala and BLA. Furthermore, they display reductions in the ITC marker Foxp2 and ectopic persistence of the dorsal lateral ganglionic eminence marker Sp8. Tshz1 mutant ITCs show increased cell death at postnatal time points, leading to a dramatic reduction by 3 weeks of age. In line with this, Foxp2-null mutants also show a loss of ITCs at postnatal time points, suggesting that Foxp2 may function downstream of Tshz1 in the maintenance of ITCs. Behavioral analysis of male Tshz1 cKOs revealed defects in fear extinction as well as an increase in floating during the forced swim test, indicative of a depression-like phenotype. Moreover, Tshz1 cKOs display significantly impaired social interaction (i.e., increased passivity) regardless of partner genetics. Together, these results suggest that Tshz1 plays a critical role in the development of ITCs and that fear, depression-like and social behavioral deficits arise in their absence. SIGNIFICANCE STATEMENT We show here that the zinc finger transcription factor Tshz1 is expressed during development of the intercalated cells (ITCs) within the mouse amygdala. These neurons have previously been shown to play a crucial role in fear extinction. Tshz1 mouse mutants exhibit severely reduced numbers of ITCs as a result of abnormal migration, differentiation, and survival of these neurons. Furthermore, the loss of ITCs in mouse Tshz1 mutants correlates well with defects in fear extinction as well as the appearance of depression-like and abnormal social interaction behaviors reminiscent of depressive disorders observed in human patients with distal 18q deletions, including the Tshz1 locus.
  • Liang, S., Vega, R., Kong, X., Deng, W., Wang, Q., Ma, X., Li, M., Hu, X., Greenshaw, A. J., Greiner, R., & Li, T. (2018). Neurocognitive Graphs of First-Episode Schizophrenia and Major Depression Based on Cognitive Features. Neuroscience Bulletin, 34(2), 312-320. doi:10.1007/s12264-017-0190-6.

    Abstract

    Neurocognitive deficits are frequently observed in patients with schizophrenia and major depressive disorder (MDD). The relations between cognitive features may be represented by neurocognitive graphs based on cognitive features, modeled as Gaussian Markov random fields. However, it is unclear whether it is possible to differentiate between phenotypic patterns associated with the differential diagnosis of schizophrenia and depression using this neurocognitive graph approach. In this study, we enrolled 215 first-episode patients with schizophrenia (FES), 125 with MDD, and 237 demographically-matched healthy controls (HCs). The cognitive performance of all participants was evaluated using a battery of neurocognitive tests. The graphical LASSO model was trained with a one-vs-one scenario to learn the conditional independent structure of neurocognitive features of each group. Participants in the holdout dataset were classified into different groups with the highest likelihood. A partial correlation matrix was transformed from the graphical model to further explore the neurocognitive graph for each group. The classification approach identified the diagnostic class for individuals with an average accuracy of 73.41% for FES vs HC, 67.07% for MDD vs HC, and 59.48% for FES vs MDD. Both of the neurocognitive graphs for FES and MDD had more connections and higher node centrality than those for HC. The neurocognitive graph for FES was less sparse and had more connections than that for MDD. Thus, neurocognitive graphs based on cognitive features are promising for describing endophenotypes that may discriminate schizophrenia from depression.

    Supplementary material

    Liang_etal_2017sup.pdf
  • Ligthart, S., Vaez, A., Võsa, U., Stathopoulou, M. G., De Vries, P. S., Prins, B. P., Van der Most, P. J., Tanaka, T., Naderi, E., Rose, L. M., Wu, Y., Karlsson, R., Barbalic, M., Lin, H., Pool, R., Zhu, G., Macé, A., Sidore, C., Trompet, S., Mangino, M. and 267 moreLigthart, S., Vaez, A., Võsa, U., Stathopoulou, M. G., De Vries, P. S., Prins, B. P., Van der Most, P. J., Tanaka, T., Naderi, E., Rose, L. M., Wu, Y., Karlsson, R., Barbalic, M., Lin, H., Pool, R., Zhu, G., Macé, A., Sidore, C., Trompet, S., Mangino, M., Sabater-Lleal, M., Kemp, J. P., Abbasi, A., Kacprowski, T., Verweij, N., Smith, A. V., Huang, T., Marzi, C., Feitosa, M. F., Lohman, K. K., Kleber, M. E., Milaneschi, Y., Mueller, C., Huq, M., Vlachopoulou, E., Lyytikäinen, L.-P., Oldmeadow, C., Deelen, J., Perola, M., Zhao, J. H., Feenstra, B., LifeLines Cohort Study, Amini, M., CHARGE Inflammation Working Group, Lahti, J., Schraut, K. E., Fornage, M., Suktitipat, B., Chen, W.-M., Li, X., Nutile, T., Malerba, G., Luan, J., Bak, T., Schork, N., Del Greco M., F., Thiering, E., Mahajan, A., Marioni, R. E., Mihailov, E., Eriksson, J., Ozel, A. B., Zhang, W., Nethander, M., Cheng, Y.-C., Aslibekyan, S., Ang, W., Gandin, I., Yengo, L., Portas, L., Kooperberg, C., Hofer, E., Rajan, K. B., Schurmann, C., Den Hollander, W., Ahluwalia, T. S., Zhao, J., Draisma, H. H. M., Ford, I., Timpson, N., Teumer, A., Huang, H., Wahl, S., Liu, Y., Huang, J., Uh, H.-W., Geller, F., Joshi, P. K., Yanek, L. R., Trabetti, E., Lehne, B., Vozzi, D., Verbanck, M., Biino, G., Saba, Y., Meulenbelt, I., O’Connell, J. R., Laakso, M., Giulianini, F., Magnusson, P. K. E., Ballantyne, C. M., Hottenga, J. J., Montgomery, G. W., Rivadineira, F., Rueedi, R., Steri, M., Herzig, K.-H., Stott, D. J., Menni, C., Franberg, M., St Pourcain, B., Felix, S. B., Pers, T. H., Bakker, S. J. L., Kraft, P., Peters, A., Vaidya, D., Delgado, G., Smit, J. H., Großmann, V., Sinisalo, J., Seppälä, I., Williams, S. R., Holliday, E. G., Moed, M., Langenberg, C., Räikkönen, K., Ding, J., Campbell, H., Sale, M. M., Chen, Y.-D.-I., James, A. L., Ruggiero, D., Soranzo, N., Hartman, C. A., Smith, E. N., Berenson, G. S., Fuchsberger, C., Hernandez, D., Tiesler, C. M. T., Giedraitis, V., Liewald, D., Fischer, K., Mellström, D., Larsson, A., Wang, Y., Scott, W. R., Lorentzon, M., Beilby, J., Ryan, K. A., Pennell, C. E., Vuckovic, D., Balkau, B., Concas, M. P., Schmidt, R., Mendes de Leon, C. F., Bottinger, E. P., Kloppenburg, M., Paternoster, L., Boehnke, M., Musk, A. W., Willemsen, G., Evans, D. M., Madden, P. A. F., Kähönen, M., Kutalik, Z., Zoledziewska, M., Karhunen, V., Kritchevsky, S. B., Sattar, N., Lachance, G., Clarke, R., Harris, T. B., Raitakari, O. T., Attia, J. R., Van Heemst, D., Kajantie, E., Sorice, R., Gambaro, G., Scott, R. A., Hicks, A. A., Ferrucci, L., Standl, M., Lindgren, C. M., Starr, J. M., Karlsson, M., Lind, L., Li, J. Z., Chambers, J. C., Mori, T. A., De Geus, E. J. C. N., Heath, A. C., Martin, N. G., Auvinen, J., Buckley, B. M., De Craen, A. J. M., Waldenberger, M., Strauch, K., Meitinger, T., Scott, R. J., McEvoy, M., Beekman, M., Bombieri, C., Ridker, P. M., Mohlke, K. L., Pedersen, N. L., Morrison, A. C., Boomsma, D. I., Whitfield, J. B., Strachan, D. P., Hofman, A., Vollenweider, P., Cucca, F., Jarvelin, M.-R., Jukema, J. W., Spector, T. D., Hamsten, A., Zeller, T., Uitterlinden, A. G., Nauck, M., Gudnason, V., Qi, L., Grallert, H., Borecki, I. B., Rotter, J. I., März, W., Wild, P. S., Lokki, M.-L., Boyle, M., Salomaa, V., Melbye, M., Eriksson, J. G., Wilson, J. F., Penninx, B. W. J. H., Becker, D. M., Worrall, B. B., Gibson, G., Krauss, R. M., Ciullo, M., Zaza, G., Wareham, N. J., Oldehinkel, A. J., Palmer, L. J., Murray, S. S., Pramstaller, P. P., Bandinelli, S., Heinrich, J., Ingelsson, E., Deary, I. J., Ma¨gi, R., Vandenput, L., Van der Harst, P., Desch, K. C., Kooner, J. S., Ohlsson, C., Hayward, C., Lehtima¨ki, T., Shuldiner, A. R., Arnett, D. K., Beilin, L. J., Robino, A., Froguel, P., Pirastu, M., Jess, T., Koenig, W., Loos, R. J. F., Evans, D. A., Schmidt, H., Smith, G. D., Slagboom, P. E., Eiriksdottir, G., Morris, A. P., Psaty, B. M., Tracy, R. P., Nolte, I. M., Boerwinkle, E., Visvikis-Siest, S., Reiner, A. P., Gross, M., Bis, J. C., Franke, L., Franco, O. H., Benjamin, E. J., Chasman, D. I., Dupuis, J., Snieder, H., Dehghan, A., & Alizadeh, B. Z. (2018). Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders. The American Journal of Human Genetics, 103(5), 691-706. doi:10.1016/j.ajhg.2018.09.009.

    Abstract

    C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10−8). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.
  • Xu, S., Liu, P., Chen, Y., Chen, Y., Zhang, W., Zhao, H., Cao, Y., Wang, F., Jiang, N., Lin, S., Li, B., Zhang, Z., Wei, Z., Fan, Y., Jin, Y., He, L., Zhou, R., Dekker, J. D., Tucker, H. O., Fisher, S. E. and 4 moreXu, S., Liu, P., Chen, Y., Chen, Y., Zhang, W., Zhao, H., Cao, Y., Wang, F., Jiang, N., Lin, S., Li, B., Zhang, Z., Wei, Z., Fan, Y., Jin, Y., He, L., Zhou, R., Dekker, J. D., Tucker, H. O., Fisher, S. E., Yao, Z., Liu, Q., Xia, X., & Guo, X. (2018). Foxp2 regulates anatomical features that may be relevant for vocal behaviors and bipedal locomotion. Proceedings of the National Academy of Sciences of the United States of America, 115(35), 8799-8804. doi:10.1073/pnas.1721820115.

    Abstract

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

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  • Mandy, W., Pellicano, L., St Pourcain, B., Skuse, D., & Heron, J. (2018). The development of autistic social traits across childhood and adolescence in males and females. The Journal of Child Psychology and Psychiatry, 59(11), 1143-1151. doi:10.1111/jcpp.12913.

    Abstract

    Background Autism is a dimensional condition, representing the extreme end of a continuum of social competence that extends throughout the general population. Currently, little is known about how autistic social traits (ASTs), measured across the full spectrum of severity, develop during childhood and adolescence, including whether there are developmental differences between boys and girls. Therefore, we sought to chart the trajectories of ASTs in the general population across childhood and adolescence, with a focus on gender differences. Methods Participants were 9,744 males (n = 4,784) and females (n = 4,960) from ALSPAC, a UK birth cohort study. ASTs were assessed when participants were aged 7, 10, 13 and 16 years, using the parent‐report Social Communication Disorders Checklist. Data were modelled using latent growth curve analysis. Results Developmental trajectories of males and females were nonlinear, showing a decline from 7 to 10 years, followed by an increase between 10 and 16 years. At 7 years, males had higher levels of ASTs than females (mean raw score difference = 0.88, 95% CI [.72, 1.04]), and were more likely (odds ratio [OR] = 1.99; 95% CI, 1.82, 2.16) to score in the clinical range on the SCDC. By 16 years this gender difference had disappeared: males and females had, on average, similar levels of ASTs (mean difference = 0.00, 95% CI [−0.19, 0.19]) and were equally likely to score in the SCDC's clinical range (OR = 0.91, 95% CI, 0.73, 1.10). This was the result of an increase in females’ ASTs between 10 and 16 years. Conclusions There are gender‐specific trajectories of autistic social impairment, with females more likely than males to experience an escalation of ASTs during early‐ and midadolescence. It remains to be discovered whether the observed female adolescent increase in ASTs represents the genuine late onset of social difficulties or earlier, subtle, pre‐existing difficulties becoming more obvious.

    Supplementary material

    jcpp12913-sup-0001-supinfo.docx
  • Mei, C., Fedorenko, E., Amor, D. J., Boys, A., Hoeflin, C., Carew, P., Burgess, T., Fisher, S. E., & Morgan, A. T. (2018). Deep phenotyping of speech and language skills in individuals with 16p11.2 deletion. European journal of human genetics, 26(5), 676-686. doi:10.1038/s41431-018-0102-x.

    Abstract

    Recurrent deletions of a ~600-kb region of 16p11.2 have been associated with a highly penetrant form of childhood apraxia of speech (CAS). Yet prior findings have been based on a small, potentially biased sample using retrospectively collected data. We examine the prevalence of CAS in a larger cohort of individuals with 16p11.2 deletion using a prospectively designed assessment battery. The broader speech and language phenotype associated with carrying this deletion was also examined. 55 participants with 16p11.2 deletion (47 children, 8 adults) underwent deep phenotyping to test for the presence of CAS and other speech and language diagnoses. Standardized tests of oral motor functioning, speech production, language, and non-verbal IQ were conducted. The majority of children (77%) and half of adults (50%) met criteria for CAS. Other speech outcomes were observed including articulation or phonological errors (i.e., phonetic and cognitive-linguistic errors, respectively), dysarthria (i.e., neuromuscular speech disorder), minimal verbal output, and even typical speech in some. Receptive and expressive language impairment was present in 73% and 70% of children, respectively. Co-occurring neurodevelopmental conditions (e.g., autism) and non-verbal IQ did not correlate with the presence of CAS. Findings indicate that CAS is highly prevalent in children with 16p11.2 deletion with symptoms persisting into adulthood for many. Yet CAS occurs in the context of a broader speech and language profile and other neurobehavioral deficits. Further research will elucidate specific genetic and neural pathways leading to speech and language deficits in individuals with 16p11.2 deletions, resulting in more targeted speech therapies addressing etiological pathways.

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