Journal article

Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders

Tianyun Wang, Kendra Hoekzema, Davide Vecchio, Huidan Wu, Arvis Sulovari, Bradley P Coe, Madelyn A Gillentine, Amy B Wilfert, Luis A Perez-Jurado, Malin Kvarnung, Yoeri Sleyp, Rachel K Earl, Jill A Rosenfeld, Madeleine R Geisheker, Lin Han, Bing Du, Chris Barnett, Elizabeth Thompson, Marie Shaw, Renee Carroll Show all

Nature Communications | NATURE RESEARCH | Published : 2020

Abstract

Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case-control mutation burden analysis is unestablished. Here, we sequence 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. By combining these with published data, we assess a total of 125 genes in over 16,000 NDD cases and compare the mutation burden to nonpsychiatric controls from ExAC. We identify 48 genes (25 newly reported) showing significant burden of ultra-rare (MAF < 0.01%) gene-disruptive mutations (FDR 5%), six of which reach family-wise error rate (FWER) significance (p < 1.25E-06). Among these 125 targeted gen..

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Grants

Awarded by US National Institutes of Health (NIH)


Awarded by Simons Foundation (SFARI)


Awarded by National Natural Science Foundation of China (NSFC)


Awarded by Science and Technology Projects of Hunan Province


Awarded by Australian National Health and Medical Research Council


Awarded by Czech Ministry of Health


Awarded by Netherlands Organization for Scientific Research (NWO)


Awarded by Italian Ministry of Health


Awarded by NIH


Funding Acknowledgements

The authors are grateful to all of the families for participation in this study. We thank the following: the SPARK Consortium for access to the SPARK-27K exome data; Tychele N. Turner for the early access of autism sex-biased candidate genes during gene selection; Marlies Schimmel-Naber for help with sample management and logistics of the RadboudUMC cohort; Cherie Green for the help in the preparation of Melbourne samples; Yafei Mao for the helpful discussion during the manuscript preparation; and Tonia Brown for assistance in editing this manuscript. This work was supported, in part, by a US National Institutes of Health (NIH) grant (R01MH101221) and a grant from the Simons Foundation (SFARI #608045) to E.E.E.; National Natural Science Foundation of China (NSFC) (81525007 and 81730036) and the Science and Technology Projects of Hunan Province (2018SK1030) to K.X.; Australian National Health and Medical Research Council (APP1091593 and 1155224) and Channel 7 Children's Research Foundation to J.G. The Charles University group was supported by grant 17-29423A from the Czech Ministry of Health. R.F.K. acknowledges support of the Research Fund of the University of Antwerp (Methusalem-OEC grant-GENOMED). The BOA study was partly funded by a grant assigned to N. Rommelse by the Netherlands Organization for Scientific Research (NWO grant #91610024). C.R., E.A., G.C., M.E., and D.G. were supported in part by the Italian Ministry of Health (RC2019 no. 2751604). I.E.S., M.D., and P.J.L. were supported by an Australian National Health and Medical Research Council project grant; I.E.S. is supported by a NHRMC Practitioner Fellowship and P.J.L. is supported by the Vincent Chiodo Foundation. A.S. and M.A.G. were supported by NIH Genome Training Grant T32 HG000035-23. G.V.D.W. holds an FWO postdoctoral fellowship. We thank Daniel H. Geschwind for the early access of the candidate genes from their autism network analysis, which was supported, in part, by NIH (R01MH109912). E.E.E. is an investigator of the Howard Hughes Medical Institute.