Abstract
Autism spectrum disorders (ASD) are believed to have genetic and environmental origins, yet in only a modest fraction of individuals can specific causes be identified1,2. To identify further genetic risk factors, here we assess the role of de novo mutations in ASD by sequencing the exomes of ASD cases and their parents (n = 175 trios). Fewer than half of the cases (46.3%) carry a missense or nonsense de novo variant, and the overall rate of mutation is only modestly higher than the expected rate. In contrast, the proteins encoded by genes that harboured de novo missense or nonsense mutations showed a higher degree of connectivity among themselves and to previous ASD genes3 as indexed by protein-protein interaction screens. The small increase in the rate of de novo events, when taken together with the protein interaction results, are consistent with an important but limited role for de novo point mutations in ASD, similar to that documented for de novo copy number variants. Genetic models incorporating these data indicate that most of the observed de novo events are unconnected to ASD; those that do confer risk are distributed across many genes and are incompletely penetrant (that is, not necessarily sufficient for disease). Our results support polygenic models in which spontaneous coding mutations in any of a large number of genes increases risk by 5- to 20-fold. Despite the challenge posed by such models, results from de novo events and a large parallel case–control study provide strong evidence in favour of CHD8 and KATNAL2 as genuine autism risk factors.
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Data deposits
Data included in this manuscript have been deposited at dbGaP under accession number phs000298.v1.p1 and is available for download at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id5phs000298.v1.p1.
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Acknowledgements
This work was directly supported by NIH grants R01MH089208 (M.J.D.), R01 MH089025 (J.D.B.), R01 MH089004 (G.D.S.), R01MH089175 (R.A.G.) and R01 MH089482 (J.S.S.), and supported in part by NIH grants P50 HD055751 (E.H.C.), RO1 MH057881 (B.D.) and R01 MH061009 (J.S.S.). Y.K., G.C. and S.Y. are Seaver Fellows, supported by the Seaver Foundation. We thank T. Lehner, A. Felsenfeld and P. Bender for their support and contribution to the project. We thank S. Sanders and M. State for discussions on the interpretation of de novo events. We thank D. Reich for comments on the abstract and message of the manuscript. We thank E. Lander and D. Altshuler for comments on the manuscript. We acknowledge the assistance of M. Potter, A. McGrew and G. Crockett without whom these studies would not be possible, and Center for Human Genetics Research resources: Computational Genomics Core, Genetic Studies Ascertainment Core and DNA Resources core, supported in part by NIH NCRR grant UL1 RR024975, and the Vanderbilt Kennedy Center for Research on Human Development (P30 HD015052). This work was supported in part by R01MH084676 (S.S.). We acknowledge the clinicians and organizations that contributed to samples used in this study and the particular support of the Mount Sinai School of Medicine, University of Illinois-Chicago, Vanderbilt University, the Autism Genetics Resource Exchange and the institutions of the Boston Autism Consortium. We acknowledge A. Estes and G. Dawson for patient collection/characterization. We acknowledge partial support from U54 HG003273 (R.A.G.) and U54 HG003067 (E. Lander). J.D.B., B.D., M.J.D., R.A.G., A.S., G.D.S. and J.S.S. are lead investigators in the Autism Sequencing Consortium (ASC). The ASC is comprised of groups sharing massively parallel sequencing data in autism. Finally, we are grateful to the many families, without whose participation this project would not have been possible.
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Laboratory work: A.S., C.St., G.C., O.J., Z.P., J.D.B., D.M., I.N., Y.W., L.L., Y.H., S.G., E.L.C., N.G.C. and E.T.G. Data processing: B.M.N., K.E.S., E.L., A.K., J.F., M.F., K.S., T.F., K.G., E.Ba., R.P., M.DeP., S.G., S.Y., V.M., J.L., J.D.B., A.S., C.St., U.N., J.G.R., J.R.W., B.E.B., S.E.L., C.F.L., L.S.W. and O.V. Statistical analysis: B.M.N., L.L., K.E.S., C.Sh., B.F.V., J.M., E.R., S.S., P.P., Y.K., A.M., R.D., C.-F.L., L.-S.W., H.L., T.Z., E.Bo., R.A.G., J.D.B., C.B., E.H.C., J.S.S., G.D.S., B.D., K.R. and M.J.D. Principal Investigators/study design: E.Bo., R.A.G., E.H.C., J.D.B., K.R., B.D., G.D.S., J.S.S. and M.J.D. Y.K., L.L., A.M., K.E.S., A.S. and C.-F.L. contributed equally to this work. E.Bo., J.D.B., E.H.C., B.D., R.A.G., K.R., G.D.S., J.S.S. and M.J.D. are lead investigators of the ARRA Autism Sequencing Collaboration.
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Neale, B., Kou, Y., Liu, L. et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 485, 242–245 (2012). https://doi.org/10.1038/nature11011
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DOI: https://doi.org/10.1038/nature11011
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