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Identification of common genetic risk variants for autism spectrum disorder

Abstract

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

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Fig. 1: Manhattan plots.
Fig. 2: Genetic correlation with other traits.
Fig. 3: Profiling PRS load across distinct ASD subgroups.
Fig. 4: Decile plots (OR) by PRS within each decile for 13,076 cases and 22,664 controls.
Fig. 5: Chromatin interactions identify putative target genes of ASD loci.

Data availability

The summary statistics are available for download the iPSYCH and at the PGC download sites (see URLs). For access to genotype data from the PGC samples and the iPSYCH sample, researchers should contact the lead principal investigators M.J.D. and A.D.B. for PGC-ASD and iPSYCH-ASD, respectively.

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Acknowledgements

The iPSYCH project is funded by the Lundbeck Foundation (R102-A9118 and R155-2014-1724) and the universities and university hospitals of Aarhus and Copenhagen. Genotyping of iPSYCH and PGC samples was supported by grants from the Lundbeck Foundation, the Stanley Foundation, the Simons Foundation (SFARI 311789 to M.J.D.), and NIMH (5U01MH094432-02 to M.J.D.). The Danish National Biobank resource was supported by the Novo Nordisk Foundation. Data handling and analysis on the GenomeDK HPC facility was supported by NIMH (1U01MH109514-01 to M.C.O.D and A.D.B.). High-performance computer capacity for handling and statistical analysis of iPSYCH data on the GenomeDK HPC facility was provided by the Centre for Integrative Sequencing, iSEQ, Aarhus University, Denmark (grant to A.D.B.). S.D.R. and J.D.B. were supported by NIH grants MH097849 (to J.D.B.) and MH111661 (to J.D.B.), and by the Seaver Foundation (to S.D.R. and J.D.B.). J. Martine was supported by the Wellcome Trust (grant 106047). O.A.A. received funding from the Research Council of Norway (213694, 223273, 248980, and 248778), Stiftelsen KG Jebsen, and South-East Norway Health Authority. We thank the research participants and employees of 23andMe for making this work possible.

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Analysis: J.G., S.R., T.D.A., M.M., R.K.W., H.W., J.P., S.A., F.B., J.H.C., C.C., K.D., S.D.R., B.D., S.D., M.E.H., S.H., D.P.H., H.H., L.K., J. Maller, J. Martin, A.R.M., M. Nyegaard, T.N., D.S.P., T.P., B.S.P., P.Q., J.R., E.B.R., K. Roeder, P.R., S. Sandin, F.K.S., S. Steinberg, P.F.S., P.T., G.B.W., X.X., D.H.G., B.M.N., M.J.D., A.D.B. J.G., B.M.N., M.J.D., and A.D.B. supervised and coordinated the analyses. Sample and/or data provider and processing: J.G., S.R., M.M., R.K.W., E.A., O.A.A., R.A., R.B., J.D.B., J.B.-G., M.B.-H., F.C., K.C., D.D., A.L.D., J.I.G., C.S.H., M.V.H., C.M.H., J.L.M., A.P., C.B.P., M.G.P., J.B.P., K. Rehnström, A.R., E.S., G.D.S., H.S., C.R.S., Autism Spectrum Disorder Working Group of the Psychiatric Genomics Consortium, BUPGEN, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, 23andMe Research Team, K.S., D.M.H., O.M., P.B.M., B.M.N., M.J.D., and A.D.B. Core PI group: K.S., D.H.G., M. Nordentoft, D.M.H., T.W., O.M., P.B.M., B.M.N., M.J.D., and A.D.B. Core writing group: J.G., M.J.D., and A.D.B. Direction of study: M.J.D. and A.D.B.

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Correspondence to Mark J. Daly or Anders D. Børglum.

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H.S., K.S., S. Steinberg, and G.B.W. are employees of deCODE genetics/Amgen. The 23andMe Research Team members are employed by 23andMe. D.H.G. is a scientific advisor for Ovid Therapeutic, Falcon Computing, and Axial Biotherapeutics. T.W. has acted as scientific advisor and lecturer for H. Lundbeck A/S.

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Grove, J., Ripke, S., Als, T.D. et al. Identification of common genetic risk variants for autism spectrum disorder. Nat Genet 51, 431–444 (2019). https://doi.org/10.1038/s41588-019-0344-8

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