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Identification of common genetic risk variants for autism spectrum disorder

Grove J 1 , Ripke S 2 , Als TD 1 , Mattheisen M 1 , Walters RK 2 , Won H 3 Show all authors , Pallesen J 1 , Agerbo E 1 , Andreassen OA 4 , Anney R 5 , Awashti S 6 , Belliveau R 7 , Bettella F 4 , Buxbaum JD 8 , Bybjerg-Grauholm J 1 , Bækvad-Hansen M 1 , Cerrato F 7 , Chambert K 7 , Christensen JH 1 , Churchhouse C 2 , Dellenvall K 9 , Demontis D 1 , De Rubeis S 8 , Devlin B 10 , Djurovic S 4 , Dumont AL 7 , Goldstein JI 2 , Hansen CS 1 , Hauberg ME 1 , Hollegaard MV 1 , Hope S 4 , Howrigan DP 2 , Huang H 2 , Hultman CM 9 , Klei L 10 , Maller J 7 , Martin J 7 , Martin AR 2 , Moran JL 7 , Nyegaard M 1 , Nærland T 4 , Palmer DS 2 , Palotie A 2 , Pedersen CB 1 , Pedersen MG 1 , dPoterba T 2 , Poulsen JB 1 , Pourcain BS 11 , Qvist P 1 , Rehnström K 12 , Reichenberg A 8 , Reichert J 8 , Robinson EB 2 , Roeder K 13 , Roussos P 14 , Saemundsen E 15 , Sandin S 8 , Satterstrom FK 2 , Davey Smith G 16 , Stefansson H 17 , Steinberg S 17 , Stevens CR 7 , Sullivan PF 3 , Turley P 2 , Walters GB 17 , Xu X 8 , Autism Spectrum Disorder Working Group of the Psychiatric Genomics Consortium , BUPGEN , Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium , 23andMe Research Team , Stefansson K 17 , Geschwind DH 18 , Nordentoft M 1 , Hougaard DM 1 , Werge T 1 , Mors O 1 , Mortensen PB 1 , Neale BM 2 , Daly MJ 19 , Børglum AD 20

Affiliations 

  • 1 The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark
  • 2 Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
  • 3 Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
  • 4 NORMENT-KG Jebsen Centre for Psychosis Research, University of Oslo, Oslo, Norway
  • 5 MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK
  • 6 Department of Psychiatry and Psychotherapy, Charité-Universitätsmedizin, Berlin, Germany
  • 7 Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA
  • 8 Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA
  • 9 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
  • 10 Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
  • 11 Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, the Netherlands
  • 12 Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK
  • 13 Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA, USA
  • 14 Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
  • 15 The State Diagnostic and Counselling Centre, Kópavogur, Iceland
  • 16 MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK
  • 17 deCODE genetics/Amgen, Reykjavík, Iceland
  • 18 Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
  • 19 Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. mjdaly@atgu.mgh.harvard.edu
  • 20 The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark. anders@biomed.au.dk
Nat Genet, 2019 03;51(3):431-444.
PMID: 30804558 DOI: 10.1038/s41588-019-0344-8

Abstract

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

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