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Nat Genet. 2019 Mar;51(3):431-444. doi: 10.1038/s41588-019-0344-8. Epub 2019 Feb 25.

Identification of common genetic risk variants for autism spectrum disorder.

Collaborators (200)

Wray NR, Trzaskowski M, Byrne EM, Abdellaoui A, Adams MJ, Air TM, Andlauer TFM, Bacanu SA, Beekman ATF, Bigdeli TB, Binder EB, Blackwood DHR, Bryois J, Buttenschøn HN, Cai N, Castelao E, Clarke TK, Coleman JRI, Colodro-Conde L, Couvy-Duchesne B, Craddock N, Crawford GE, Davies G, Deary IJ, Degenhardt F, Derks EM, Direk N, Dolan CV, Dunn EC, Eley TC, Escott-Price V, Kiadeh FFH, Finucane HK, Forstner AJ, Frank J, Gaspar HA, Gill M, Goes FS, Gordon SD, Hall LS, Hansen TF, Herms S, Hickie IB, Hoffmann P, Homuth G, Horn C, Hottenga JJ, Ising M, Jansen R, Jorgenson E, Knowles JA, Kohane IS, Kraft J, Kretzschmar WW, Krogh J, Kutalik Z, Li Y, Lind PA, MacIntyre DJ, MacKinnon DF, Maier RM, Maier W, Marchini J, Mbarek H, McGrath P, McGuffin P, Medland SE, Mehta D, Middeldorp CM, Mihailov E, Milaneschi Y, Milani L, Mondimore FM, Montgomery GW, Mostafavi S, Mullins N, Nauck M, Ng B, Nivard MG, Nyholt DR, O'Reilly PF, Oskarsson H, Owen MJ, Painter JN, Peterson RE, Pettersson E, Peyrot WJ, Pistis G, Posthuma D, Quiroz JA, Rice JP, Riley BP, Rivera M, Mirza SS, Schoevers R, Schulte EC, Shen L, Shi J, Shyn SI, Sigurdsson E, Sinnamon GCB, Smit JH, Smith DJ, Streit F, Strohmaier J, Tansey KE, Teismann H, Teumer A, Thompson W, Thomson PA, Thorgeirsson TE, Traylor M, Treutlein J, Trubetskoy V, Uitterlinden AG, Umbricht D, Van der Auwera S, van Hemert AM, Viktorin A, Visscher PM, Wang Y, Webb BT, Weinsheimer SM, Wellmann J, Willemsen G, Witt SH, Wu Y, Xi HS, Yang J, Zhang F, Arolt V, Baune BT, Berger K, Boomsma DI, Cichon S, Dannlowski U, de Geus EJC, DePaulo JR, Domenici E, Domschke K, Esko T, Grabe HJ, Hamilton SP, Hayward C, Heath AC, Kendler KS, Kloiber S, Lewis G, Li QS, Lucae S, Madden PAF, Magnusson PK, Martin NG, McIntosh AM, Metspalu A, Müller-Myhsok B, Nöthen MM, O'Donovan MC, Paciga SA, Pedersen NL, Penninx BWJH, Perlis RH, Porteous DJ, Potash JB, Preisig M, Rietschel M, Schaefer C, Schulze TG, Smoller JW, Tiemeier H, Uher R, Völzke H, Weissman MM, Lewis CM, Levinson DF, Breen G, Agee M, Alipanahi B, Auton A, Bell RK, Bryc K, Elson SL, Fontanillas P, Furlotte NA, Hromatka BS, Huber KE, Kleinman A, Litterman NK, McIntyre MH, Mountain JL, Noblin ES, Northover CAM, Pitts SJ, Sathirapongsasuti JF, Sazonova OV, Shelton JF, Shringarpure S, Tung JY, Vacic V, Wilson CH.

Author information

1
The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark.
2
Centre for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark.
3
Department of Biomedicine-Human Genetics, Aarhus University, Aarhus, Denmark.
4
Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark.
5
Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
6
Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
7
Department of Psychiatry and Psychotherapy, Charité-Universitätsmedizin, Berlin, Germany.
8
Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Würzburg, Germany.
9
Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
10
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
11
UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
12
National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark.
13
Centre for Integrated Register-based Research, Aarhus University, Aarhus, Denmark.
14
NORMENT-KG Jebsen Centre for Psychosis Research, University of Oslo, Oslo, Norway.
15
Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
16
MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
17
Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
18
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
19
Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
20
Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
21
Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark.
22
Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
23
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
24
Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
25
Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
26
Institute of Biological Psychiatry, MHC SctHans, Mental Health Services, Copenhagen, Denmark.
27
Department of Neurohabilitation, Oslo University Hospital, Oslo, Norway.
28
Genomics plc, Oxford, UK.
29
Vertex Pharmaceuticals, Abingdon, UK.
30
NevSom, Department of Rare Disorders and Disabilities, , Oslo University Hospital, Oslo, Norway.
31
Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
32
Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, the Netherlands.
33
MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
34
Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, the Netherlands.
35
Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
36
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
37
Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA, USA.
38
Department of Statistics and Data Science, Carnegie Mellon University, Pittsburgh, PA, USA.
39
Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
40
Friedman Brain Institute, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
41
Mental Illness Research Education and Clinical Center (MIRECC), James J. Peters VA Medical Center, Bronx, NY, USA.
42
The State Diagnostic and Counselling Centre, Kópavogur, Iceland.
43
Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
44
deCODE genetics/Amgen, Reykjavík, Iceland.
45
Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
46
Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
47
Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
48
Center for Autism Research and Treatment and Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA.
49
Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
50
Mental Health Services in the Capital Region of Denmark, Mental Health Center Copenhagen, University of Copenhagen, Copenhagen, Denmark.
51
Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
52
Psychosis Research Unit, Aarhus University Hospital, Risskov, Denmark.
53
Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. mjdaly@atgu.mgh.harvard.edu.
54
Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA. mjdaly@atgu.mgh.harvard.edu.
55
Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA. mjdaly@atgu.mgh.harvard.edu.
56
Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland. mjdaly@atgu.mgh.harvard.edu.
57
The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark. anders@biomed.au.dk.
58
Centre for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark. anders@biomed.au.dk.
59
Department of Biomedicine-Human Genetics, Aarhus University, Aarhus, Denmark. anders@biomed.au.dk.

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.

PMID:
30804558
PMCID:
PMC6454898
DOI:
10.1038/s41588-019-0344-8
[Indexed for MEDLINE]
Free PMC Article

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