Identification of common genetic risk variants for autism spectrum disorder

被引：1423

作者：

Grove, Jakob ^{[1
,2
,3
,4
]}

Ripke, Stephan ^{[5
,6
,7
,8
,9
]}

Als, Thomas D. ^{[1
,2
,3
]}

Mattheisen, Manuel ^{[1
,2
,3
,10
,11
]}

Walters, Raymond K. ^{[5
,6
,7
,8
]}

Won, Hyejung ^{[12
,13
]}

Pallesen, Jonatan ^{[1
,2
,3
]}

Agerbo, Esben ^{[1
,14
,15
]}

Andreassen, Ole A. ^{[16
,17
]}

Anney, Richard ^{[18
]}

Awashti, Swapnil ^{[9
]}

Belliveau, Rich ^{[7
,8
]}

Bettella, Francesco ^{[16
,17
]}

Buxbaum, Joseph D. ^{[19
,20
,21
,22
]}

Bybjerg-Grauholm, Jonas ^{[1
,23
]}

Baekvad-Hansen, Marie ^{[1
,23
]}

Cerrato, Felecia ^{[7
,8
]}

Chambert, Kimberly ^{[7
,8
]}

Christensen, Jane H. ^{[1
,2
,3
]}

Churchhouse, Claire ^{[5
,6
,7
,8
,24
]}

Dellenvall, Karin ^{[25
]}

Demontis, Ditte ^{[1
,2
,3
]}

De Rubeis, Silvia ^{[19
,20
]}

Devlin, Bernie ^{[26
]}

Djurovic, Srdjan ^{[16
,27
]}

Dumont, Ashley L. ^{[7
,8
]}

Goldstein, Jacqueline, I ^{[5
,6
,7
,8
,24
]}

Hansen, Christine S. ^{[1
,23
,28
]}

Hauberg, Mads Engel ^{[1
,2
,3
]}

Hollegaard, Mads, V ^{[1
,23
]}

Hope, Sigrun ^{[16
,29
]}

Howrigan, Daniel P. ^{[5
,6
,7
,8
]}

Huang, Hailiang ^{[5
,6
,7
,8
]}

Hultman, Christina M. ^{[25
]}

Klei, Lambertus ^{[26
]}

Maller, Julian ^{[7
,8
,30
,31
]}

Martin, Joanna ^{[7
,8
,18
,25
]}

Martin, Alicia R. ^{[5
,6
,7
,8
,24
]}

Moran, Jennifer L. ^{[7
,8
]}

Nyegaard, Mette ^{[1
,2
,3
]}

Naerland, Terje ^{[16
,32
]}

Palmer, Duncan S. ^{[5
,6
,7
,8
]}

Palotie, Aarno ^{[5
,6
,7
,8
,24
,33
]}

Pedersen, Carsten Bocker ^{[1
,14
,15
]}

Pedersen, Marianne Giortz ^{[1
,14
,15
]}

dPoterba, Timothy ^{[5
,6
,7
,8
,24
]}

Poulsen, Jesper Buchhave ^{[1
,23
]}

St Pourcain, Beate ^{[34
,35
,36
]}

Qvist, Per ^{[1
,2
,3
]}

Rehnstrom, Karola ^{[37
]}

机构：

[1] Lundbeck Fdn Initiat Integrat Psychiat Res, iPSYCH, Aarhus, Denmark

[2] Aarhus Univ, Ctr Integrat Sequencing, iSEQ, Aarhus, Denmark

[3] Aarhus Univ, Dept Biomed Human Genet, Aarhus, Denmark

[4] Aarhus Univ, Bioinformat Res Ctr, Aarhus, Denmark

[5] Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA

[6] Harvard Med Sch, Boston, MA 02115 USA

[7] Board Inst Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA

[8] MIT, 77 Massachusetts Ave, Cambridge, MA 02139 USA

[9] Charite, Dept Psychiat & Psychotherapy, Berlin, Germany

[10] Univ Wurzburg, Dept Psychiat Psychosomat & Psychotherapy, Wurzburg, Germany

[11] Karolinska Inst, Ctr Psychiat Res, Dept Clin Neurosci, Stockholm, Sweden

[12] Univ N Carolina, Dept Genet, Chapel Hill, NC 27515 USA

[13] Univ N Carolina, UNC Neurosci Ctr, Chapel Hill, NC 27515 USA

[14] Aarhus Univ, Natl Ctr Register Based Res, Aarhus, Denmark

[15] Aarhus Univ, Ctr Integrated Register Based Res, Aarhus, Denmark

[16] Univ Oslo, NORMENT KG Jebsen Ctr Psychosis Res, Oslo, Norway

[17] Oslo Univ Hosp, Div Mental Hlth & Addict, Oslo, Norway

[18] Cardiff Univ, MRC Ctr Neuropsychiat Genet & Genom, Cardiff, S Glam, Wales

[19] Icahn Sch Med Mt Sinai, Seaver Autism Ctr Res & Treatment, New York, NY 10029 USA

[20] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA

[21] Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 10029 USA

[22] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA

[23] Statens Serum Inst, Ctr Neonatal Screening, Dept Congenital Disorders, Copenhagen, Denmark

[24] Broad Inst Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA

[25] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden

[26] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA

[27] Oslo Univ Hosp, Dept Med Genet, Oslo, Norway

[28] Inst Biol Psychiat, Mental Hlth Serv, MHC SctHans, Copenhagen, Denmark

[29] Oslo Univ Hosp, Dept Neurohabilitat, Oslo, Norway

[30] Genom Plc, Oxford, England

[31] Vertex Pharmaceut, Abingdon, Oxon, England

[32] Oslo Univ Hosp, Dept Rare Disorders & Disabil, NevSom, Oslo, Norway

[33] Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland

[34] Max Planck Inst Psycholinguist, Language & Genet Dept, Nijmegen, Netherlands

[35] Univ Bristol, MRC Integrat Epidemiol Unit, Bristol, Avon, England

[36] Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands

[37] Wellcome Trust Sanger Inst, Cambridge, England

[38] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA

[39] Carnegie Mellon Univ, Computat Biol Dept, Pittsburgh, PA 15213 USA

[40] Carnegie Mellon Univ, Dept Stat & Data Sci, Pittsburgh, PA 15213 USA

[41] Icahn Sch Med Mt Sinai, Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, New York, NY 10029 USA

[42] Icahn Sch Med Mt Sinai, Friedman Brain Inst, Dept Neurosci, New York, NY 10029 USA

[43] James J Peters VA Med Ctr, Mental Illness Res Educ & Clin Ctr, Bronx, NY USA

[44] State Diagnost & Counselling Ctr, Kopavogur, Iceland

[45] Univ Bristol, Bristol Med Sch, Populat Hlth Sci, Bristol, Avon, England

[46] deCODE Genet Amgen, Reykjavik, Iceland

[47] Univ N Carolina, Dept Psychiat, Chapel Hill, NC 27515 USA

[48] Univ Iceland, Fac Med, Reykjavik, Iceland

[49] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Program Neurogenet, Los Angeles, CA 90095 USA

[50] Univ Calif Los Angeles, Ctr Autism Res & Treatment, Los Angeles, CA USA

来源：

NATURE GENETICS | 2019年 / 51卷 / 03期

基金：

英国惠康基金;

关键词：

GENOME-WIDE ASSOCIATION; SIMONS SIMPLEX COLLECTION; LD SCORE REGRESSION; DE-NOVO; SYNAPTIC PLASTICITY; NEURITE OUTGROWTH; CELL-SURFACE; LOCI; HERITABILITY; METAANALYSIS;

D O I：

10.1038/s41588-019-0344-8

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：431 / +

页数：16

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