Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder

被引：1354

作者：

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

Walters, Raymond K. ^{[4
,5
,6
]}

Martin, Joanna ^{[6
,7
,8
]}

Mattheisen, Manuel ^{[1
,2
,3
,9
,10
,11
]}

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

Agerbo, Esben ^{[1
,12
,13
]}

Baldursson, Gisli ^{[14
]}

Belliveau, Rich ^{[6
]}

Bybjerg-Grauholm, Jonas ^{[1
,15
]}

Baekvad-Hansen, Marie ^{[1
,15
]}

Cerrato, Felecia ^{[6
]}

Chambert, Kimberly ^{[6
]}

Churchhouse, Claire ^{[4
,5
,6
,16
]}

Dumont, Ashley ^{[6
]}

Eriksson, Nicholas ^{[17
]}

Gandal, Michael ^{[18
,19
,20
,21
,22
]}

Goldstein, Jacqueline I. ^{[4
,5
,6
,16
]}

Grasby, Katrina L. ^{[23
]}

Grove, Jakob ^{[1
,2
,3
,24
]}

Gudmundsson, Olafur O. ^{[14
,25
,26
]}

Hansen, Christine S. ^{[1
,15
,27
]}

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

Hollegaard, Mads V. ^{[1
,15
]}

Howrigan, Daniel P. ^{[4
,5
,6
]}

Huang, Hailiang ^{[4
,5
,6
]}

Maller, Julian B. ^{[6
,28
]}

Martin, Alicia R. ^{[4
,5
,6
,16
]}

Martin, Nicholas G. ^{[23
]}

Moran, Jennifer ^{[6
]}

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

Palmer, Duncan S. ^{[4
,5
,6
]}

Pedersen, Carsten Bocker ^{[1
,12
,13
]}

Pedersen, Marianne Giortz ^{[1
,12
,13
]}

Poterba, Timothy ^{[4
,5
,6
,16
]}

Poulsen, Jesper Buchhave ^{[1
,15
]}

Ripke, Stephan ^{[4
,5
,6
,29
]}

Robinson, Elise B. ^{[4
,5
,30
]}

Satterstrom, F. Kyle ^{[4
,5
,6
,16
]}

Stefansson, Hreinn ^{[25
]}

Stevens, Christine ^{[6
]}

Turley, Patrick ^{[4
,5
,6
]}

Walters, G. Bragi ^{[25
,26
]}

Won, Hyejung ^{[18
,19
,20
]}

Wright, Margaret J. ^{[31
]}

Andreassen, Ole A. ^{[32
,33
]}

Asherson, Philip ^{[34
]}

Burton, Christie L. ^{[35
]}

Boomsma, Dorret I. ^{[36
,37
]}

Cormand, Bru ^{[38
,39
,40
,41
]}

Dalsgaard, Soren ^{[12
]}

机构：

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

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

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

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

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

[6] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA

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

[8] Cardiff Univ, Sch Med, MRC Ctr Neuropsychiat Genet & Genom, Cardiff, S Glam, Wales

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

[10] Stockholm Cty Council, Stockholm Hlth Care Serv, Stockholm, Sweden

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

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

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

[14] Natl Univ Hosp Reykjavik, Dept Child & Adolescent Psychiat, Reykjavik, Iceland

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

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

[17] 23andMe Inc, Mountain View, CA USA

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

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

[20] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Ctr Neurobehav Genet, Los Angeles, CA 90024 USA

[21] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA

[22] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Dept Psychiat, Los Angeles, CA 90024 USA

[23] QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia

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

[25] deCODE Genet Amgen, Reykjavik, Iceland

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

[27] Mental Hlth Serv Copenhagen, Inst Biol Psychiat, MHC Sct Hans, Roskilde, Denmark

[28] Genomics Plc, Oxford, England

[29] Charite Univ Med Berlin, Dept Psychiat & Psychotherapy, Berlin, Germany

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

[31] Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia

[32] Univ Oslo, NORMENT KG Jebsen Ctr Psychosis Res, Div Mental Hlth & Addict, Oslo, Norway

[33] Oslo Univ Hosp, Oslo, Norway

[34] Kings Coll London, Social Genet & Dev Psychiat Ctr, Inst Psychiat Psychol & Neurosci, London, England

[35] Univ Toronto, Hosp Sick Children, Psychiat Neurosci & Mental Hlth, Toronto, ON, Canada

[36] Vrije Univ Amsterdam, Neurosci Campus Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands

[37] EMGO Inst Hlth & Care Res, Amsterdam, Netherlands

[38] Univ Barcelona, Fac Biol, Dept Genet Microbiol & Estadist, Barcelona, Catalonia, Spain

[39] Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Raras CIBERER, Madrid, Spain

[40] Univ Barcelona, Inst Biomed, Barcelona, Catalonia, Spain

[41] Inst Recerca St Joan Deu IRSJD, Barcelona, Catalonia, Spain

[42] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet 855, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands

[43] Yale Univ, Sch Med, Dept Psychiat Genet & Neurosci, New Haven, CT USA

[44] Vet Affairs Connecticut Healthcare Ctr, West Haven, CT USA

[45] Univ Penn, Childrens Hosp Philadelphia, Perelman Sch Med, Ctr Appl Genom, Philadelphia, PA 19104 USA

[46] Univ Bergen, KG Jebsen Ctr Neuropsychiat Disorders, Dept Biomed, Bergen, Norway

[47] Haukeland Hosp, Bergen, Norway

[48] Univ Penn, Perelman Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA

[49] Crescenz VA Med Ctr, Vet Integrated Serv Network VISN4, Mental Illness Res Educ & Clin Ctr, Philadelphia, PA USA

[50] Cardiff Univ, Sch Psychol, Cardiff, S Glam, Wales

来源：

NATURE GENETICS | 2019年 / 51卷 / 01期

基金：

英国医学研究理事会; 澳大利亚国家健康与医学研究理事会; 英国惠康基金; 澳大利亚研究理事会; 欧洲研究理事会;

关键词：

DEFICIT-HYPERACTIVITY DISORDER; LD SCORE REGRESSION; ASSOCIATION METAANALYSIS; GENETIC ARCHITECTURE; PROVIDES INSIGHTS; MAJOR DEPRESSION; SEXUAL-BEHAVIOR; POLYGENIC RISK; IDENTIFIES; 11; US CHILDREN;

D O I：

10.1038/s41588-018-0269-7

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits.

引用

页码：63 / +

页数：16

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