Genome-wide analyses of ADHD identify 27 risk loci, refine the genetic architecture and implicate several cognitive domains

被引：316

作者：

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

Walters, G. Bragi ^{[4
,5
]}

Athanasiadis, Georgios ^{[2
,6
,7
]}

Walters, Raymond ^{[8
,9
,10
]}

Therrien, Karen ^{[11
,12
,13
,14
,15
,16
]}

Nielsen, Trine Tollerup ^{[1
,2
,3
]}

Farajzadeh, Leila ^{[1
,2
,3
]}

Voloudakis, Georgios ^{[11
,12
,13
,14
,15
]}

Bendl, Jaroslav ^{[11
,12
,13
,15
]}

Zeng, Biau ^{[11
,12
,13
,15
]}

Zhang, Wen ^{[11
,12
,13
,15
]}

Grove, Jakob ^{[1
,2
,17
]}

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

Duan, Jinjie ^{[1
,2
,3
]}

Satterstrom, F. Kyle ^{[8
,9
,10
]}

Bybjerg-Grauholm, Jonas ^{[2
,18
]}

Baekved-Hansen, Marie ^{[2
,18
]}

Gudmundsson, Olafur O. ^{[4
,5
]}

Magnusson, Sigurdur H. ^{[4
]}

Baldursson, Gisli ^{[19
]}

Davidsdottir, Katrin ^{[20
]}

Haraldsdottir, Gyda S. ^{[20
]}

Agerbo, Esben ^{[2
,21
,22
]}

Hoffman, Gabriel E. ^{[11
,12
,13
,15
]}

Dalsgaard, Soren ^{[21
,23
,24
]}

Martin, Joanna ^{[25
]}

Ribases, Marta ^{[26
,27
,28
,29
]}

Boomsma, Dorret, I ^{[30
,31
]}

Artigas, Maria Soler ^{[26
,27
,28
,29
]}

Mota, Nina Roth ^{[32
,33
]}

Howrigan, Daniel ^{[8
,9
,10
]}

Medland, Sarah E. ^{[34
]}

Zayats, Tetyana ^{[8
,9
,10
,35
]}

Rajagopal, Veera M. ^{[1
,2
,3
]}

Nordentoft, Merete ^{[2
,36
]}

Mors, Ole ^{[2
,37
]}

Hougaard, David M. ^{[2
,18
]}

Mortensen, Preben Bo ^{[2
,21
,22
]}

Daly, Mark J. ^{[8
,9
,10
,38
,39
]}

Faraone, Stephen, V ^{[40
,41
]}

Stefansson, Hreinn ^{[4
]}

Roussos, Panos ^{[11
,12
,13
,14
,15
,42
]}

Franke, Barbara ^{[32
,33
,43
]}

Werge, Thomas ^{[2
,6
]}

Neale, Benjamin M. ^{[8
,9
,10
]}

Stefansson, Kari ^{[4
,5
]}

Borglum, Anders D. ^{[1
,2
,3
]}

机构：

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

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

[3] Ctr Genom & Personalized Med, Aarhus, Denmark

[4] Amgen Inc, deCODE Genet, Reykjavik, Iceland

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

[6] Copenhagen Univ Hosp, Mental Hlth Ctr Sct Hans, Inst Biol Psychiat, Capital Reg Denmark, Copenhagen, Denmark

[7] Univ Barcelona, Dept Evolutionary Biol Ecol & Environm Sci, Barcelona, Spain

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

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

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

[11] Icahn Sch Med Mt Sinai, Ctr Dis Neurogen, New York, NY 10029 USA

[12] Icahn Sch Med Mt Sinai, Icahn Inst Data Sci & Genom Technol, New York, NY 10029 USA

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

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

[15] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA

[16] Icahn Sch Med Mt Sinai, Nash Family Dept Neurosci, New York, NY 10029 USA

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

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

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

[20] Capital Area Primary Hlth Care, Ctr Child Dev & Behav, Reykjavik, Iceland

[21] Aarhus Univ, Natl Ctr Register Based Res Business & Social Sci, Aarhus, Denmark

[22] Aarhus Univ, Ctr Integrated Register Based Res, CIRRAU, Aarhus, Denmark

[23] Child & Adolescent Psychiat Ctr, Mental Hlth Serv Capital Reg, Glostrup, Denmark

[24] Univ Copenhagen, Inst Clin Med, Copenhagen, Denmark

[25] Cardiff Univ, Psychol Med & Clin Neurosci, Cardiff, Wales

[26] Univ Autonoma Barcelona, Vall dHebron Res Inst VHIR, Psychiat Genet Unit, Grp Psychiat Mental Hlth & Addict, Barcelona, Spain

[27] Hosp Univ Vall dHebron, Dept Psychiat, Barcelona, Spain

[28] Inst Salud Carlos III, Biomed Network Res Ctr Mental Hlth CIBERSAM, Madrid, Spain

[29] Univ Barcelona, Fac Biol, Dept Genet Microbiol & Stat, Barcelona, Spain

[30] Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands

[31] Amsterdam Publ Hlth Res Inst, Amsterdam, Netherlands

[32] Radboud Univ Nijmegen Med Ctr, Dept Human Genet, Nijmegen, Netherlands

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

[34] QIMR Berghofer Med Res Inst, Psychiat Genet, Brisbane, Qld, Australia

[35] Univ Oslo, Dept Psychol, PROMENTA, Oslo, Norway

[36] Copenhagen Univ Hosp, Mental Hlth Ctr Copenhagen, Capital Reg Denmark, Copenhagen, Denmark

[37] Aarhus Univ Hosp Psychiat, Psychosis Res Unit, Aarhus, Denmark

[38] Harvard Med Sch, Dept Med, Boston, MA 02115 USA

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

[40] SUNY Upstate Med Univ, Dept Psychiat, Syracuse, NY 13210 USA

[41] SUNY Upstate Med Univ, Dept Neurosci & Physiol, Syracuse, NY 13210 USA

[42] JJ Peters VA Med Ctr, Mental Illness Res Educ & Clin Ctr, Bronx, NY USA

[43] Radboud Univ Nijmegen Med Ctr, Dept Psychiat, Nijmegen, Netherlands

来源：

NATURE GENETICS | 2023年 / 55卷 / 2期

基金：

美国国家卫生研究院; 欧盟地平线“2020”; 英国医学研究理事会;

关键词：

DEFICIT HYPERACTIVITY DISORDER; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; AUTISM SPECTRUM DISORDER; LD SCORE REGRESSION; CAUSAL VARIANTS; HERITABILITY; ASSOCIATION; POPULATION; CHILDREN; COHORT;

D O I：

10.1038/s41588-022-01285-8

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 prevalent neurodevelopmental disorder with a major genetic component. Here, we present a genome-wide association study meta-analysis of ADHD comprising 38,691 individuals with ADHD and 186,843 controls. We identified 27 genome-wide significant loci, highlighting 76 potential risk genes enriched among genes expressed particularly in early brain development. Overall, ADHD genetic risk was associated with several brain-specific neuronal subtypes and midbrain dopaminergic neurons. In exome-sequencing data from 17,896 individuals, we identified an increased load of rare protein-truncating variants in ADHD for a set of risk genes enriched with probable causal common variants, potentially implicating SORCS3 in ADHD by both common and rare variants. Bivariate Gaussian mixture modeling estimated that 84-98% of ADHD-influencing variants are shared with other psychiatric disorders. In addition, common-variant ADHD risk was associated with impaired complex cognition such as verbal reasoning and a range of executive functions, including attention. Genome-wide analyses identify 27 loci associated with attention-deficit hyperactivity disorder and provide insights into its genetic architecture in relation to other psychiatric disorders and cognitive traits.

引用

页码：198 / 208

页数：18

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