Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence

被引：750

作者：

Savage, Jeanne E. ^{[1
]}

Jansen, Philip R. ^{[1
,2
]}

Stringer, Sven ^{[1
]}

Watanabe, Kyoko ^{[1
]}

Bryois, Julien ^{[3
]}

de Leeuw, Christiaan A. ^{[1
]}

Nagel, Mats ^{[4
]}

Awasthi, Swapnil ^{[5
]}

Barr, Peter B. ^{[6
]}

Coleman, Jonathan R. I. ^{[7
,8
]}

Grasby, Katrina L. ^{[9
]}

Hammerschlag, Anke R. ^{[1
]}

Kaminski, Jakob A. ^{[5
,10
]}

Karlsson, Robert ^{[3
]}

Krapohl, Eva ^{[7
]}

Lam, Max ^{[11
]}

Nygaard, Marianne ^{[12
,13
,14
]}

Reynolds, Chandra A. ^{[15
]}

Trampush, Joey W. ^{[16
,17
]}

Young, Hannah ^{[18
]}

Zabaneh, Delilah ^{[7
]}

Hagg, Sara ^{[3
]}

Hansell, Narelle K. ^{[19
]}

Karlsson, Ida K. ^{[3
]}

Linnarsson, Sten ^{[20
]}

Montgomery, Grant W. ^{[9
,21
]}

Munoz-Manchado, Ana B. ^{[20
]}

Quinlan, Erin B. ^{[22
]}

Schumann, Gunter ^{[22
]}

Skene, Nathan G. ^{[20
,23
]}

Webb, Bradley T. ^{[24
,25
]}

White, Tonya ^{[2
]}

Arking, Dan E. ^{[26
]}

Avramopoulos, Dimitrios ^{[26
,27
]}

Bilder, Robert M. ^{[28
]}

Bitsios, Panos ^{[29
]}

Burdick, Katherine E. ^{[30
,31
,32
]}

Cannon, Tyrone D. ^{[33
]}

Chiba-Falek, Ornit ^{[34
,35
]}

Christoforou, Andrea ^{[36
]}

Cirulli, Elizabeth T. ^{[37
]}

Congdon, Eliza ^{[28
]}

Corvin, Aiden ^{[38
,39
]}

Davies, Gail ^{[40
,41
]}

Deary, Ian J. ^{[40
,41
]}

DeRosse, Pamela ^{[42
,43
,44
]}

Dickinson, Dwight ^{[45
]}

Djurovic, Srdjan ^{[46
,47
]}

Donohoe, Gary ^{[48
,49
]}

Conley, Emily Drabant ^{[50
]}

机构：

[1] Vrije Univ Amsterdam, Ctr Neurogen & Cognit Res, Dept Complex Trait Genet, Amsterdam, Netherlands

[2] Erasmus MC, Dept Child & Adolescent Psychiat, Rotterdam, Netherlands

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

[4] Vrije Univ Amsterdam Med Ctr, Dept Clin Genet, Sect Complex Trait Genet, Neurosci Campus Amsterdam, Amsterdam, Netherlands

[5] Charite Univ Med Berlin, Dept Psychiat & Psychotherapy, Campus Mitte, Berlin, Germany

[6] Virginia Commonwealth Univ, Dept Psychol, Box 2018, Richmond, VA 23284 USA

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

[8] South London & Maudsley NHS Trust, NIHR Biomed Res Ctr Mental Hlth, London, England

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

[10] Berlin Inst Hlth, Berlin, Germany

[11] Inst Mental Hlth, Singapore, Singapore

[12] Univ Southern Denmark, Danish Twin Registry, Odense, Denmark

[13] Univ Southern Denmark, Danish Aging Res Ctr, Dept Publ Hlth, Odense, Denmark

[14] Univ Southern Denmark, Dept Publ Hlth, Epidemiol Biostat & Biodemog, Odense, Denmark

[15] Univ Calif Riverside, Dept Psychol, Riverside, CA 92521 USA

[16] BrainWorkup LLC, Los Angeles, CA USA

[17] Univ Southern Calif, Keck Sch Med, Dep Psychiat & Behav Sci, Los Angeles, CA USA

[18] Univ Minnesota, Dept Psychol, St Paul, MN 55108 USA

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

[20] Karolinska Inst, Dept Med Biochem & Biophys, Lab Mol Neurobiol, Stockholm, Sweden

[21] Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia

[22] Kings Coll London, MRC SGDP Ctr, Inst Psychiat Psychol & Neurosci, Ctr Populat Neurosci & Precis Med PONS, London, England

[23] UCL, Inst Neurol, Queen Sq, London, England

[24] Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Richmond, VA USA

[25] Virginia Commonwealth Univ, Dept Psychiat, Richmond, VA USA

[26] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA

[27] Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA

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

[29] Univ Crete, Dept Psychiat & Behav Sci, Fac Med, Iraklion, Greece

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

[31] James J Peters VA Med Ctr, Mental Illness Res Educ & Clin Ctr VISN 2, Bronx, NY USA

[32] Harvard Med Sch, Brigham & Womens Hosp, Dept Psychiat, Boston, MA USA

[33] Yale Univ, Dept Psychol, New Haven, CT USA

[34] Duke Univ, Med Ctr, Dept Neurol, Bryan Alzheimers Dis Res Ctr, Durham, NC USA

[35] Duke Univ, Med Ctr, Ctr Genom & Computat Biol, Durham, NC USA

[36] Haukeland Hosp, Dr Einar Martens Res Grp Biol Psychiat, Ctr Med Genet & Mol Med, Bergen, Norway

[37] Human Longev Inc, Durham, NC USA

[38] Trinity Coll Dublin, Dept Psychiat, Neuropsychiat Genet Res Grp, Dublin, Ireland

[39] Trinity Coll Dublin, Trinity Coll Inst Neurosci, Dublin, Ireland

[40] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland

[41] Univ Edinburgh, Dept Psychol, Edinburgh, Midlothian, Scotland

[42] Zucker Hillside Hosp, Div Psychiat Res, Glen Oaks, NY USA

[43] Hofstra Northwell Sch Med, Dept Psychiat, Hempstead, NY USA

[44] Feinstein Inst Med Res, Ctr Psychiat Neurosci, Manhasset, NY USA

[45] NIMH, Clin & Translat Neurosci Branch, Intramural Res Program, US Natl Inst Hlth, Bethesda, MD 20892 USA

[46] Univ Bergen, Oslo Univ Hosp, Dept Med Genet, Oslo, Norway

[47] Univ Bergen, KG Jebsen Ctr Psychosis Res, NORMENT, Bergen, Norway

[48] Natl Univ Ireland, Neuroimaging Cognit & Genom NICOG, Sch Psychol, Galway, Ireland

[49] Natl Univ Ireland, Discipline Biochem, Galway, Ireland

[50] 23andMe Inc, Mountain View, CA USA

来源：

NATURE GENETICS | 2018年 / 50卷 / 07期

基金：

英国惠康基金; 瑞典研究理事会; 英国生物技术与生命科学研究理事会; 瑞士国家科学基金会;

关键词：

GENERAL COGNITIVE FUNCTION; EDUCATIONAL-ATTAINMENT; TEST BATTERIES; GWAS; TRAITS; RISK; LOCI; HERITABILITY; ANNOTATION; CONSORTIUM;

D O I：

10.1038/s41588-018-0152-6

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Intelligence is highly heritable(1) and a major determinant of human health and well-being(2). Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence3-7, but much about its genetic underpinnings remains to be discovered. Here, we present a large-scale genetic association study of intelligence (n = 269,867), identifying 205 associated genomic loci (190 new) and 1,016 genes (939 new) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and associations with 146 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain, specifically in striatal medium spiny neurons and hippocampal pyramidal neurons. Gene set analyses implicate pathways related to nervous system development and synaptic structure. We confirm previous strong genetic correlations with multiple health-related outcomes, and Mendelian randomization analysis results suggest protective effects of intelligence for Alzheimer's disease and ADHD and bidirectional causation with pleiotropic effects for schizophrenia. These results are a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders.

引用

页码：912 / +

页数：11

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