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Nat Genet. 2018 Jul;50(7):912-919. doi: 10.1038/s41588-018-0152-6. Epub 2018 Jun 25.

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

Savage JE1, Jansen PR1,2, Stringer S1, Watanabe K1, Bryois J3, de Leeuw CA1, Nagel M4, Awasthi S5, Barr PB6, Coleman JRI7,8, Grasby KL9, Hammerschlag AR1, Kaminski JA5,10, Karlsson R3, Krapohl E7, Lam M11, Nygaard M12,13, Reynolds CA14, Trampush JW15,16, Young H17, Zabaneh D7, Hägg S3, Hansell NK18, Karlsson IK3, Linnarsson S19, Montgomery GW9,20, Muñoz-Manchado AB19, Quinlan EB21, Schumann G21, Skene NG19,22, Webb BT23,24, White T2, Arking DE25, Avramopoulos D25,26, Bilder RM27, Bitsios P28, Burdick KE29,30,31, Cannon TD32, Chiba-Falek O33, Christoforou A34, Cirulli ET35, Congdon E27, Corvin A36, Davies G37,38, Deary IJ37,38, DeRosse P39,40,41, Dickinson D42, Djurovic S43,44, Donohoe G45, Conley ED46, Eriksson JG47, Espeseth T48,49, Freimer NA27, Giakoumaki S50, Giegling I51, Gill M36, Glahn DC52, Hariri AR53, Hatzimanolis A54,55,56, Keller MC57, Knowles E52, Koltai D58, Konte B51, Lahti J59,60, Le Hellard S34,44, Lencz T39,40,41, Liewald DC38, London E27,61, Lundervold AJ62,63, Malhotra AK39,40,41, Melle I44,49, Morris D45, Need AC64, Ollier W65, Palotie A66,67,68, Payton A69, Pendleton N70, Poldrack RA71, Räikkönen K72, Reinvang I48, Roussos P29,30,73, Rujescu D51, Sabb FW74, Scult MA53, Smeland OB75, Smyrnis N54,55, Starr JM37,76, Steen VM34,44, Stefanis NC54,55,56, Straub RE77, Sundet K48,49, Tiemeier H2,78, Voineskos AN79, Weinberger DR77, Widen E66, Yu J39, Abecasis G80,81, Andreassen OA49,75,82, Breen G7,8, Christiansen L12,13, Debrabant B13, Dick DM6,83,84, Heinz A5, Hjerling-Leffler J19, Ikram MA78, Kendler KS23,24,83, Martin NG9, Medland SE9, Pedersen NL3, Plomin R7, Polderman TJC1, Ripke S5,85,86, van der Sluis S4, Sullivan PF3,87, Vrieze SI17, Wright MJ18,88, Posthuma D89,90.

Author information

1
Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
2
Department of Child and Adolescent Psychiatry, Erasmus Medical Center, Rotterdam, The Netherlands.
3
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
4
Department of Clinical Genetics, Section of Complex Trait Genetics, Neuroscience Campus Amsterdam, VU Medical Center, Amsterdam, The Netherlands.
5
Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany.
6
Department of Psychology, Virginia Commonwealth University, Richmond, VA, USA.
7
Social, Genetic, and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, UK.
8
NIHR Biomedical Research Centre for Mental Health, South London and Maudsley NHS Trust, London, UK.
9
QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland, Australia.
10
Berlin Institute of Health (BIH), Berlin, Germany.
11
Institute of Mental Health, Singapore, Singapore.
12
The Danish Twin Registry and the Danish Aging Research Center, Department of Public Health, University of Southern Denmark, Odense, Denmark.
13
Epidemiology, Biostatistics, and Biodemography, Department of Public Health, University of Southern Denmark, Odense, Denmark.
14
Department of Psychology, University of California Riverside, Riverside, CA, USA.
15
BrainWorkup, LLC, Los Angeles, CA, USA.
16
Department of Psychiatry and the Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
17
Department of Psychology, University of Minnesota, St. Paul, MN, USA.
18
Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia.
19
Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
20
Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
21
Centre for Population Neuroscience and Precision Medicine (PONS), Institute of Psychiatry, Psychology, and Neuroscience, MRC-SGDP Centre, King's College London, London, UK.
22
UCL Institute of Neurology, Queen Square, London, UK.
23
Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA.
24
Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, USA.
25
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
26
Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
27
UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles, CA, USA.
28
Department of Psychiatry and Behavioral Sciences, Faculty of Medicine, University of Crete, Heraklion, Greece.
29
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
30
Mental Illness Research, Education and Clinical Center (VISN 2), James J. Peters VA Medical Center, Bronx, NY, USA.
31
Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
32
Department of Psychology, Yale University, New Haven, CT, USA.
33
Department of Neurology, Bryan Alzheimer's Disease Research Center, and Center for Genomic and Computational Biology, Duke University Medical Center, Durham, NC, USA.
34
Dr. Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
35
Human Longevity, Inc., Durham, NC, USA.
36
Neuropsychiatric Genetics Research Group, Department of Psychiatry and Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland.
37
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
38
Department of Psychology, University of Edinburgh, Edinburgh, UK.
39
Division of Psychiatry Research, Zucker Hillside Hospital, Glen Oaks, NY, USA.
40
Department of Psychiatry, Hofstra Northwell School of Medicine, Hempstead, NY, USA.
41
Center for Psychiatric Neuroscience, Feinstein Institute for Medical Research, Manhasset, NY, USA.
42
Clinical and Translational Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, US National Institutes of Health, Bethesda, MD, USA.
43
Department of Medical Genetics, Oslo University Hospital, University of Bergen, Oslo, Norway.
44
NORMENT, K.G. Jebsen Centre for Psychosis Research, University of Bergen, Bergen, Norway.
45
Neuroimaging, Cognition, and Genomics (NICOG) Centre, School of Psychology and Discipline of Biochemistry, National University of Ireland, Galway, Ireland.
46
23andMe, Inc., Mountain View, CA, USA.
47
Department of General Practice and Primary Health Care, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
48
Department of Psychology, University of Oslo, Oslo, Norway.
49
Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
50
Department of Psychology, University of Crete, Rethymno, Greece.
51
Department of Psychiatry, Martin Luther University of Halle-Wittenberg, Halle, Germany.
52
Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
53
Laboratory of NeuroGenetics, Department of Psychology and Neuroscience, Duke University, Durham, NC, USA.
54
Department of Psychiatry, National and Kapodistrian University of Athens Medical School, Eginition Hospital, Athens, Greece.
55
University Mental Health Research Institute, Athens, Greece.
56
Neurobiology Research Institute, Theodor-Theohari Cozzika Foundation, Athens, Greece.
57
Institute for Behavioral Genetics, University of Colorado, Boulder, CO, USA.
58
Psychiatry and Behavioral Sciences, Division of Medical Psychology and Department of Neurology, Duke University Medical Center, Durham, NC, USA.
59
Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
60
Helsinki Collegium for Advanced Studies, University of Helsinki, Helsinki, Finland.
61
Department of Psychiatry and Biobehavioral Sciences and Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA.
62
Department of Biological and Medical Psychology, University of Bergen, Bergen, Norway.
63
K.G. Jebsen Center for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway.
64
Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK.
65
Centre for Integrated Genomic Medical Research, Institute of Population Health, University of Manchester, Manchester, UK.
66
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
67
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.
68
Center for Human Genetic Research, Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
69
Centre for Epidemiology, Division of Population Health, Health Services Research, and Primary Care, University of Manchester, Manchester, UK.
70
Division of Neuroscience and Experimental Psychology/School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Salford Royal NHS Foundation Trust, Manchester, UK.
71
Department of Psychology, Stanford University, Palo Alto, CA, USA.
72
Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland.
73
Department of Genetics and Genomic Science and Institute for Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
74
Robert and Beverly Lewis Center for Neuroimaging, University of Oregon, Eugene, OR, USA.
75
NORMENT, K.G. Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
76
Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, UK.
77
Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, MD, USA.
78
Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
79
Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada.
80
Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
81
Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
82
Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
83
Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, USA.
84
College Behavioral and Emotional Health Institute, Virginia Commonwealth University, Richmond, VA, USA.
85
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
86
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
87
Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
88
Centre for Advanced Imaging, University of Queensland, Brisbane, Queensland, Australia.
89
Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands. d.posthuma@vu.nl.
90
Department of Clinical Genetics, Section of Complex Trait Genetics, Neuroscience Campus Amsterdam, VU Medical Center, Amsterdam, The Netherlands. d.posthuma@vu.nl.

Abstract

Intelligence is highly heritable1 and a major determinant of human health and well-being2. 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.

PMID:
29942086
PMCID:
PMC6411041
DOI:
10.1038/s41588-018-0152-6
[Indexed for MEDLINE]
Free PMC Article

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