Meta-Analysis

. 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

Jeanne E Savage¹, Philip R Jansen^{1

2}, Sven Stringer¹, Kyoko Watanabe¹, Julien Bryois³, Christiaan A de Leeuw¹, Mats Nagel⁴, Swapnil Awasthi⁵, Peter B Barr⁶, Jonathan R I Coleman^{7

8}, Katrina L Grasby⁹, Anke R Hammerschlag¹, Jakob A Kaminski^{5

10}, Robert Karlsson³, Eva Krapohl⁷, Max Lam¹¹, Marianne Nygaard^{12

13}, Chandra A Reynolds¹⁴, Joey W Trampush^{15

16}, Hannah Young¹⁷, Delilah Zabaneh⁷, Sara Hägg³, Narelle K Hansell¹⁸, Ida K Karlsson³, Sten Linnarsson¹⁹, Grant W Montgomery^{9

20}, Ana B Muñoz-Manchado¹⁹, Erin B Quinlan²¹, Gunter Schumann²¹, Nathan G Skene^{19

22}, Bradley T Webb^{23

24}, Tonya White², Dan E Arking²⁵, Dimitrios Avramopoulos^{25

26}, Robert M Bilder²⁷, Panos Bitsios²⁸, Katherine E Burdick^{29

30

31}, Tyrone D Cannon³², Ornit Chiba-Falek³³, Andrea Christoforou³⁴, Elizabeth T Cirulli³⁵, Eliza Congdon²⁷, Aiden Corvin³⁶, Gail Davies^{37

38}, Ian J Deary^{37

38}, Pamela DeRosse^{39

40

41}, Dwight Dickinson⁴², Srdjan Djurovic^{43

44}, Gary Donohoe⁴⁵, Emily Drabant Conley⁴⁶, Johan G Eriksson⁴⁷, Thomas Espeseth^{48

49}, Nelson A Freimer²⁷, Stella Giakoumaki⁵⁰, Ina Giegling⁵¹, Michael Gill³⁶, David C Glahn⁵², Ahmad R Hariri⁵³, Alex Hatzimanolis^{54

55

56}, Matthew C Keller⁵⁷, Emma Knowles⁵², Deborah Koltai⁵⁸, Bettina Konte⁵¹, Jari Lahti^{59

60}, Stephanie Le Hellard^{34

44}, Todd Lencz^{39

40

41}, David C Liewald³⁸, Edythe London^{27

61}, Astri J Lundervold^{62

63}, Anil K Malhotra^{39

40

41}, Ingrid Melle^{44

49}, Derek Morris⁴⁵, Anna C Need⁶⁴, William Ollier⁶⁵, Aarno Palotie^{66

67

68}, Antony Payton⁶⁹, Neil Pendleton⁷⁰, Russell A Poldrack⁷¹, Katri Räikkönen⁷², Ivar Reinvang⁴⁸, Panos Roussos^{29

30

73}, Dan Rujescu⁵¹, Fred W Sabb⁷⁴, Matthew A Scult⁵³, Olav B Smeland⁷⁵, Nikolaos Smyrnis^{54

55}, John M Starr^{37

76}, Vidar M Steen^{34

44}, Nikos C Stefanis^{54

55

56}, Richard E Straub⁷⁷, Kjetil Sundet^{48

49}, Henning Tiemeier^{2

78}, Aristotle N Voineskos⁷⁹, Daniel R Weinberger⁷⁷, Elisabeth Widen⁶⁶, Jin Yu³⁹, Goncalo Abecasis^{80

81}, Ole A Andreassen^{49

75

82}, Gerome Breen^{7

8}, Lene Christiansen^{12

13}, Birgit Debrabant¹³, Danielle M Dick^{6

83

84}, Andreas Heinz⁵, Jens Hjerling-Leffler¹⁹, M Arfan Ikram⁷⁸, Kenneth S Kendler^{23

24

83}, Nicholas G Martin⁹, Sarah E Medland⁹, Nancy L Pedersen³, Robert Plomin⁷, Tinca J C Polderman¹, Stephan Ripke^{5

85

86}, Sophie van der Sluis⁴, Patrick F Sullivan^{3

87}, Scott I Vrieze¹⁷, Margaret J Wright^{18

88}, Danielle Posthuma^{89

90}

Affiliations

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.

PMID: 29942086
PMCID: PMC6411041
DOI: 10.1038/s41588-018-0152-6

Meta-Analysis

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

Jeanne E Savage et al. Nat Genet. 2018 Jul.

. 2018 Jul;50(7):912-919.

doi: 10.1038/s41588-018-0152-6. Epub 2018 Jun 25.

Authors

Affiliations

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.

PMID: 29942086
PMCID: PMC6411041
DOI: 10.1038/s41588-018-0152-6

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 intelligence^3-7, 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.

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Conflict of interest statement

Competing Financial Interests Statement

PF Sullivan reports the following potentially competing financial interests: Lundbeck (advisory committee), Pfizer (Scientific Advisory Board member), and Roche (grant recipient, speaker reimbursement). G Breen reports consultancy and speaker fees from Eli Lilly and Illumina and grant funding from Eli Lilly. J Hjerling-Leffler reports interests from Cartana (Scientific Advisor) and Roche (grant recipient). TD Cannon is a consultant to Boehringer Ingelheim Pharmaceuticals and Lundbeck A/S. All other authors declare no financial interests or potential conflicts of interest.

Figures

**Figure 1.. SNP-based associations with intelligence in the GWAS meta-analysis of N=269,867 independent individuals.**
**(a)** Manhattan plot showing the −log10 transformed two-tailed P-value of each SNP from the GWAS meta-analysis (of linear and logistic regression statistics) on the y-axis and base pair positions along the chromosomes on the x-axis. The dotted red line indicates Bonferroni-corrected genome-wide significance (P<5×10⁻⁸); the blue line the threshold for suggestive associations (P<1×10⁻⁵). Independent lead SNPs are indicated by a diamond. **(b)** Heritability enrichment of 28 functional annotation categories for SNPs in the meta-analysis, calculated with stratified LD score regression. Error bars show 95% confidence intervals around the enrichment estimate. The dashed horizontal line indicates no enrichment of the annotation category. Red dots indicate significant Bonferroni-corrected two-tailed P-values and beige dots indicate suggestive (P<.05) values. UTR=untranslated region; TSS=transcription start site; CTCF=CCCTC-binding factor; DHS=DNaseI Hypersensitive Site; TFBS=transcription factor binding site; DGF=DNaseI digital genomic footprint. **(c)** Distribution of functional consequences of SNPs in genomic risk loci in the meta-analysis. **(d)** Distribution of RegulomeDB score for SNPs in genomic risk loci, with a low score indicating a higher likelihood of having a regulatory function (Online methods). **(e)** The minimum chromatin state across 127 tissue and cell types for SNPs in genomic risk loci, with lower states indicating higher accessibility and states 1–7 referring to open chromatin states (Online Methods).

**Figure 2.. Cross-locus interactions for genomic regions associated with intelligence in 269,867 independent individuals.**
Circos plots showing genes on chromosomes 2 **(a)**, 5 **(b),** 6 **(c),** 9 **(d)**, and 22 **(e)** that were linked to genomic risk loci in the GWAS meta-analysis (blue regions) by eQTL mapping (green lines connecting an eQTL SNP to its associated gene), and/or chromatin interactions (orange lines connecting two interacting regions) and showed evidence of interaction across two independent genomic risk loci. Genes implicated by eQTL are in green, by chromatin interactions in orange, and by both eQTL and chromatin interactions mapping in red. The outer layer shows a Manhattan plot containing the −log10 transformed two-tailed P-value of each SNP from the GWAS meta-analysis (of linear and logistic regression statistics), with genome-wide significant SNPs colored according to linkage disequilibrium patterns with the lead SNP. Circos plots for all chromosomes are provided in Supplementary Fig. 8.

**Figure 3.. Implicated genes, pathways, and tissue- and cell- expression profiles for intelligence in 269,867 independent individuals.**
**(a)** Manhattan plot of the genome-wide gene-based association analysis (GWGAS). The y-axis shows the −log10 transformed two-tailed P-value of each gene from a linear model, and the chromosomal position on the x-axis. The red dotted line indicates the Bonferroni-corrected threshold for genome-wide significance of the gene-based test (P<2.76×10⁻⁶; 0.05/18,128 genes), and the blue line indicates the suggestive threshold (P<2.76×10⁻⁵; 0.5/18,128 genes) **(b)** Venn diagram showing overlap of genes implicated by positional mapping, eQTL mapping, chromatin interaction mapping, and GWGAS. **(c)** Gene expression profiles of associated genes in 53 tissue types. The y-axis shows the −log10 transformed two-tailed P-value of association of GWGAS test statistics with tissue-specific gene expression levels in a linear model. Expression data were extracted from the Genotype-Tissue Expression (GTEx) database. Expression values (RPKM) were log2 transformed with pseudocount 1 after winsorization at 50 and averaged per tissue. The dotted blue line indicates the Bonferroni-corrected significance threshold (P=0.05/7,323 gene-sets=6.83×10⁻⁶). **(d)** Single-cell gene-expression analysis of genes related to intelligence in 24 cell-types. The x-axis shows the −log10 transformed two-tailed P-value of association of GWGAS test statistics with cell-specific gene expression levels in a linear model. The dotted blue line indicates the Bonferroni-corrected significance threshold (P=0.05/7,323 gene-sets=6.83×10⁻⁶).

See this image and copyright information in PMC

References

1. Polderman TJ et al. Meta-analysis of the heritability of human traits based on fifty years of twin studies. Nat Genet 47, 702–709, doi:10.1038/ng.3285 (2015). - DOI - PubMed
1. Wraw C, Deary IJ, Gale CR & Der G Intelligence in youth and health at age 50. Intelligence 53, 23–32, doi:10.1016/j.intell.2015.08.001 (2015). - DOI - PMC - PubMed
1. Davies G et al. Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53949). Mol Psychiatry 20, 183–192, doi:10.1038/mp.2014.188 (2015). - DOI - PMC - PubMed
1. Davies G et al. Genome-wide association study of cognitive functions and educational attainment in UK Biobank (N=112 151). Mol Psychiatry 21, 758–767, doi:10.1038/mp.2016.45 (2016). - DOI - PMC - PubMed
1. Sniekers S et al. Genome-wide association meta-analysis of 78,308 individuals identifies new loci and genes influencing human intelligence. Nat Genet 49, 1107–1112, doi:10.1038/ng.3869 (2017). - DOI - PMC - PubMed

Methods-Only References

1. Willer CJ, Li Y & Abecasis GR METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26, 2190–2191, doi:10.1093/bioinformatics/btq340 (2010). - DOI - PMC - PubMed
1. Peloso GM et al. Phenotypic extremes in rare variant study designs. Eur J Hum Genet 24, 924–930, doi:10.1038/ejhg.2015.197 (2016). - DOI - PMC - PubMed
1. Purcell S, Cherny SS & Sham PC Genetic Power Calculator: design of linkage and association genetic mapping studies of complex traits. Bioinformatics 19, 149–150 (2003). - PubMed
1. Coleman J et al. Biological annotation of genetic loci associated with intelligence in a meta-analysis of 87,740 individuals. Mol Psychiatry, doi:10.1038/s41380-018-0040-6 (in press). - DOI - PMC - PubMed
1. Konig IR, Loley C, Erdmann J & Ziegler A How to include chromosome X in your genome-wide association study. Genet Epidemiol 38, 97–103, doi:10.1002/gepi.21782 (2014). - DOI - PubMed

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

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

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