Genetic Epidemiology, Translational Neurogenomics, Psychiatric Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
29942086
TITLE
Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence.
ABSTRACT
Intelligence is highly heritable and a major determinant of human health and well-being . Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence , 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.
DATE PUBLISHED
2018 07
HISTORY
PUBSTATUS PUBSTATUSDATE
received 2017/09/18
accepted 2018/04/20
pubmed 2018/06/27 06:00
medline 2019/04/25 06:00
entrez 2018/06/27 06:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Savage JE Savage Jeanne E JE Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
Jansen PR Jansen Philip R PR Department of Child and Adolescent Psychiatry, Erasmus Medical Center, Rotterdam, The Netherlands.
Stringer S Stringer Sven S Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
Watanabe K Watanabe Kyoko K Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
Bryois J Bryois Julien J Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
de Leeuw CA de Leeuw Christiaan A CA Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
Nagel M Nagel Mats M Department of Clinical Genetics, Section of Complex Trait Genetics, Neuroscience Campus Amsterdam, VU Medical Center, Amsterdam, The Netherlands.
Awasthi S Awasthi Swapnil S Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany.
Barr PB Barr Peter B PB Department of Psychology, Virginia Commonwealth University, Richmond, VA, USA.
Coleman JRI Coleman Jonathan R I JRI NIHR Biomedical Research Centre for Mental Health, South London and Maudsley NHS Trust, London, UK.
Grasby KL Grasby Katrina L KL QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland, Australia.
Hammerschlag AR Hammerschlag Anke R AR Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
Kaminski JA Kaminski Jakob A JA Berlin Institute of Health (BIH), Berlin, Germany.
Karlsson R Karlsson Robert R Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Krapohl E Krapohl Eva E Social, Genetic, and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, UK.
Lam M Lam Max M Institute of Mental Health, Singapore, Singapore.
Nygaard M Nygaard Marianne M Epidemiology, Biostatistics, and Biodemography, Department of Public Health, University of Southern Denmark, Odense, Denmark.
Reynolds CA Reynolds Chandra A CA Department of Psychology, University of California Riverside, Riverside, CA, USA.
Trampush JW Trampush Joey W JW Department of Psychiatry and the Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Young H Young Hannah H Department of Psychology, University of Minnesota, St. Paul, MN, USA.
Zabaneh D Zabaneh Delilah D Social, Genetic, and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, UK.
Hägg S Hägg Sara S Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Hansell NK Hansell Narelle K NK Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia.
Karlsson IK Karlsson Ida K IK Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Linnarsson S Linnarsson Sten S Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
Montgomery GW Montgomery Grant W GW Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
Muñoz-Manchado AB Muñoz-Manchado Ana B AB Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
Quinlan EB Quinlan Erin B EB Centre for Population Neuroscience and Precision Medicine (PONS), Institute of Psychiatry, Psychology, and Neuroscience, MRC-SGDP Centre, King's College London, London, UK.
Schumann G Schumann Gunter G Centre for Population Neuroscience and Precision Medicine (PONS), Institute of Psychiatry, Psychology, and Neuroscience, MRC-SGDP Centre, King's College London, London, UK.
Skene NG Skene Nathan G NG UCL Institute of Neurology, Queen Square, London, UK.
Webb BT Webb Bradley T BT Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, USA.
White T White Tonya T Department of Child and Adolescent Psychiatry, Erasmus Medical Center, Rotterdam, The Netherlands.
Arking DE Arking Dan E DE McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Avramopoulos D Avramopoulos Dimitrios D Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Bilder RM Bilder Robert M RM UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles, CA, USA.
Bitsios P Bitsios Panos P Department of Psychiatry and Behavioral Sciences, Faculty of Medicine, University of Crete, Heraklion, Greece.
Burdick KE Burdick Katherine E KE Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Cannon TD Cannon Tyrone D TD Department of Psychology, Yale University, New Haven, CT, USA.
Chiba-Falek O Chiba-Falek Ornit O Department of Neurology, Bryan Alzheimer's Disease Research Center, and Center for Genomic and Computational Biology, Duke University Medical Center, Durham, NC, USA.
Christoforou A Christoforou Andrea A Dr. Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
Cirulli ET Cirulli Elizabeth T ET Human Longevity, Inc., Durham, NC, USA.
Congdon E Congdon Eliza E UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles, CA, USA.
Corvin A Corvin Aiden A Neuropsychiatric Genetics Research Group, Department of Psychiatry and Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland.
Davies G Davies Gail G Department of Psychology, University of Edinburgh, Edinburgh, UK.
Deary IJ Deary Ian J IJ Department of Psychology, University of Edinburgh, Edinburgh, UK.
DeRosse P DeRosse Pamela P Center for Psychiatric Neuroscience, Feinstein Institute for Medical Research, Manhasset, NY, USA.
Dickinson D Dickinson Dwight D Clinical and Translational Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, US National Institutes of Health, Bethesda, MD, USA.
Djurovic S Djurovic Srdjan S NORMENT, K.G. Jebsen Centre for Psychosis Research, University of Bergen, Bergen, Norway.
Donohoe G Donohoe Gary G Neuroimaging, Cognition, and Genomics (NICOG) Centre, School of Psychology and Discipline of Biochemistry, National University of Ireland, Galway, Ireland.
Conley ED Conley Emily Drabant ED 23andMe, Inc., Mountain View, CA, USA.
Eriksson JG Eriksson Johan G JG Department of General Practice and Primary Health Care, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Espeseth T Espeseth Thomas T Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
Freimer NA Freimer Nelson A NA UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles, CA, USA.
Giakoumaki S Giakoumaki Stella S Department of Psychology, University of Crete, Rethymno, Greece.
Giegling I Giegling Ina I Department of Psychiatry, Martin Luther University of Halle-Wittenberg, Halle, Germany.
Gill M Gill Michael M Neuropsychiatric Genetics Research Group, Department of Psychiatry and Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland.
Glahn DC Glahn David C DC Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
Hariri AR Hariri Ahmad R AR Laboratory of NeuroGenetics, Department of Psychology and Neuroscience, Duke University, Durham, NC, USA.
Hatzimanolis A Hatzimanolis Alex A Neurobiology Research Institute, Theodor-Theohari Cozzika Foundation, Athens, Greece.
Keller MC Keller Matthew C MC Institute for Behavioral Genetics, University of Colorado, Boulder, CO, USA.
Knowles E Knowles Emma E Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
Koltai D Koltai Deborah D Psychiatry and Behavioral Sciences, Division of Medical Psychology and Department of Neurology, Duke University Medical Center, Durham, NC, USA.
Konte B Konte Bettina B Department of Psychiatry, Martin Luther University of Halle-Wittenberg, Halle, Germany.
Lahti J Lahti Jari J Helsinki Collegium for Advanced Studies, University of Helsinki, Helsinki, Finland.
Le Hellard S Le Hellard Stephanie S NORMENT, K.G. Jebsen Centre for Psychosis Research, University of Bergen, Bergen, Norway.
Lencz T Lencz Todd T Center for Psychiatric Neuroscience, Feinstein Institute for Medical Research, Manhasset, NY, USA.
Liewald DC Liewald David C DC Department of Psychology, University of Edinburgh, Edinburgh, UK.
London E London Edythe E Department of Psychiatry and Biobehavioral Sciences and Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA.
Lundervold AJ Lundervold Astri J AJ K.G. Jebsen Center for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway.
Malhotra AK Malhotra Anil K AK Center for Psychiatric Neuroscience, Feinstein Institute for Medical Research, Manhasset, NY, USA.
Melle I Melle Ingrid I Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
Morris D Morris Derek D Neuroimaging, Cognition, and Genomics (NICOG) Centre, School of Psychology and Discipline of Biochemistry, National University of Ireland, Galway, Ireland.
Need AC Need Anna C AC Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK.
Ollier W Ollier William W Centre for Integrated Genomic Medical Research, Institute of Population Health, University of Manchester, Manchester, UK.
Palotie A Palotie Aarno A Center for Human Genetic Research, Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
Payton A Payton Antony A Centre for Epidemiology, Division of Population Health, Health Services Research, and Primary Care, University of Manchester, Manchester, UK.
Pendleton N Pendleton Neil N 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.
Poldrack RA Poldrack Russell A RA Department of Psychology, Stanford University, Palo Alto, CA, USA.
Räikkönen K Räikkönen Katri K Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland.
Reinvang I Reinvang Ivar I Department of Psychology, University of Oslo, Oslo, Norway.
Roussos P Roussos Panos P Department of Genetics and Genomic Science and Institute for Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Rujescu D Rujescu Dan D Department of Psychiatry, Martin Luther University of Halle-Wittenberg, Halle, Germany.
Sabb FW Sabb Fred W FW Robert and Beverly Lewis Center for Neuroimaging, University of Oregon, Eugene, OR, USA.
Scult MA Scult Matthew A MA Laboratory of NeuroGenetics, Department of Psychology and Neuroscience, Duke University, Durham, NC, USA.
Smeland OB Smeland Olav B OB 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.
Smyrnis N Smyrnis Nikolaos N University Mental Health Research Institute, Athens, Greece.
Starr JM Starr John M JM Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, UK.
Steen VM Steen Vidar M VM NORMENT, K.G. Jebsen Centre for Psychosis Research, University of Bergen, Bergen, Norway.
Stefanis NC Stefanis Nikos C NC Neurobiology Research Institute, Theodor-Theohari Cozzika Foundation, Athens, Greece.
Straub RE Straub Richard E RE Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, MD, USA.
Sundet K Sundet Kjetil K Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
Tiemeier H Tiemeier Henning H Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
Voineskos AN Voineskos Aristotle N AN Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada.
Weinberger DR Weinberger Daniel R DR Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, MD, USA.
Widen E Widen Elisabeth E Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
Yu J Yu Jin J Division of Psychiatry Research, Zucker Hillside Hospital, Glen Oaks, NY, USA.
Abecasis G Abecasis Goncalo G Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
Andreassen OA Andreassen Ole A OA Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Breen G Breen Gerome G NIHR Biomedical Research Centre for Mental Health, South London and Maudsley NHS Trust, London, UK.
Christiansen L Christiansen Lene L Epidemiology, Biostatistics, and Biodemography, Department of Public Health, University of Southern Denmark, Odense, Denmark.
Debrabant B Debrabant Birgit B Epidemiology, Biostatistics, and Biodemography, Department of Public Health, University of Southern Denmark, Odense, Denmark.
Dick DM Dick Danielle M DM College Behavioral and Emotional Health Institute, Virginia Commonwealth University, Richmond, VA, USA.
Heinz A Heinz Andreas A Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany.
Hjerling-Leffler J Hjerling-Leffler Jens J Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
Ikram MA Ikram M Arfan MA Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
Kendler KS Kendler Kenneth S KS Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, USA.
Martin NG Martin Nicholas G NG QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland, Australia.
Medland SE Medland Sarah E SE QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland, Australia.
Pedersen NL Pedersen Nancy L NL Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Plomin R Plomin Robert R Social, Genetic, and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, UK.
Polderman TJC Polderman Tinca J C TJC Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
Ripke S Ripke Stephan S Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
van der Sluis S van der Sluis Sophie S Department of Clinical Genetics, Section of Complex Trait Genetics, Neuroscience Campus Amsterdam, VU Medical Center, Amsterdam, The Netherlands.
Sullivan PF Sullivan Patrick F PF Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
Vrieze SI Vrieze Scott I SI Department of Psychology, University of Minnesota, St. Paul, MN, USA.
Wright MJ Wright Margaret J MJ Centre for Advanced Imaging, University of Queensland, Brisbane, Queensland, Australia.
Posthuma D Posthuma Danielle D Department of Clinical Genetics, Section of Complex Trait Genetics, Neuroscience Campus Amsterdam, VU Medical Center, Amsterdam, The Netherlands. d.posthuma@vu.nl.
INVESTIGATORS
JOURNAL
VOLUME: 50
ISSUE: 7
TITLE: Nature genetics
ISOABBREVIATION: Nat Genet
YEAR: 2018
MONTH: 07
DAY:
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 1546-1718
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: Nat Genet
COUNTRY: United States
ISSNLINKING: 1061-4036
NLMUNIQUEID: 9216904
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
Meta-Analysis
Research Support, Non-U.S. Gov't
COMMENTS AND CORRECTIONS
GRANTS
GRANTID AGENCY COUNTRY
R01 AG049789 NIA NIH HHS United States
R01 MH079800 NIMH NIH HHS United States
P20 AA017828 NIAAA NIH HHS United States
K01 MH098126 NIMH NIH HHS United States
PL1 MH083271 NIMH NIH HHS United States
L30 MH104879 NIMH NIH HHS United States
R01 MH085772 NIMH NIH HHS United States
MR/K026992/1 Medical Research Council United Kingdom
R01 AG037985 NIA NIH HHS United States
PL1 NS062410 NINDS NIH HHS United States
G19/2 Medical Research Council United Kingdom
K23 MH077807 NIMH NIH HHS United States
R01 MH092515 NIMH NIH HHS United States
G0600237 Medical Research Council United Kingdom
R01 MH080912 NIMH NIH HHS United States
R01 DA033369 NIDA NIH HHS United States
K01 MH085812 NIMH NIH HHS United States
R01 MH085018 NIMH NIH HHS United States
RL1 MH083269 NIMH NIH HHS United States
UL1 DE019580 NIDCR NIH HHS United States
R01 AG028555 NIA NIH HHS United States
R01 HG008983 NHGRI NIH HHS United States
U54 EB020403 NIBIB NIH HHS United States
UL1 RR031990 NCRR NIH HHS United States
R03 AG045633 NIA NIH HHS United States
P50 AA022537 NIAAA NIH HHS United States
K02 AA018755 NIAAA NIH HHS United States
P50 MH080173 NIMH NIH HHS United States
P01 AG008761 NIA NIH HHS United States
R37 AA011408 NIAAA NIH HHS United States
R01 DA037904 NIDA NIH HHS United States
R01 AA023974 NIAAA NIH HHS United States
S10 OD018164 NIH HHS United States
BB/F019394/1 Biotechnology and Biological Sciences Research Council United Kingdom
G0100594 Medical Research Council United Kingdom
R01 AG010175 NIA NIH HHS United States
RL1 DA024853 NIDA NIH HHS United States
BB/F022441/1 Biotechnology and Biological Sciences Research Council United Kingdom
G0901461 Medical Research Council United Kingdom
GENERAL NOTE
KEYWORDS
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
Adolescent
Brain physiology
Female physiology
Genetic Predisposition to Disease physiology
Genome-Wide Association Study methods
Humans methods
Intelligence genetics
Male genetics
Middle Aged genetics
Polymorphism, Single Nucleotide genetics
Quantitative Trait Loci genetics
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
OTHER ID's
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