Cell Reports (Nov 2017)
Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets
- Max Lam,
- Joey W. Trampush,
- Jin Yu,
- Emma Knowles,
- Gail Davies,
- David C. Liewald,
- John M. Starr,
- Srdjan Djurovic,
- Ingrid Melle,
- Kjetil Sundet,
- Andrea Christoforou,
- Ivar Reinvang,
- Pamela DeRosse,
- Astri J. Lundervold,
- Vidar M. Steen,
- Thomas Espeseth,
- Katri Räikkönen,
- Elisabeth Widen,
- Aarno Palotie,
- Johan G. Eriksson,
- Ina Giegling,
- Bettina Konte,
- Panos Roussos,
- Stella Giakoumaki,
- Katherine E. Burdick,
- Antony Payton,
- William Ollier,
- Ornit Chiba-Falek,
- Deborah K. Attix,
- Anna C. Need,
- Elizabeth T. Cirulli,
- Aristotle N. Voineskos,
- Nikos C. Stefanis,
- Dimitrios Avramopoulos,
- Alex Hatzimanolis,
- Dan E. Arking,
- Nikolaos Smyrnis,
- Robert M. Bilder,
- Nelson A. Freimer,
- Tyrone D. Cannon,
- Edythe London,
- Russell A. Poldrack,
- Fred W. Sabb,
- Eliza Congdon,
- Emily Drabant Conley,
- Matthew A. Scult,
- Dwight Dickinson,
- Richard E. Straub,
- Gary Donohoe,
- Derek Morris,
- Aiden Corvin,
- Michael Gill,
- Ahmad R. Hariri,
- Daniel R. Weinberger,
- Neil Pendleton,
- Panos Bitsios,
- Dan Rujescu,
- Jari Lahti,
- Stephanie Le Hellard,
- Matthew C. Keller,
- Ole A. Andreassen,
- Ian J. Deary,
- David C. Glahn,
- Anil K. Malhotra,
- Todd Lencz
Affiliations
- Max Lam
- Institute of Mental Health, Singapore, Singapore
- Joey W. Trampush
- BrainWorkup, LLC, Los Angeles, CA, USA
- Jin Yu
- Division of Psychiatry Research, Zucker Hillside Hospital, Glen Oaks, NY, USA
- Emma Knowles
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
- Gail Davies
- Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK
- David C. Liewald
- Department of Psychology, University of Edinburgh, Edinburgh, UK
- John M. Starr
- Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK
- Srdjan Djurovic
- Department of Medical Genetics, Oslo University Hospital, University of Bergen, Oslo, Norway
- Ingrid Melle
- NORMENT, K.G. Jebsen Centre for Psychosis Research, University of Bergen, Bergen, Norway
- Kjetil Sundet
- Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
- Andrea Christoforou
- Dr. Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway
- Ivar Reinvang
- Department of Psychology, University of Oslo, Oslo, Norway
- Pamela DeRosse
- Division of Psychiatry Research, Zucker Hillside Hospital, Glen Oaks, NY, USA
- Astri J. Lundervold
- Department of Biological and Medical Psychology, University of Bergen, Bergen, Norway
- Vidar M. Steen
- NORMENT, K.G. Jebsen Centre for Psychosis Research, University of Bergen, Bergen, Norway
- Thomas Espeseth
- Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
- Katri Räikkönen
- Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland
- Elisabeth Widen
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
- Aarno Palotie
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
- Johan G. Eriksson
- Department of General Practice, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Ina Giegling
- Department of Psychiatry, Martin Luther University of Halle-Wittenberg, Halle, Germany
- Bettina Konte
- Department of Psychiatry, Martin Luther University of Halle-Wittenberg, Halle, Germany
- Panos Roussos
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Stella Giakoumaki
- Department of Psychology, University of Crete, Crete, Greece
- Katherine E. Burdick
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Antony Payton
- Centre for Epidemiology, Division of Population Health, Health Services Research & Primary Care, The University of Manchester, Manchester, UK
- William Ollier
- Centre for Epidemiology, Division of Population Health, Health Services Research & Primary Care, The University of Manchester, Manchester, UK
- Ornit Chiba-Falek
- Department of Neurology, Bryan Alzheimer’s Disease Research Center and Center for Genomic and Computational Biology, Duke University Medical Center, Durham, NC, USA
- Deborah K. Attix
- Department of Neurology, Bryan Alzheimer’s Disease Research Center and Center for Genomic and Computational Biology, Duke University Medical Center, Durham, NC, USA
- Anna C. Need
- Division of Brain Sciences, Department of Medicine, Imperial College, London, UK
- Elizabeth T. Cirulli
- Human Longevity Inc., Durham, NC, USA
- Aristotle N. Voineskos
- Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, University of Toronto, Toronto, Canada
- Nikos C. Stefanis
- Department of Psychiatry, National and Kapodistrian University of Athens Medical School, Eginition Hospital, Athens, Greece
- Dimitrios Avramopoulos
- Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Alex Hatzimanolis
- Department of Psychiatry, National and Kapodistrian University of Athens Medical School, Eginition Hospital, Athens, Greece
- Dan E. Arking
- McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Nikolaos Smyrnis
- Department of Psychiatry, National and Kapodistrian University of Athens Medical School, Eginition Hospital, Athens, Greece
- Robert M. Bilder
- UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles, CA, USA
- Nelson A. Freimer
- UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles, CA, USA
- Tyrone D. Cannon
- Department of Psychology, Yale University, New Haven, CT, USA
- Edythe London
- UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles, CA, USA
- Russell A. Poldrack
- Department of Psychology, Stanford University, Palo Alto, CA, USA
- Fred W. Sabb
- Robert and Beverly Lewis Center for Neuroimaging, University of Oregon, Eugene, OR, USA
- Eliza Congdon
- UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles, CA, USA
- Emily Drabant Conley
- 23andMe, Inc., Mountain View, CA, USA
- Matthew A. Scult
- Laboratory of NeuroGenetics, Department of Psychology & Neuroscience, Duke University, Durham, NC, USA
- Dwight Dickinson
- Clinical and Translational Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, National Institute of Health, Bethesda, MD, USA
- Richard E. Straub
- Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, MD, USA
- Gary Donohoe
- Neuroimaging, Cognition & Genomics (NICOG) Centre, School of Psychology and Discipline of Biochemistry, National University of Ireland, Galway, Ireland
- Derek Morris
- Neuroimaging, Cognition & Genomics (NICOG) Centre, School of Psychology and Discipline of Biochemistry, National University of Ireland, Galway, Ireland
- Aiden Corvin
- Neuropsychiatric Genetics Research Group, Department of Psychiatry and Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland
- Michael Gill
- Neuropsychiatric Genetics Research Group, Department of Psychiatry and Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland
- Ahmad R. Hariri
- Laboratory of NeuroGenetics, Department of Psychology & Neuroscience, Duke University, Durham, NC, USA
- Daniel R. Weinberger
- Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, MD, USA
- Neil Pendleton
- 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
- Panos Bitsios
- Department of Psychiatry and Behavioral Sciences, Faculty of Medicine, University of Crete, Heraklion, Crete, Greece
- Dan Rujescu
- Department of Psychiatry, Martin Luther University of Halle-Wittenberg, Halle, Germany
- Jari Lahti
- Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland
- Stephanie Le Hellard
- NORMENT, K.G. Jebsen Centre for Psychosis Research, University of Bergen, Bergen, Norway
- Matthew C. Keller
- Institute for Behavioral Genetics, University of Colorado, Boulder, CO, USA
- Ole A. Andreassen
- NORMENT, K.G. Jebsen Centre for Psychosis Research, University of Bergen, Bergen, Norway
- Ian J. Deary
- Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK
- David C. Glahn
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
- Anil K. Malhotra
- Division of Psychiatry Research, Zucker Hillside Hospital, Glen Oaks, NY, USA
- Todd Lencz
- Division of Psychiatry Research, Zucker Hillside Hospital, Glen Oaks, NY, USA
- DOI
- https://doi.org/10.1016/j.celrep.2017.11.028
- Journal volume & issue
-
Vol. 21,
no. 9
pp. 2597 – 2613
Abstract
Here, we present a large (n = 107,207) genome-wide association study (GWAS) of general cognitive ability (“g”), further enhanced by combining results with a large-scale GWAS of educational attainment. We identified 70 independent genomic loci associated with general cognitive ability. Results showed significant enrichment for genes causing Mendelian disorders with an intellectual disability phenotype. Competitive pathway analysis implicated the biological processes of neurogenesis and synaptic regulation, as well as the gene targets of two pharmacologic agents: cinnarizine, a T-type calcium channel blocker, and LY97241, a potassium channel inhibitor. Transcriptome-wide and epigenome-wide analysis revealed that the implicated loci were enriched for genes expressed across all brain regions (most strongly in the cerebellum). Enrichment was exclusive to genes expressed in neurons but not oligodendrocytes or astrocytes. Finally, we report genetic correlations between cognitive ability and disparate phenotypes including psychiatric disorders, several autoimmune disorders, longevity, and maternal age at first birth.
Keywords
- GWAS
- general cognitive ability
- nootropics
- gene expression
- neurodevelopment
- synapse
- calcium channel
- potassium channel
- cerebellum
