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Large-Scale Cognitive Study Reveals New Genes Associated with Cognitive Ability

Large-Scale cognitive GWAS meta-analysis reveals tissue-specific neural expression and potential nootropic drug targets


Photo: CC--Nico Jensen

Celiac.com 01/01/2018 - A team of researchers recently set out to conduct a genome-wide association study (GWAS) of general cognitive ability ("g"), further enhanced by combining results with a large-scale GWAS of educational attainment.

The research team included 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, and Todd Lencz. They are variously associated with the dozens of research facilities listed below.

Their study provided a large-scale GWAS of cognitive performance, combined with GWAS of educational attainment; 70 independent genomic loci associated with individual differences in cognition. The study found that implicated genes suggest potential treatment targets for cognitive enhancement. The team also observed genetic overlap between cognitive ability and multiple health-related phenotypes.

For their genome-wide association study (GWAS) of general cognitive ability ("g"), the team evaluated 107,207 subjects. They further enhanced their data pool by combining results with a large-scale GWAS of educational attainment. They also identified 70 independent genomic loci associated with general cognitive ability.

Observing the outcomes, the team saw substantial enrichment for genes triggering Mendelian disorders with an intellectual disability phenotype. Analysis of competitive pathways pointed to 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.

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According to the researchers: "we observed modest, yet nominally significant, inverse correlations between cognition and autoimmune diseases such as eczema and Crohn's disease, attaining Bonferroni significance for rheumatoid arthritis (rg for MTAG results = −0.2086; p = 1.60E−08). There was also a Bonferroni-significant positive genetic correlation with celiac disease (rg for MTAG results = 0.1922; p = 0.0001)."
Full analysis of both the transcriptome and epigenome showed that the implicated loci were enriched for genes expressed across all brain regions; mostly in the cerebellum.

Interestingly, only genes expressed in neurons were enriched, not those expressed in oligodendrocytes or astrocytes.

Lastly, the team observed genetic correlations between cognitive ability and various phenotypes, including psychiatric disorders, autoimmune disorders, longevity, and maternal age at first birth.

Source:


The research team members are variously associated with the following:

  • Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, University of Toronto, Toronto, Canada
  • Institute of Mental Health, Singapore, Singapore
  • BrainWorkup, LLC, Los Angeles, CA, USA
  • Institute for Behavioral Genetics, University of Colorado, Boulder, CO, USA
  • Division of Psychiatry Research, Zucker Hillside Hospital, Glen Oaks, NY, USA
  • Department of Psychiatry, Hofstra Northwell School of Medicine, Hempstead, NY, USA
  • Center for Psychiatric Neuroscience, Feinstein Institute for Medical Research, Manhasset, NY, USA
  • Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
  • Department of Genetics and Genomic Science and Institute for Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
  • Mental Illness Research, Education, and Clinical Center (VISN 2), James J. Peters VA Medical Center, Bronx, NY, USA
  • Department of Neurology, Bryan Alzheimer's Disease Research Center and Center for Genomic and Computational Biology, Duke University Medical Center, Durham, NC, USA
  • Department of Psychiatry and Behavioral Sciences, Division of Medical Psychology, Duke University Medical Center, Durham, NC, USA
  • Laboratory of NeuroGenetics, Department of Psychology & Neuroscience, Duke University, Durham, NC, USA
  • Human Longevity Inc., Durham, NC, USA
  • Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
  • Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
  • Department of Psychology, Yale University, New Haven, CT, USA
  • Department of Psychology, Stanford University, Palo Alto, CA, USA
  • Clinical and Translational Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, National Institute of Health, Bethesda, MD, USA
  • Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, MD, USA
  • Neuroimaging, Cognition & Genomics (NICOG) Centre, School of Psychology and Discipline of Biochemistry, National University of Ireland, Galway, Ireland
  • Neuropsychiatric Genetics Research Group, Department of Psychiatry and Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland
  • Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK
  • Department of Psychology, University of Edinburgh, Edinburgh, UK
  • Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, UK
  • Division of Brain Sciences, Department of Medicine, Imperial College, London, UK
  • Centre for Epidemiology, Division of Population Health, Health Services Research & Primary Care, The University of Manchester, Manchester, UK
  • Centre for Integrated Genomic Medical Research, Institute of Population Health, University of Manchester, Manchester, UK
  • 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
  • Department of Biological and Medical Psychology, University of Bergen, Bergen, Norway
  • Department of Medical Genetics, Oslo University Hospital, University of Bergen, Oslo, Norway
  • NORMENT, K.G. Jebsen Centre for Psychosis Research, University of Bergen, Bergen, Norway
  • Dr. Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway
  • Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
  • Department of Psychology, University of Oslo, Oslo, Norway
  • Department of Psychology, University of Edinburgh, Edinburgh, UK
  • Dr. Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway
  • Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland
  • Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
  • Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK
  • Department of Medical Genetics, University of Helsinki and University Central Hospital, Helsinki, Finland
  • Department of General Practice, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
  • National Institute for Health and Welfare, Helsinki, Finland
  • Folkhälsan Research Center, Helsinki, Finland
  • Helsinki Collegium for Advanced Studies, University of Helsinki, Helsinki, Finland
  • Department of Psychiatry, Martin Luther University of Halle-Wittenberg, Halle, Germany
  • Department of Psychology, University of Crete, Crete, Greece
  • Department of Psychiatry, National and Kapodistrian University of Athens Medical School, Eginition Hospital, Athens, Greece
  • University Mental Health Research Institute, Athens, Greece
  • Neurobiology Research Institute, Theodor-Theohari Cozzika Foundation, Athens, Greece
  • Department of Psychiatry and Behavioral Sciences, Faculty of Medicine, University of Crete, Heraklion, Crete, Greece
  • Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA
  • McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
  • UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles, CA, USA
  • 23andMe, Inc., Mountain View, CA, USA

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