Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets
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...
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2017-11-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124717316480 |
| _version_ | 1818919702923051008 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Max Lam |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-20T01:10:04Z |
| format | Article |
| id | doaj.art-175db294f4384aa58ea8e8e076c3bded |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-20T01:10:04Z |
| publishDate | 2017-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-175db294f4384aa58ea8e8e076c3bded2022-12-21T19:58:42ZengElsevierCell Reports2211-12472017-11-012192597261310.1016/j.celrep.2017.11.028Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug TargetsMax Lam0Joey W. Trampush1Jin Yu2Emma Knowles3Gail Davies4David C. Liewald5John M. Starr6Srdjan Djurovic7Ingrid Melle8Kjetil Sundet9Andrea Christoforou10Ivar Reinvang11Pamela DeRosse12Astri J. Lundervold13Vidar M. Steen14Thomas Espeseth15Katri Räikkönen16Elisabeth Widen17Aarno Palotie18Johan G. Eriksson19Ina Giegling20Bettina Konte21Panos Roussos22Stella Giakoumaki23Katherine E. Burdick24Antony Payton25William Ollier26Ornit Chiba-Falek27Deborah K. Attix28Anna C. Need29Elizabeth T. Cirulli30Aristotle N. Voineskos31Nikos C. Stefanis32Dimitrios Avramopoulos33Alex Hatzimanolis34Dan E. Arking35Nikolaos Smyrnis36Robert M. Bilder37Nelson A. Freimer38Tyrone D. Cannon39Edythe London40Russell A. Poldrack41Fred W. Sabb42Eliza Congdon43Emily Drabant Conley44Matthew A. Scult45Dwight Dickinson46Richard E. Straub47Gary Donohoe48Derek Morris49Aiden Corvin50Michael Gill51Ahmad R. Hariri52Daniel R. Weinberger53Neil Pendleton54Panos Bitsios55Dan Rujescu56Jari Lahti57Stephanie Le Hellard58Matthew C. Keller59Ole A. Andreassen60Ian J. Deary61David C. Glahn62Anil K. Malhotra63Todd Lencz64Institute of Mental Health, Singapore, SingaporeBrainWorkup, LLC, Los Angeles, CA, USADivision of Psychiatry Research, Zucker Hillside Hospital, Glen Oaks, NY, USADepartment of Psychiatry, Yale University School of Medicine, New Haven, CT, USACentre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UKDepartment of Psychology, University of Edinburgh, Edinburgh, UKCentre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UKDepartment of Medical Genetics, Oslo University Hospital, University of Bergen, Oslo, NorwayNORMENT, K.G. Jebsen Centre for Psychosis Research, University of Bergen, Bergen, NorwayDivision of Mental Health and Addiction, Oslo University Hospital, Oslo, NorwayDr. Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, NorwayDepartment of Psychology, University of Oslo, Oslo, NorwayDivision of Psychiatry Research, Zucker Hillside Hospital, Glen Oaks, NY, USADepartment of Biological and Medical Psychology, University of Bergen, Bergen, NorwayNORMENT, K.G. Jebsen Centre for Psychosis Research, University of Bergen, Bergen, NorwayDivision of Mental Health and Addiction, Oslo University Hospital, Oslo, NorwayInstitute of Behavioural Sciences, University of Helsinki, Helsinki, FinlandInstitute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, FinlandInstitute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, FinlandDepartment of General Practice, University of Helsinki and Helsinki University Hospital, Helsinki, FinlandDepartment of Psychiatry, Martin Luther University of Halle-Wittenberg, Halle, GermanyDepartment of Psychiatry, Martin Luther University of Halle-Wittenberg, Halle, GermanyDepartment of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USADepartment of Psychology, University of Crete, Crete, GreeceDepartment of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USACentre for Epidemiology, Division of Population Health, Health Services Research & Primary Care, The University of Manchester, Manchester, UKCentre for Epidemiology, Division of Population Health, Health Services Research & Primary Care, The University of Manchester, Manchester, UKDepartment of Neurology, Bryan Alzheimer’s Disease Research Center and Center for Genomic and Computational Biology, Duke University Medical Center, Durham, NC, USADepartment of Neurology, Bryan Alzheimer’s Disease Research Center and Center for Genomic and Computational Biology, Duke University Medical Center, Durham, NC, USADivision of Brain Sciences, Department of Medicine, Imperial College, London, UKHuman Longevity Inc., Durham, NC, USACampbell Family Mental Health Institute, Centre for Addiction and Mental Health, University of Toronto, Toronto, CanadaDepartment of Psychiatry, National and Kapodistrian University of Athens Medical School, Eginition Hospital, Athens, GreeceDepartment of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USADepartment of Psychiatry, National and Kapodistrian University of Athens Medical School, Eginition Hospital, Athens, GreeceMcKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USADepartment of Psychiatry, National and Kapodistrian University of Athens Medical School, Eginition Hospital, Athens, GreeceUCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles, CA, USAUCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles, CA, USADepartment of Psychology, Yale University, New Haven, CT, USAUCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles, CA, USADepartment of Psychology, Stanford University, Palo Alto, CA, USARobert and Beverly Lewis Center for Neuroimaging, University of Oregon, Eugene, OR, USAUCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles, CA, USA23andMe, Inc., Mountain View, CA, USALaboratory of NeuroGenetics, Department of Psychology & Neuroscience, Duke University, Durham, NC, USAClinical and Translational Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, National Institute of Health, Bethesda, MD, USALieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, MD, USANeuroimaging, Cognition & Genomics (NICOG) Centre, School of Psychology and Discipline of Biochemistry, National University of Ireland, Galway, IrelandNeuroimaging, Cognition & Genomics (NICOG) Centre, School of Psychology and Discipline of Biochemistry, National University of Ireland, Galway, IrelandNeuropsychiatric Genetics Research Group, Department of Psychiatry and Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, IrelandNeuropsychiatric Genetics Research Group, Department of Psychiatry and Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, IrelandLaboratory of NeuroGenetics, Department of Psychology & Neuroscience, Duke University, Durham, NC, USALieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, MD, USADivision 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, UKDepartment of Psychiatry and Behavioral Sciences, Faculty of Medicine, University of Crete, Heraklion, Crete, GreeceDepartment of Psychiatry, Martin Luther University of Halle-Wittenberg, Halle, GermanyInstitute of Behavioural Sciences, University of Helsinki, Helsinki, FinlandNORMENT, K.G. Jebsen Centre for Psychosis Research, University of Bergen, Bergen, NorwayInstitute for Behavioral Genetics, University of Colorado, Boulder, CO, USANORMENT, K.G. Jebsen Centre for Psychosis Research, University of Bergen, Bergen, NorwayCentre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UKDepartment of Psychiatry, Yale University School of Medicine, New Haven, CT, USADivision of Psychiatry Research, Zucker Hillside Hospital, Glen Oaks, NY, USADivision of Psychiatry Research, Zucker Hillside Hospital, Glen Oaks, NY, USAHere, 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.http://www.sciencedirect.com/science/article/pii/S2211124717316480GWASgeneral cognitive abilitynootropicsgene expressionneurodevelopmentsynapsecalcium channelpotassium channelcerebellum |
| spellingShingle | 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 Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets Cell Reports GWAS general cognitive ability nootropics gene expression neurodevelopment synapse calcium channel potassium channel cerebellum |
| title | Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets |
| title_full | Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets |
| title_fullStr | Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets |
| title_full_unstemmed | Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets |
| title_short | Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets |
| title_sort | large scale cognitive gwas meta analysis reveals tissue specific neural expression and potential nootropic drug targets |
| topic | GWAS general cognitive ability nootropics gene expression neurodevelopment synapse calcium channel potassium channel cerebellum |
| url | http://www.sciencedirect.com/science/article/pii/S2211124717316480 |
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