Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics.

Cognition Genome-Wide Association Study Humans Nootropic Agents Schizophrenia / drug therapy Transcriptome

Journal

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
ISSN: 1740-634X
Titre abrégé: Neuropsychopharmacology
Pays: England
ID NLM: 8904907

Informations de publication

Date de publication:
09 2021
Historique:
received: 23 10 2020
accepted: 12 04 2021
revised: 22 02 2021
pubmed: 27 5 2021
medline: 28 8 2021
entrez: 26 5 2021
Statut: ppublish

Résumé

Broad-based cognitive deficits are an enduring and disabling symptom for many patients with severe mental illness, and these impairments are inadequately addressed by current medications. While novel drug targets for schizophrenia and depression have emerged from recent large-scale genome-wide association studies (GWAS) of these psychiatric disorders, GWAS of general cognitive ability can suggest potential targets for nootropic drug repurposing. Here, we (1) meta-analyze results from two recent cognitive GWAS to further enhance power for locus discovery; (2) employ several complementary transcriptomic methods to identify genes in these loci that are credibly associated with cognition; and (3) further annotate the resulting genes using multiple chemoinformatic databases to identify "druggable" targets. Using our meta-analytic data set (N = 373,617), we identified 241 independent cognition-associated loci (29 novel), and 76 genes were identified by 2 or more methods of gene identification. Actin and chromatin binding gene sets were identified as novel pathways that could be targeted via drug repurposing. Leveraging our transcriptomic and chemoinformatic databases, we identified 16 putative genes targeted by existing drugs potentially available for cognitive repurposing.

Identifiants

DOI: 10.1038/s41386-021-01023-4 PMID: 34035472 PMC: PMC8357785
pubmed: 34035472
doi: 10.1038/s41386-021-01023-4
pii: 10.1038/s41386-021-01023-4
pmc: PMC8357785
doi:

Substances chimiques

Nootropic Agents 0

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Langues

eng

Sous-ensembles de citation

IM

Pagination

1788-1801

Subventions

Organisme : NIA NIH HHS
ID : K99 AG054573
Pays : United States
Organisme : Medical Research Council
ID : G0700704
Pays : United Kingdom
Organisme : NHLBI NIH HHS
ID : N01HC55222
Pays : United States
Organisme : NHLBI NIH HHS
ID : N01HC25195
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG049789
Pays : United States
Organisme : NICHD NIH HHS
ID : U54 HD090255
Pays : United States
Organisme : NIMH NIH HHS
ID : RL1 MH083269
Pays : United States
Organisme : NHLBI NIH HHS
ID : N01HC85081
Pays : United States
Organisme : Medical Research Council
ID : G0700704/84698
Pays : United Kingdom
Organisme : NIMH NIH HHS
ID : R01 MH085018
Pays : United States
Organisme : Chief Scientist Office
ID : CZB/4/505
Pays : United Kingdom
Organisme : NIMH NIH HHS
ID : P50 MH080173
Pays : United States
Organisme : NIMH NIH HHS
ID : RC2 MH089924
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH117646
Pays : United States
Organisme : NHLBI NIH HHS
ID : N01HC85080
Pays : United States
Organisme : Biotechnology and Biological Sciences Research Council
ID : 15/S18386
Pays : United Kingdom
Organisme : NCATS NIH HHS
ID : UL1 TR000124
Pays : United States
Organisme : Medical Research Council
ID : MR/K026992/1
Pays : United Kingdom
Organisme : NIA NIH HHS
ID : R00 AG054573
Pays : United States
Organisme : NIMH NIH HHS
ID : K01 MH098126
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG023629
Pays : United States
Organisme : NIMH NIH HHS
ID : K01 MH085812
Pays : United States
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/F019394/1
Pays : United Kingdom
Organisme : NIMH NIH HHS
ID : K23 MH077807
Pays : United States
Organisme : NHLBI NIH HHS
ID : U01 HL080295
Pays : United States
Organisme : Medical Research Council
ID : MR/T030852/1
Pays : United Kingdom
Organisme : NHLBI NIH HHS
ID : N01HC65226
Pays : United States
Organisme : NHLBI NIH HHS
ID : HHSN268201200036C
Pays : United States
Organisme : NIMH NIH HHS
ID : RC2 MH089983
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH079800
Pays : United States
Organisme : Chief Scientist Office
ID : CZH/4/213
Pays : United Kingdom
Organisme : Chief Scientist Office
ID : CZG/3/2/79
Pays : United Kingdom
Organisme : NHLBI NIH HHS
ID : N01HC85082
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH080912
Pays : United States
Organisme : NHLBI NIH HHS
ID : N02 HL64278
Pays : United States
Organisme : NHLBI NIH HHS
ID : HHSN268201500001I
Pays : United States
Organisme : Chief Scientist Office
ID : ETM/55
Pays : United Kingdom
Organisme : NHLBI NIH HHS
ID : N01HC85079
Pays : United States
Organisme : CIHR
Pays : Canada
Organisme : NIDA NIH HHS
ID : R01 DA033369
Pays : United States
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ID : N01HC85083
Pays : United States
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ID : N01HC85086
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Organisme : NIDCR NIH HHS
ID : UL1 DE019580
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ID : N01HC75150
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Pays : United States
Organisme : NIDA NIH HHS
ID : U01 DA024417
Pays : United States
Organisme : Biotechnology and Biological Sciences Research Council
ID : 15/SAG09977
Pays : United Kingdom
Organisme : NHLBI NIH HHS
ID : HHSN268200800007C
Pays : United States

Informations de copyright

© 2021. The Author(s).

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Auteurs

Max Lam (M)

Division of Psychiatry Research, The Zucker Hillside Hospital, Glen Oaks, NY, USA.
Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
Institute for Behavioral Science, Feinstein Institutes for Medical Research, Manhasset, NY, USA.
Institute of Mental Health, Singapore, Singapore.
ORCID: 0000-0002-4256-7844

Chia-Yen Chen (CY)

Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
Biogen, Inc, Cambridge, MA, USA.
Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.

Tian Ge (T)

Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.

Yan Xia (Y)

Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, China.
Psychiatry Department, SUNY Upstate Medical University, Syracuse, NY, USA.

David W Hill (DW)

Lothian Birth Cohorts, University of Edinburgh, Edinburgh, Scotland, UK.
Lothian Birth Cohorts group, Department of Psychology, University of Edinburgh, Edinburgh, UK.

Joey W Trampush (JW)

Department of Psychiatry and the Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Jin Yu (J)

Division of Psychiatry Research, The Zucker Hillside Hospital, Glen Oaks, NY, USA.

Emma Knowles (E)

Tommy Fuss Center for Neuropsychiatric Disease Research, Boston Children's Hospital, Boston, MA, USA.
Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
Olin Neuropsychic Research Center, Institute of Living, Hartford Hospital, Hartford, CT, USA.

Gail Davies (G)

Lothian Birth Cohorts, University of Edinburgh, Edinburgh, Scotland, UK.
Lothian Birth Cohorts group, Department of Psychology, University of Edinburgh, Edinburgh, UK.
ORCID: 0000-0003-1120-7026

Eli A Stahl (EA)

Regeneron Pharmaceuticals, Inc., Tarrytown, 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.

Laura Huckins (L)

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.

David C Liewald (DC)

Lothian Birth Cohorts group, Department of Psychology, University of Edinburgh, Edinburgh, UK.
ORCID: 0000-0002-0544-7368

Srdjan Djurovic (S)

Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
NORMENT, Department of Clinical Science, University of Bergen, Bergen, Norway.

Ingrid Melle (I)

Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
ORCID: 0000-0002-9783-548X

Andrea Christoforou (A)

Spaulding Rehabilitation Hospital Boston, Charlestown, MA, USA.
Dr. Einar Martens Research Group for Biological Psychiatry, Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway.

Ivar Reinvang (I)

Department of Psychology, University of Oslo, Oslo, Norway.

Pamela DeRosse (P)

Division of Psychiatry Research, The Zucker Hillside Hospital, Glen Oaks, NY, USA.
Institute for Behavioral Science, Feinstein Institutes for Medical Research, Manhasset, NY, USA.
Department of Psychiatry, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA.
ORCID: 0000-0003-0823-8163

Astri J Lundervold (AJ)

Department of Biological and Medical Psychology, University of Bergen, Bergen, Norway.
ORCID: 0000-0002-6819-6164

Vidar M Steen (VM)

NORMENT, Department of Clinical Science, University of Bergen, Bergen, Norway.
Dr. Einar Martens Research Group for Biological Psychiatry, Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway.

Thomas Espeseth (T)

Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
Department of Psychology, University of Oslo, Oslo, Norway.

Katri Räikkönen (K)

Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Helsinki, Finland.

Elisabeth Widen (E)

Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.

Aarno Palotie (A)

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.

Johan G Eriksson (JG)

Department of General Practice, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Department of Obstetrics & Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
Folkhälsan Research Center, Helsinki, Finland.

Ina Giegling (I)

Department of Psychiatry, Martin Luther University of Halle-Wittenberg, Halle, Germany.

Bettina Konte (B)

Department of Psychiatry, Martin Luther University of Halle-Wittenberg, Halle, Germany.
ORCID: 0000-0001-5287-308X

Annette M Hartmann (AM)

Department of Psychiatry, Martin Luther University of Halle-Wittenberg, Halle, Germany.

Panos Roussos (P)

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.
ORCID: 0000-0002-4640-6239

Stella Giakoumaki (S)

Department of Psychology, University of Crete, Crete, Greece.

Katherine E Burdick (KE)

Department of Psychiatry, 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 Psychiatry - Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Antony Payton (A)

Division of Informatics, Imaging & Data Sciences, School of Health Sciences, The University of Manchester, Manchester, UK.

William Ollier (W)

Centre for Epidemiology, Division of Population Health, Health Services Research & Primary Care, The University of Manchester, Manchester, UK.
School of Healthcare Sciences, Manchester Metropolitan University, Manchester, United Kingdom.

Ornit Chiba-Falek (O)

Division of Translational Brain Sciences, Department of Neurology, Bryan Alzheimer's Disease Research Center, and Center for Genomic and Computational Biology, Duke University Medical Center, Durham, NC, USA.
ORCID: 0000-0002-2529-8785

Deborah C Koltai (DC)

Psychiatry and Behavioral Sciences, Division of Medical Psychology, and Department of Neurology, Duke University Medical Center, Durham, NC, USA.

Anna C Need (AC)

William Harvey Research Institute, Queen Mary University of London, London, UK.

Elizabeth T Cirulli (ET)

Helix Inc., San Diego, CA, USA.

Aristotle N Voineskos (AN)

Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, University of Toronto, Toronto, ON, Canada.
ORCID: 0000-0003-0156-0395

Nikos C Stefanis (NC)

2nd Department of Psychiatry, National and Kapodistrian University of Athens Medical School, University General Hospital "ATTIKON", Athens, Greece.
University Mental Health Research Institute, Athens, Greece.
Neurobiology Research Institute, Theodor-Theohari Cozzika Foundation, Athens, Greece.

Dimitrios Avramopoulos (D)

Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
ORCID: 0000-0003-1492-9104

Alex Hatzimanolis (A)

2nd Department of Psychiatry, National and Kapodistrian University of Athens Medical School, University General Hospital "ATTIKON", Athens, Greece.
University Mental Health Research Institute, Athens, Greece.
Neurobiology Research Institute, Theodor-Theohari Cozzika Foundation, Athens, Greece.

Nikolaos Smyrnis (N)

2nd Department of Psychiatry, National and Kapodistrian University of Athens Medical School, University General Hospital "ATTIKON", Athens, Greece.
University Mental Health Research Institute, Athens, Greece.

Robert M Bilder (RM)

UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles, CA, USA.
ORCID: 0000-0001-5085-7852

Nelson B Freimer (NB)

UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles, CA, USA.

Tyrone D Cannon (TD)

Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
Department of Psychology, Yale University, New Haven, CT, USA.

Edythe London (E)

UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles, CA, USA.
ORCID: 0000-0003-3577-7808

Russell A Poldrack (RA)

Department of Psychology, Stanford University, Palo Alto, CA, USA.
ORCID: 0000-0001-6755-0259

Fred W Sabb (FW)

Robert and Beverly Lewis Center for Neuroimaging, University of Oregon, Eugene, OR, USA.

Eliza Congdon (E)

UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles, CA, USA.

Emily Drabant Conley (ED)

23andMe, Inc., Mountain View, CA, USA.

Matthew A Scult (MA)

Weill Cornell Psychiatry at NewYork-Presbyterian, Weill Cornell Medical Center, New York, NY, USA.
Laboratory of NeuroGenetics, Department of Psychology & Neuroscience, Duke University, Durham, NC, USA.

Dwight Dickinson (D)

Clinical and Translational Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, National Institute of Health, Bethesda, MD, USA.

Richard E Straub (RE)

Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, MD, USA.

Gary Donohoe (G)

Neuroimaging, Cognition & Genomics (NICOG) Centre, School of Psychology and Discipline of Biochemistry, National University of Ireland, Galway, Ireland.

Derek Morris (D)

Neuroimaging, Cognition & Genomics (NICOG) Centre, School of Psychology and Discipline of Biochemistry, National University of Ireland, Galway, Ireland.
ORCID: 0000-0002-3413-570X

Aiden Corvin (A)

Neuropsychiatric Genetics Research Group, Department of Psychiatry and Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland.

Michael Gill (M)

Neuropsychiatric Genetics Research Group, Department of Psychiatry and Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland.
ORCID: 0000-0003-0206-5337

Ahmad R Hariri (AR)

Laboratory of NeuroGenetics, Department of Psychology & Neuroscience, Duke University, Durham, NC, USA.

Daniel R Weinberger (DR)

Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, MD, USA.
ORCID: 0000-0003-2409-2969

Neil Pendleton (N)

Division of Neuroscience and Experimental Psychology/School of Biological Sciences, Faculty of Biology Medicine and Health, Manchester Academic Health Science Centre, Salford Royal NHS Foundation Trust, University of Manchester, Manchester, UK.

Panos Bitsios (P)

Department of Psychiatry and Behavioral Sciences, Faculty of Medicine, University of Crete, Heraklion, Crete, GR, Greece.

Dan Rujescu (D)

Department of Psychiatry, Martin Luther University of Halle-Wittenberg, Halle, Germany.

Jari Lahti (J)

Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
Helsinki Collegium for Advanced Studies, University of Helsinki, Helsinki, Finland.
ORCID: 0000-0002-4310-5297

Stephanie Le Hellard (S)

NORMENT, Department of Clinical Science, University of Bergen, Bergen, Norway.
Dr. Einar Martens Research Group for Biological Psychiatry, Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway.

Matthew C Keller (MC)

Institute for Behavioral Genetics, University of Colorado, Boulder, CO, USA.

Ole A Andreassen (OA)

Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
ORCID: 0000-0002-4461-3568

Ian J Deary (IJ)

Lothian Birth Cohorts, University of Edinburgh, Edinburgh, Scotland, UK.
Lothian Birth Cohorts group, Department of Psychology, University of Edinburgh, Edinburgh, UK.
ORCID: 0000-0002-1733-263X

David C Glahn (DC)

Tommy Fuss Center for Neuropsychiatric Disease Research, Boston Children's Hospital, Boston, MA, USA.
Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
Olin Neuropsychic Research Center, Institute of Living, Hartford Hospital, Hartford, CT, USA.

Hailiang Huang (H)

Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.

Chunyu Liu (C)

Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, China.
Psychiatry Department, SUNY Upstate Medical University, Syracuse, NY, USA.
ORCID: 0000-0002-5986-4415

Anil K Malhotra (AK)

Division of Psychiatry Research, The Zucker Hillside Hospital, Glen Oaks, NY, USA.
Institute for Behavioral Science, Feinstein Institutes for Medical Research, Manhasset, NY, USA.
Department of Psychiatry, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA.

Todd Lencz (T)

Division of Psychiatry Research, The Zucker Hillside Hospital, Glen Oaks, NY, USA. tlencz@northwell.edu.
Institute for Behavioral Science, Feinstein Institutes for Medical Research, Manhasset, NY, USA. tlencz@northwell.edu.
Department of Psychiatry, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA. tlencz@northwell.edu.
ORCID: 0000-0001-8586-338X

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Classifications MeSH

questionsmedicales.fr › Phénomènes psychologiques › Processus mentaux › Cognition › Identifying nootropic drug targets via...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Épidémiologie moléculaire › Étude d'association pangénomique › Identifying nootropic drug targets via...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Identifying nootropic drug targets via...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Agents du système nerveux central › Nootropiques › Identifying nootropic drug targets via...
questionsmedicales.fr › Troubles mentaux › Schizophrénie et troubles avec traits psychotiques › Schizophrénie › Identifying nootropic drug targets via...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Transcriptome › Identifying nootropic drug targets via...