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

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Lam , M , Chen , C-Y , Ge , T , Xia , Y , Hill , D W , Trampush , J W , Yu , J , Knowles , E , Davies , G , Stahl , E A , Huckins , L , Liewald , D C , Djurovic , S , Melle , I , Christoforou , A , Reinvang , I , DeRosse , P , Lundervold , A J , Steen , V M , Espeseth , T , Raikkonen , K , Widen , E , Palotie , A , Eriksson , J G , Giegling , I , Konte , B , Hartmann , A M , Roussos , P , Giakoumaki , S , Burdick , K E , Payton , A , Ollier , W , Chiba-Falek , O , Koltai , D C , Need , A C , Cirulli , E T , Voineskos , A N , Stefanis , N C , Avramopoulos , D , Hatzimanolis , A , Smyrnis , N , Bilder , R M , Freimer , N B , Cannon , T D , London , E , Poldrack , R A , Sabb , F W , Congdon , E , Conley , E D , Scult , M A , Dickinson , D , Straub , R E , Donohoe , G , Morris , D , Corvin , A , Gill , M , Hariri , A R , Weinberger , D R , Pendleton , N , Bitsios , P , Rujescu , D , Lahti , J , Hellard , S L , Keller , M C , Andreassen , O A , Deary , I J , Glahn , D C , Huang , H , Liu , C , Malhotra , A K & Lencz , T 2021 , ' Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics ' , Neuropsychopharmacology , vol. 46 , no. 10 , pp. 1788-1801 . https://doi.org/10.1038/s41386-021-01023-4

Title: Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics
Author: Lam, Max; Chen, Chia-Yen; Ge, Tian; Xia, Yan; Hill, David W.; Trampush, Joey W.; Yu, Jin; Knowles, Emma; Davies, Gail; Stahl, Eli A.; Huckins, Laura; Liewald, David C.; Djurovic, Srdjan; Melle, Ingrid; Christoforou, Andrea; Reinvang, Ivar; DeRosse, Pamela; Lundervold, Astri J.; Steen, Vidar M.; Espeseth, Thomas; Raikkonen, Katri; Widen, Elisabeth; Palotie, Aarno; Eriksson, Johan G.; Giegling, Ina; Konte, Bettina; Hartmann, Annette M.; Roussos, Panos; Giakoumaki, Stella; Burdick, Katherine E.; Payton, Antony; Ollier, William; Chiba-Falek, Ornit; Koltai, Deborah C.; Need, Anna C.; Cirulli, Elizabeth T.; Voineskos, Aristotle N.; Stefanis, Nikos C.; Avramopoulos, Dimitrios; Hatzimanolis, Alex; Smyrnis, Nikolaos; Bilder, Robert M.; Freimer, Nelson B.; Cannon, Tyrone D.; London, Edythe; Poldrack, Russell A.; Sabb, Fred W.; Congdon, Eliza; Conley, Emily Drabant; Scult, Matthew A.; Dickinson, Dwight; Straub, Richard E.; Donohoe, Gary; Morris, Derek; Corvin, Aiden; Gill, Michael; Hariri, Ahmad R.; Weinberger, Daniel R.; Pendleton, Neil; Bitsios, Panos; Rujescu, Dan; Lahti, Jari; Hellard, Stephanie Le; Keller, Matthew C.; Andreassen, Ole A.; Deary, Ian J.; Glahn, David C.; Huang, Hailiang; Liu, Chunyu; Malhotra, Anil K.; Lencz, Todd
Contributor organization: Centre of Excellence in Complex Disease Genetics
Elisabeth Ingrid Maria Widen / Principal Investigator
Institute for Molecular Medicine Finland
Genomic Discoveries and Clinical Translation
University of Helsinki
Aarno Palotie / Principal Investigator
Genomics of Neurological and Neuropsychiatric Disorders
Department of Medical and Clinical Genetics
Helsinki University Hospital Area
Clinicum
Johan Eriksson / Principal Investigator
Department of General Practice and Primary Health Care
Department of Psychology and Logopedics
Helsinki Collegium for Advanced Studies
Date: 2021-09
Language: eng
Number of pages: 14
Belongs to series: Neuropsychopharmacology
ISSN: 0893-133X
DOI: https://doi.org/10.1038/s41386-021-01023-4
URI: http://hdl.handle.net/10138/340451
Abstract: 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.
Subject: GENOME-WIDE
METAANALYSIS REVEALS
SCHIZOPHRENIA
EXPRESSION
IDENTIFICATION
OPPORTUNITIES
THERAPEUTICS
IMPAIRMENT
COMPLEX
MEMORY
3111 Biomedicine
3112 Neurosciences
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion


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