biostudies-literatureLam MNIDCR NIH HHSNCATS NIH HHSNIA NIH HHSNIDA NIH HHSNCRR NIH HHSNIDDK NIH HHSMedical Research CouncilNHLBI NIH HHSNIMH NIH HHSNIAAA NIH HHSNINDS NIH HHSBiotechnology and Biological Sciences Research Council2597-2613https://www.ebi.ac.uk/biostudies/studies/S-EPMC5789458biostudies-literatureUnknown21(9)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.Cell reportsLarge-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets.PMC5789458N01 HC085084G1001245R01 MH079800R01 AA009367N01 HC085085R01 AA011886R01 MH080912R01 AG023629G0900753G0700704U01 AG023746R01 HL085251N01HC25195G0901461N01HC75150HHSN268201500001CBB/F019394/1UL1 TR000124RC2 MH089983MR/K026992/1P50 MH080173HHSN268200800007CMR/K002279/1UL1 DE019580U01 DA024417R37 DA005147K23 MH077807N01HC85079P30 DK063491R01 MH092515HHSN268201500001IR01 AG049789RL1 DA024853PL1 NS062410U01 HL080295UL1 RR033176N01HC85081N01HC85082N01HC85080HHSN268201200036CN01HC85086N01 HC035129N01HC85083G0600237R01 DA013240R01 MH100141R01 MH066140R01 HL087652RC2 MH089924K01 MH098126K01 MH085812N01 HC015103R01 MH085018R01 DA033369N01HC55222PL1 MH083271N02HL64278BB/F022441/1RL1 MH083269N01HC65226R01 HL105756N01 HC045133G0100594Payton AConley EDGill MPalotie ALencz THariri ARAndreassen OADeary IJEspeseth TKonte BBitsios PLahti JScult MARoussos PPendleton NKnowles EMelle IChristoforou ADonohoe GCorvin AStefanis NCEriksson JGReinvang IPoldrack RASmyrnis NDavies GKeller MCOllier WSabb FWDeRosse PVoineskos ANChiba-Falek OBilder RMAttix DKHatzimanolis AAvramopoulos DLondon EYu JGiakoumaki SBurdick KELiewald DCStraub REDjurovic SLundervold AJWiden EDickinson DGlahn DCFreimer NAMorris DSteen VMMalhotra AKRaikkonen KGiegling IRujescu DNeed ACSundet KArking DECongdon EStarr JMLe Hellard SLam MCirulli ETWeinberger DRTrampush JWCannon TDfalseLarge-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 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.2017-01-01T00:00:00Z2017 Nov2021-02-20T02:16:28Z2019-03-26T22:59:32ZS-EPMC57894582918669410.1016/j.celrep.2017.11.028