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Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets.

Citation
Lam, M., et al. “Large-Scale Cognitive Gwas Meta-Analysis Reveals Tissue-Specific Neural Expression And Potential Nootropic Drug Targets.”. Cell Reports, pp. 2597-2613.
Center UCSD-UCLA
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
Keywords GWAS, calcium channel, cerebellum, gene expression, general cognitive ability, neurodevelopment, nootropics, potassium channel, synapse
Abstract

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.

Year of Publication
2017
Journal
Cell reports
Volume
21
Issue
9
Number of Pages
2597-2613
Date Published
11/2017
ISSN Number
2211-1247
DOI
10.1016/j.celrep.2017.11.028
Alternate Journal
Cell Rep
PMID
29186694
PMCID
PMC5789458
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