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

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. ErikssonIna 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

Research output: Contribution to journalArticle

36 Scopus citations

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. Lam et al. conduct a large-scale genome-wide association study of cognitive ability, identifying 70 associated loci. Results provide biological insights into the molecular basis of individual differences in cognitive ability, as well as their relationship to psychiatric and other health-relevant phenotypes.

Original languageEnglish (US)
Pages (from-to)2597-2613
Number of pages17
JournalCell Reports
Volume21
Issue number9
DOIs
StatePublished - Nov 28 2017
Externally publishedYes

Keywords

  • GWAS
  • calcium channel
  • cerebellum
  • gene expression
  • general cognitive ability
  • neurodevelopment
  • nootropics
  • potassium channel
  • synapse

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Lam, M., Trampush, J. W., Yu, J., Knowles, E., Davies, G., Liewald, D. C., Starr, J. M., Djurovic, S., Melle, I., Sundet, K., Christoforou, A., Reinvang, I., DeRosse, P., Lundervold, A. J., Steen, V. M., Espeseth, T., Räikkönen, K., Widen, E., Palotie, A., ... Lencz, T. (2017). Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets. Cell Reports, 21(9), 2597-2613. https://doi.org/10.1016/j.celrep.2017.11.028