Cell Reports
Volume 21, Issue 9, 28 November 2017, Pages 2597-2613
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Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets

https://doi.org/10.1016/j.celrep.2017.11.028Get rights and content
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Highlights

  • Large-scale GWAS of cognitive performance, combined with GWAS of educational attainment

  • 70 independent genomic loci associated with individual differences in cognition

  • Implicated genes suggest potential treatment targets for cognitive enhancement

  • Genetic overlap between cognitive ability and multiple health-related phenotypes

Summary

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.

Keywords

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

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