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Genome-Wide Association Study Shows that Executive Functioning Is Influenced by GABAergic Processes and Is a Neurocognitive Genetic Correlate of Psychiatric Disorders

      Abstract

      Background

      Deficits in executive functions (EFs), cognitive processes that control goal-directed behaviors, are associated with psychopathology and neurological disorders. Little is known about the molecular bases of EF individual differences. Prior candidate gene studies have been underpowered in their search for dopaminergic processes involved in cognitive functioning, and existing EF genome-wide association studies (GWASs) used small sample sizes and/or focused on individual tasks that are imprecise measures of EF.

      Methods

      We conducted a GWAS of a Common EF (cEF) factor score based on multiple tasks in the UK Biobank (N=427,037 European-descent individuals).

      Results

      We found 129 independent genome-wide significant lead variants in 112 distinct loci and that cEF was associated with fast synaptic transmission processes (synaptic, potassium channel, and GABA pathways) in gene-based analyses. cEF was genetically correlated with measures of intelligence (IQ) and cognitive processing speed, but cEF and IQ showed differential genetic associations with psychiatric disorders and educational attainment.

      Conclusions

      Results suggest that cEF is a genetically distinct cognitive construct that is particularly relevant to understanding the genetic variance in psychiatric disorders.

      Key words

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