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

• Published in: Biological psychiatry (1969) 2023-01, Vol.93 (1), p.59-70
• Main Authors: Hatoum, Alexander S., Morrison, Claire L., Mitchell, Evann C., Lam, Max, Benca-Bachman, Chelsie E., Reineberg, Andrew E., Palmer, Rohan H.C., Evans, Luke M., Keller, Matthew C., Friedman, Naomi P.
• Format: Article
• Language: English
• Subjects: Cognition; Cognitive control; Executive Function; Executive functioning; Genetic correlations; Genome-wide association analysis; Genome-Wide Association Study; Humans; Intelligence - genetics; Latent variable measurement; Mental Disorders - genetics; Neurocognitive functioning
• ISSN: 0006-3223; 1873-2402; 1873-2402
• DOI: 10.1016/j.biopsych.2022.06.034

Deficits in executive functions (EFs), cognitive processes that control goal-directed behaviors, are associated with psychopathology and neurologic disorders. Little is known about the molecular bases of individual differences in EFs. Prior candidate gene studies have been underpowered in their search for dopaminergic processes involved in cognitive functioning, and existing genome-wide association studies of EFs used small sample sizes and/or focused on individual tasks that are imprecise measures of EFs. We conducted a genome-wide association study of a common EF (cEF) factor score based on multiple tasks in the UK Biobank (n = 427,037 individuals of European descent). We found 129 independent genome-wide significant lead variants in 112 distinct loci. cEF was associated with fast synaptic transmission processes (synaptic, potassium channel, and GABA [gamma-aminobutyric acid] 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. Results suggest that cEF is a genetically distinct cognitive construct that is particularly relevant to understanding the genetic variance in psychiatric disorders.