TY - JOUR
T1 - Genome-wide Association Study Shows That Executive Functioning Is Influenced by GABAergic Processes and Is a Neurocognitive Genetic Correlate of Psychiatric Disorders
AU - Hatoum, Alexander S.
AU - Morrison, Claire L.
AU - Mitchell, Evann C.
AU - Lam, Max
AU - Benca-Bachman, Chelsie E.
AU - Reineberg, Andrew E.
AU - Palmer, Rohan H.C.
AU - Evans, Luke M.
AU - Keller, Matthew C.
AU - Friedman, Naomi P.
N1 - Publisher Copyright:
© 2022 Society of Biological Psychiatry
PY - 2023/1/1
Y1 - 2023/1/1
N2 - Background: 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. Methods: 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). Results: 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. Conclusions: Results suggest that cEF is a genetically distinct cognitive construct that is particularly relevant to understanding the genetic variance in psychiatric disorders.
AB - Background: 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. Methods: 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). Results: 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. Conclusions: Results suggest that cEF is a genetically distinct cognitive construct that is particularly relevant to understanding the genetic variance in psychiatric disorders.
KW - Cognitive control
KW - Executive functioning
KW - Genetic correlations
KW - Genome-wide association analysis
KW - Latent variable measurement
KW - Neurocognitive functioning
UR - https://www.scopus.com/pages/publications/85138556921
U2 - 10.1016/j.biopsych.2022.06.034
DO - 10.1016/j.biopsych.2022.06.034
M3 - Article
C2 - 36150907
AN - SCOPUS:85138556921
SN - 0006-3223
VL - 93
SP - 59
EP - 70
JO - Biological Psychiatry
JF - Biological Psychiatry
IS - 1
ER -