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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Article Info
Publication History
Accepted:
June 23,
2022
Received in revised form:
June 8,
2022
Received:
December 9,
2021
Publication stage
In Press Journal Pre-ProofFootnotes
Author Contributions
ASH ran the genome-wide association analysis and analyses with summary statistics along with ECM and CLM. ASH, CLM and NPF wrote the manuscript. NPF sponsored the research, generated the phenotype in the UKB, and conducted the PGS analyses along with CEB. LME organized the raw genotype data from the UKB as well as the genotype data in the twin samples. MCK, LME, AER, ML, and RHCP provided advice and assistance with analyses and manuscript preparation. All authors contributed to the final written version of the manuscript.
Data Access
Summary statistics for all GWASs (cEF, IQ, RT, and all indicators) will be available upon publication of this work through the FriedmanLab github or available upon request. All results run on FUMA have been made publicly available through that platform. cEF results can be accessed via FUMA (cEF full sample: https://fuma.ctglab.nl/browse/65, cEF densely phenotyped sample: https://fuma.ctglab.nl/browse/66, cEF sparsely phenotyped sample: https://fuma.ctglab.nl/browse/67). Full results for the IQ and Speed GWAS are also available on FUMA (IQ: https://fuma.ctglab.nl/browse/114, Speed: https://fuma.ctglab.nl/browse/118). All biological results for cEF-specific and IQ-specific GWAS can be downloaded here (cEF-specific: https://fuma.ctglab.nl/browse/116, IQ-specific: https://fuma.ctglab.nl/browse/117).
Identification
Copyright
© 2022 Published by Elsevier Inc on behalf of Society of Biological Psychiatry.
