全基因组关联研究表明，执行功能受 GABA 能过程的影响，是精神障碍的神经认知遗传相关性。
Genome-wide Association Study Shows That Executive Functioning Is Influenced by GABAergic Processes and Is a Neurocognitive Genetic Correlate of Psychiatric Disorders.
机构信息
Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, Colorado; Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, Colorado; Department of Psychiatry, University of Washington St. Louis Medical School, St. Louis, Missouri.
Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, Colorado; Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, Colorado.
出版信息
Biol Psychiatry. 2023 Jan 1;93(1):59-70. doi: 10.1016/j.biopsych.2022.06.034. Epub 2022 Jul 14.
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.
背景
执行功能（EFs）是控制目标导向行为的认知过程，存在缺陷与精神病理学和神经障碍有关。对于个体执行功能差异的分子基础知之甚少。先前的候选基因研究在寻找与认知功能相关的多巴胺能过程时，其研究能力不足，而现有的执行功能全基因组关联研究样本量较小，或者只关注个体任务，而这些任务是对执行功能的不精确测量。
方法
我们在英国生物库（n=427,037 名欧洲血统个体）中进行了一项基于多项任务的常见执行功能（cEF）因子评分的全基因组关联研究。
结果
我们在 112 个不同的基因座中发现了 129 个独立的全基因组显著的先导变异。基于基因的分析显示，cEF 与快速突触传递过程（突触、钾通道和 GABA[γ-氨基丁酸]途径）有关。cEF 与智力（IQ）和认知加工速度呈遗传相关性，但 cEF 和 IQ 与精神障碍和教育程度的遗传关联存在差异。
结论
结果表明，cEF 是一种具有遗传差异的认知结构，对于理解精神障碍的遗传变异特别重要。
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