Brain tissue- and cell type-specific eQTL Mendelian randomization reveals efficacy of FADS1 and FADS2 on cognitive function

作者：Xueyan Wu, Lei Jiang, Hongyan Qi, Chunyan Hu, Xiaojing Jia, Hong Lin, Shuangyuan Wang, Lin Lin, Yifang Zhang, Ruizhi Zheng, Mian Li, Tiange Wang, Zhiyun Zhao, Min Xu, Yu Xu, Yuhong Chen, Jie Zheng, Yufang Bi, Jieli Lu · 发表于：Translational Psychiatry · 年份：2024 · DOI：10.1038/s41398-024-02784-4 · 被引用次数：10 · 研究领域：Genetic Associations and Epidemiology、Epigenetics and DNA Methylation、Fatty Acid Research and Health

Abstract Epidemiological studies suggested an association between omega-3 fatty acids and cognitive function. However, the causal role of the fatty acid desaturase ( FADS ) gene, which play a key role in regulating omega-3 fatty acids biosynthesis, on cognitive function is unclear. Hence, we used two-sample Mendelian randomization (MR) to estimate the gene-specific causal effect of omega-3 fatty acids ( N = 114,999) on cognitive function ( N = 300,486). Tissue- and cell type-specific effects of FADS1 / FADS2 expression on cognitive function were estimated using brain tissue cis-expression quantitative trait loci (cis-eQTL) datasets (GTEx, N ≤ 209; MetaBrain, N ≤ 8,613) and single cell cis-eQTL data ( N = 373), respectively. These causal effects were further evaluated in whole blood cis-eQTL data ( N ≤ 31,684). A series of sensitivity analyses were conducted to validate MR assumptions. Leave-one-out MR showed a FADS gene-specific effect of omega-3 fatty acids on cognitive function [β = −1.3 × 10 −2 , 95% confidence interval (CI) (−2.2 × 10 −2 , −5 × 10 −3 ), P = 2 × 10 −3 ]. Tissue-specific MR showed an effect of increased FADS1 expression in cerebellar hemisphere and FADS2 expression in nucleus accumbens basal ganglia on maintaining cognitive function, while decreased FADS1 expression in nine brain tissues on maintaining cognitive function [colocalization probability (PP.H4) ranged from 71.7% to 100.0%]. Cell type-specific MR showed decreased FADS1 / FADS2 expression in oligo...