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

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

doi:10.1038/s41398-024-02784-4

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

Transl Psychiatry. 2024 Feb 5;14(1):77. doi: 10.1038/s41398-024-02784-4.

Authors

Xueyan Wu^#^{1

2}, Lei Jiang^#^{1

2}, Hongyan Qi^#^{1

2}, Chunyan Hu^{1

2}, Xiaojing Jia^{1

2}, Hong Lin^{1

2}, Shuangyuan Wang^{1

2}, Lin Lin^{1

2}, Yifang Zhang³, Ruizhi Zheng^{1

2}, Mian Li^{1

2}, Tiange Wang^{1

2}, Zhiyun Zhao^{1

2}, Min Xu^{1

2}, Yu Xu^{1

2}, Yuhong Chen^{1

2}, Jie Zheng^{4

5

6

7}, Yufang Bi^{8

9}, Jieli Lu^{10

11}

Affiliations

¹ Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
² Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
³ Network and Information Center, Shanghai Jiao Tong University, Shanghai, China.
⁴ Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Jie.Zheng@bristol.ac.uk.
⁵ Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Jie.Zheng@bristol.ac.uk.
⁶ Shanghai Digital Medicine Innovation Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Jie.Zheng@bristol.ac.uk.
⁷ MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK. Jie.Zheng@bristol.ac.uk.
⁸ Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. byf10784@rjh.com.cn.
⁹ Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. byf10784@rjh.com.cn.
¹⁰ Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. jielilu@hotmail.com.
¹¹ Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. jielilu@hotmail.com.

^# Contributed equally.

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 oligodendrocyte was associated with maintaining cognitive function (PP.H4 = 82.3%, respectively). Increased FADS1/FADS2 expression in whole blood showed an effect on cognitive function maintenance (PP.H4 = 86.6% and 88.4%, respectively). This study revealed putative causal effect of FADS1/FADS2 expression in brain tissues and blood on cognitive function. These findings provided evidence to prioritize FADS gene as potential target gene for maintenance of cognitive function.

MeSH terms

Brain / metabolism
Cognition*
Delta-5 Fatty Acid Desaturase* / genetics
Fatty Acid Desaturases* / genetics
Fatty Acids, Omega-3*
Humans
Mendelian Randomization Analysis
Polymorphism, Single Nucleotide

Substances

Fatty Acid Desaturases
Fatty Acids, Omega-3
FADS1 protein, human
FADS2 protein, human
Delta-5 Fatty Acid Desaturase

Abstract

MeSH terms

Substances

Grants and funding