{"doi":"10.1038/s41398-024-02784-4","title":"Brain tissue- and cell type-specific eQTL Mendelian randomization reveals efficacy of FADS1 and FADS2 on cognitive function","abstract":"<jats:title>Abstract</jats:title><jats:p>Epidemiological studies suggested an association between omega-3 fatty acids and cognitive function. However, the causal role of the fatty acid desaturase (<jats:italic>FADS</jats:italic>) 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 (<jats:italic>N</jats:italic> = 114,999) on cognitive function (<jats:italic>N</jats:italic> = 300,486). Tissue- and cell type-specific effects of<jats:italic>FADS1</jats:italic>/<jats:italic>FADS2</jats:italic>expression on cognitive function were estimated using brain tissue cis-expression quantitative trait loci (cis-eQTL) datasets (GTEx,<jats:italic>N</jats:italic> ≤ 209; MetaBrain,<jats:italic>N</jats:italic> ≤ 8,613) and single cell cis-eQTL data (<jats:italic>N</jats:italic> = 373), respectively. These causal effects were further evaluated in whole blood cis-eQTL data (<jats:italic>N</jats:italic> ≤ 31,684). A series of sensitivity analyses were conducted to validate MR assumptions. Leave-one-out MR showed a<jats:italic>FADS</jats:italic>gene-specific effect of omega-3 fatty acids on cognitive function [β = −1.3 × 10<jats:sup>−2</jats:sup>, 95% confidence interval (CI) (−2.2 × 10<jats:sup>−2</jats:sup>, −5 × 10<jats:sup>−3</jats:sup>),<jats:italic>P</jats:italic> = 2 × 10<jats:sup>−3</jats:sup>]. Tissue-specific MR showed an effect of increased<jats:italic>FADS1</jats:italic>expression in cerebellar hemisphere and<jats:italic>FADS2</jats:italic>expression in nucleus accumbens basal ganglia on maintaining cognitive function, while decreased<jats:italic>FADS1</jats:italic>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<jats:italic>FADS1</jats:italic>/<jats:italic>FADS2</jats:italic>expression in oligodendrocyte was associated with maintaining cognitive function (PP.H4 = 82.3%, respectively). Increased<jats:italic>FADS1</jats:italic>/<jats:italic>FADS2</jats:italic>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<jats:italic>FADS1</jats:italic>/<jats:italic>FADS2</jats:italic>expression in brain tissues and blood on cognitive function. These findings provided evidence to prioritize<jats:italic>FADS</jats:italic>gene as potential target gene for maintenance of cognitive function.</jats:p>","journal":"Translational Psychiatry","year":2024,"id":646704,"datarank":0.37273599746820013,"base_score":2.4849066497880004,"endowment":2.4849066497880004,"self_citation_contribution":0.37273599746820013,"citation_network_contribution":0.0,"self_endowment_contribution":0.37273599746820013,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":11,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1424086,"name":"Lei Jiang","orcid":"0000-0002-6365-1965","position":1,"is_corresponding":false},{"id":1684613,"name":"Hongyan Qi","orcid":null,"position":2,"is_corresponding":false},{"id":525593,"name":"Chunyan Hu","orcid":"0000-0002-8673-3859","position":3,"is_corresponding":false},{"id":818908,"name":"Xiaojing Jia","orcid":"0000-0003-3062-4861","position":4,"is_corresponding":false},{"id":1086855,"name":"Hong Lin","orcid":"0000-0001-8973-1819","position":5,"is_corresponding":false},{"id":1684617,"name":"Shuangyuan Wang","orcid":null,"position":6,"is_corresponding":false},{"id":1457894,"name":"Lin Lin","orcid":"0000-0003-2084-8183","position":7,"is_corresponding":false},{"id":1684620,"name":"Yifang Zhang","orcid":null,"position":8,"is_corresponding":false},{"id":1151477,"name":"Ruizhi Zheng","orcid":"0000-0002-2068-7597","position":9,"is_corresponding":false},{"id":1363460,"name":"Mian Li","orcid":"0000-0003-1293-3636","position":10,"is_corresponding":false},{"id":442269,"name":"Tiange Wang","orcid":"0000-0003-0723-489X","position":11,"is_corresponding":false},{"id":1405503,"name":"Zhiyun Zhao","orcid":"0000-0001-5950-2732","position":12,"is_corresponding":false},{"id":1183195,"name":"Min Xu","orcid":"0000-0001-8245-4695","position":13,"is_corresponding":false},{"id":164907,"name":"Yu Xu","orcid":"0000-0002-0894-5311","position":14,"is_corresponding":false},{"id":1116305,"name":"Yuhong Chen","orcid":"0000-0001-6131-7595","position":15,"is_corresponding":false},{"id":78817,"name":"Jie Zheng","orcid":"0000-0002-6623-6839","position":16,"is_corresponding":false},{"id":38509,"name":"Yufang Bi","orcid":"0000-0002-4829-5915","position":17,"is_corresponding":false},{"id":1405505,"name":"Jieli Lu","orcid":"0000-0003-1317-0896","position":18,"is_corresponding":false},{"id":1439056,"name":"Xueyan Wu","orcid":"0000-0001-9127-7854","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Brain tissue- and cell type-specific eQTL Mendelian randomization reveals efficacy of FADS1 and FADS2 on cognitive function","abstract":"<jats:title>Abstract</jats:title><jats:p>Epidemiological studies suggested an association between omega-3 fatty acids and cognitive function. However, the causal role of the fatty acid desaturase (<jats:italic>FADS</jats:italic>) 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 (<jats:italic>N</jats:italic> = 114,999) on cognitive function (<jats:italic>N</jats:italic> = 300,486). Tissue- and cell type-specific effects of<jats:italic>FADS1</jats:italic>/<jats:italic>FADS2</jats:italic>expression on cognitive function were estimated using brain tissue cis-expression quantitative trait loci (cis-eQTL) datasets (GTEx,<jats:italic>N</jats:italic> ≤ 209; MetaBrain,<jats:italic>N</jats:italic> ≤ 8,613) and single cell cis-eQTL data (<jats:italic>N</jats:italic> = 373), respectively. These causal effects were further evaluated in whole blood cis-eQTL data (<jats:italic>N</jats:italic> ≤ 31,684). A series of sensitivity analyses were conducted to validate MR assumptions. Leave-one-out MR showed a<jats:italic>FADS</jats:italic>gene-specific effect of omega-3 fatty acids on cognitive function [β = −1.3 × 10<jats:sup>−2</jats:sup>, 95% confidence interval (CI) (−2.2 × 10<jats:sup>−2</jats:sup>, −5 × 10<jats:sup>−3</jats:sup>),<jats:italic>P</jats:italic> = 2 × 10<jats:sup>−3</jats:sup>]. Tissue-specific MR showed an effect of increased<jats:italic>FADS1</jats:italic>expression in cerebellar hemisphere and<jats:italic>FADS2</jats:italic>expression in nucleus accumbens basal ganglia on maintaining cognitive function, while decreased<jats:italic>FADS1</jats:italic>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<jats:italic>FADS1</jats:italic>/<jats:italic>FADS2</jats:italic>expression in oligodendrocyte was associated with maintaining cognitive function (PP.H4 = 82.3%, respectively). Increased<jats:italic>FADS1</jats:italic>/<jats:italic>FADS2</jats:italic>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<jats:italic>FADS1</jats:italic>/<jats:italic>FADS2</jats:italic>expression in brain tissues and blood on cognitive function. These findings provided evidence to prioritize<jats:italic>FADS</jats:italic>gene as potential target gene for maintenance of cognitive function.</jats:p>","is_dataset_classified":null,"base_score":2.3978952727983707,"endowment":2.3978952727983707,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"38316767","pmcid":"PMC10844634","openalex_id":"https://openalex.org/W4391533010","authors":[],"funders":[{"funder_name":"Diabetes UK","grant_id":"SBF006\\1117","title":null},{"funder_name":"Wellcome Trust","grant_id":"unidentified","title":"unidentified"},{"funder_name":"Wellcome Trust","grant_id":"","title":null},{"funder_name":"Wellcome Trust","grant_id":"","title":null}],"total_grants":4,"fwci":3.8426,"citation_percentile":0.93287292,"influential_citations":0,"citation_trend":[{"year":2024,"count":1},{"year":2025,"count":4},{"year":2026,"count":5}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://www.nature.com/articles/s41398-024-02784-4.pdf","host_type":"journal"},{"url":"https://www.nature.com/articles/s41398-024-02784-4.pdf","host_type":"publisher"},{"url":"https://www.nature.com/articles/s41398-024-02784-4","host_type":"publisher"},{"url":"https://doi.org/10.1038/s41398-024-02784-4","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/38316767","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/10844634","host_type":"repository"},{"url":"https://doaj.org/article/e24dbcfd2cf54ae8befcbc7ea16a90f8","host_type":"repository"},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC10844634/pdf/41398_2024_Article_2784.pdf","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC10844634","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC10844634?pdf=render","host_type":"Europe_PMC"},{"url":"http://dx.doi.org/10.1038/s41398-024-02784-4","host_type":""}],"fields_of_study":["Genetic Associations and Epidemiology","Epigenetics and DNA Methylation","Fatty Acid Research and Health","0301 basic medicine","0303 health sciences","03 medical and health sciences","Brain","Cognition","Fatty Acid Desaturases","Fatty Acids, Omega-3","Mendelian Randomization Analysis","Polymorphism, Single Nucleotide","Humans","Delta-5 Fatty Acid Desaturase"],"mesh_terms":["Delta-5 Fatty Acid Desaturase","Brain","Cognition","Humans","Fatty Acids, Omega-3","Polymorphism, Single Nucleotide","Fatty Acid Desaturases","Mendelian Randomization Analysis"],"keywords":["FADS2","Mendelian randomization","Expression quantitative trait loci","Biology","Internal medicine","Polyunsaturated fatty acid","Medicine","Fatty acid","Genetics","Biochemistry","Docosahexaenoic acid","Gene","Fatty Acid Desaturases","Brain","Neurosciences. 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