Cited 27 times since 2022 (12.5 per year) source: EuropePMC Genome biology, Volume 23, Issue 1, 27 4 2022, Pages 268 Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis. Kanoni S, Graham SE, Wang Y, Surakka I, Ramdas S, Zhu X, Clarke SL, Bhatti KF, Vedantam S, Winkler TW, Locke AE, Marouli E, Zajac GJM, Wu KH, Ntalla I, Hui Q, Klarin D, Hilliard AT, Wang Z, Xue C, Thorleifsson G, Helgadottir A, Gudbjartsson DF, Holm H, Olafsson I, Hwang MY, Han S, Akiyama M, Sakaue S, Terao C, Kanai M, Zhou W, Brumpton BM, Rasheed H, Havulinna AS, Veturi Y, Pacheco JA, Rosenthal EA, Lingren T, Feng Q, Kullo IJ, Narita A, Takayama J, Martin HC, Hunt KA, Trivedi B, Haessler J, Giulianini F, Bradford Y, Miller JE, Campbell A, Lin K, Millwood IY, Rasheed A, Hindy G, Faul JD, Zhao W, Weir DR, Turman C, Huang H, Graff M, Choudhury A, Sengupta D, Mahajan A, Brown MR, Zhang W, Yu K, Schmidt EM, Pandit A, Gustafsson S, Yin X, Luan J, Zhao JH, Matsuda F, Jang HM, Yoon K, Medina-Gomez C, Pitsillides A, Hottenga JJ, Wood AR, Ji Y, Gao Z, Haworth S, Yousri NA, Mitchell RE, Chai JF, Aadahl M, Bjerregaard AA, Yao J, Manichaikul A, Hwu CM, Hung YJ, Warren HR, Ramirez J, Bork-Jensen J, Kårhus LL, Goel A, Saba
Background
Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.
Results
To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism.
Conclusions
Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.
