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Geofrey and Ritchie, Marylyn D. and Jousilahti, Pekka and Salomaa, Veikko and Hveem, Kristian and Asvold, Bjorn Olav and Kubo, Michiaki and Kamatani, Yoichiro and Okada, Yukinori and Murakami, Yoshinori and Kim, Bong-Jo and Thorsteinsdottir, Unnur and Stefansson, Kari and Zhang, Jifeng and Chen, Y. Eugene and Ho, Yuk-Lam and Lynch, Julie A. and Rader, Daniel J. and Tsao, Philip S. and Chang, Kyong-Mi and Cho, Kelly and O'Donnell, Christopher J. and Gaziano, John M. and Wilson, Peter W. F. and Frayling, Timothy M. and Hirschhorn, Joel N. and Kathiresan, Sekar and Mohlke, Karen L. and Sun, Yan and Morris, Andrew P. and Boehnke, Michael and Brown, Christopher D. and Natarajan, Pradeep and Deloukas, Panos and Willer, Cristen J. and Assimes, Themistocles L. and Peloso, Gina M. and Demirkan, Ayse (2022) Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis. GENOME BIOLOGY, 23 (1): 268. ISSN 1474-760X,
Full text not available from this repository. (Request a copy)Abstract
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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | GENOME-WIDE ASSOCIATION; CARDIOVASCULAR RISK-FACTORS; METABOLIZING ENZYME; CODING VARIANTS; LOW-FREQUENCY; CHOLESTEROL; DISEASE; DISCOVERY; TESTOSTERONE; UGT2B17; Cholesterol; Lipids; Genetics; Genome-wide association study; GWAS |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Abteilung für Nephrologie Medicine > Institut für Epidemiologie und Präventivmedizin > Lehrstuhl für Genetische Epidemiologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 19 Sep 2023 05:43 |
| Last Modified: | 19 Sep 2023 05:43 |
| URI: | https://pred.uni-regensburg.de/id/eprint/58866 |
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