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Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis


Kanoni, S and Graham, SE and Wang, Y and Surakka, I and Ramdas, S and Zhu, X and Clarke, SL and Bhatti, KF and Vedantam, S and Winkler, TW and Locke, AE and Marouli, E and Zajac, GJM and Wu, KHH and Ntalla, I and Hui, Q and Klarin, D and Hilliard, AT and Wang, Z and Xue, C and Thorleifsson, G and Helgadottir, A and Gudbjartsson, DF and Holm, H and Olafsson, I and Hwang, MY and Han, S and Akiyama, M and Sakaue, S and Terao, C and Kanai, M and Zhou, W and Brumpton, BM and Rasheed, H and Havulinna, AS and Veturi, Y and Pacheco, JA and Rosenthal, EA and Lingren, T and Feng, QP and Kullo, IJ and Narita, A and Takayama, J and Martin, HC and Hunt, KA and Trivedi, B and Haessler, J and Giulianini, F and Bradford, Y and Miller, JE and Campbell, A and Lin, K and Millwood, IY and Rasheed, A and Hindy, G and Faul, JD and Zhao, W and Weir, DR and Turman, C and Huang, H and Graff, M and Choudhury, A and Sengupta, D and Mahajan, A and Brown, MR and Zhang, W and Yu, K and Schmidt, EM and Schmidt, A and Gustafsson, S and Yin, X and Luan, J and Zhao, JH and Matsuda, F and Jang, HM and Yoon, K and Medina-Gomez, C and Pitsillides, A and Hottenga, JJ and Wood, AR and Ji, Y and Gao, Z and Haworth, S and Yousri, NA and Mitchell, RE and Chai, JF and Aadahl, M and Bjerregaard, AA and Yao, J and Manichaikul, A and Hwu, CM and Hung, YJ and Warren, HR and Ramirez, J and Bork-Jensen, J and Kayrhus, LL and Goel, A and Sabater-Lleal, M and Noordam, R and Hewitt, AW, Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis, Genome Biology, 23, (1) Article 268. ISSN 1474-7596 (2022) [Refereed Article]

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DOI: doi:10.1186/s13059-022-02837-1


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 Details

Item Type:Refereed Article
Keywords:Cholesterol; GWAS; Genetics; Genome-wide association study; Lipids.
Research Division:Biomedical and Clinical Sciences
Research Group:Medical biochemistry and metabolomics
Research Field:Medical biochemistry - lipids
Objective Division:Health
Objective Group:Clinical health
Objective Field:Prevention of human diseases and conditions
UTAS Author:Hewitt, AW (Professor Alex Hewitt)
ID Code:155572
Year Published:2022
Deposited By:Menzies Institute for Medical Research
Deposited On:2023-03-01
Last Modified:2023-03-01

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