University of Tasmania
Browse

File(s) under permanent embargo

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

journal contribution
posted on 2023-05-21, 16:44 authored by 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, KHH, 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, QP, 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, Schmidt, 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, Kayrhus, LL, Goel, A, Sabater-Lleal, M, Noordam, R, Alexander HewittAlexander Hewitt

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.

History

Publication title

Genome Biology

Volume

23

Article number

268

Number

268

Pagination

1-42

ISSN

1474-7596

Department/School

Menzies Institute for Medical Research

Publisher

BioMed Central Ltd

Place of publication

London

Repository Status

  • Restricted

Socio-economic Objectives

Prevention of human diseases and conditions; Treatment of human diseases and conditions

Usage metrics

    University Of Tasmania

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC