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Kanoni, S.* ; Graham, S.E.* ; Wang, Y.* ; Surakka, I.* ; Ramdas, S.* ; Zhu, X.* ; Clarke, S.L.* ; Bhatti, K.F.* ; Vedantam, S.* ; Winkler, T.W.* ; Locke, A.E.* ; Marouli, E.* ; Zajac, G.J.M.* ; Wu, K.H.H.* ; Ntalla, I.* ; Hui, Q.* ; Klarin, D.* ; Hilliard, A.T.* ; Wang, Z.* ; Xue, C.* ; Thorleifsson, G.* ; Helgadottir, A.* ; Gudbjartsson, D.F.* ; Holm, H.* ; Olafsson, I.* ; Hwang, M.Y.* ; Han, S.* ; Akiyama, M.* ; Sakaue, S.* ; Terao, C.* ; Kanai, M.* ; Zhou, W.* ; Brumpton, B.M.* ; Rasheed, H.* ; Havulinna, A.S.* ; Veturi, Y.* ; Pacheco, J.A.* ; Rosenthal, E.A.* ; Lingren, T.* ; Feng, Q.P.* ; Kullo, I.J.* ; Narita, A.* ; Takayama, J.* ; Martin, H.C.* ; Hunt, K.A.* ; Trivedi, B.* ; Haessler, J.* ; Giulianini, F.* ; Bradford, Y.* ; Miller, J.E.* ; Campbell, A.* ; Lin, K.* ; Millwood, I.Y.* ; Rasheed, A.* ; Hindy, G.* ; Faul, J.D.* ; Zhao, W.* ; Weir, D.R.* ; Turman, C.* ; Huang, H.* ; Graff, M.* ; Choudhury, A.* ; Sengupta, D.* ; Mahajan, A.* ; Brown, M.R.* ; Zhang, W.* ; Yu, K.* ; Schmidt, E.M.* ; Pandit, A.* ; Gustafsson, S.* ; Yin, X.* ; Luan, J.* ; Zhao, J.H.* ; Matsuda, F.* ; Jang, H.M.* ; Yoon, K.* ; Medina-Gomez, C.* ; Pitsillides, A.* ; Hottenga, J.J.* ; Wood, A.R.* ; Ji, Y.* ; Gao, Z. ; Haworth, S.* ; Yousri, N.A.* ; Mitchell, R.E.* ; Chai, J.F.* ; Aadahl, M.* ; Bjerregaard, A.A.* ; Yao, J.* ; Manichaikul, A.* ; Hwu, C.M.* ; Hung, Y.J.* ; Warren, H.R.* ; Ramirez, J.* ; Bork-Jensen, J.* ; Kårhus, L.L.* ; Goel, A.* ; Sabater-Lleal, M.* ; Noordam, R.* ; Mauro, P.* ; Møllehave, L.T.* ; Munz, M.* ; Zeng, L.* ; Kurbasic, A.* ; Lamina, C.* ; Scholz, M.* ; Zmuda, J.M* ; Brody, J.A.* ; Engmann, J.* ; Slieker, R.C.* ; Zilhao, N.R.* ; Iha, H.* ; Schmidt, B.* ; Fernandez‑Lopez, J.C.* ; Oldmeadow, C.* ; Prasad, G.* ; Lorés‑Motta, L.* ; Nutile, T.* ; Banas, B.* ; Hebbar, P.* ; Hofer, E.* ; Bentley, A.R.* ; Southam, L. ; Rayner, N.W. ; Wang, C.A.* ; Couture, C.* ; Cuellar‑Partida, G.* ; Giannakopoulou, O.* ; van Setten, J.* ; Liang, J.* ; Terzikhan, N.* ; Kawaguchi, T.* ; Nalls, M.A.* ; Raitakari, O.T.* ; Campbell, H.* ; Ikram, M.A.* ; Asselbergs, F.W.* ; Pasterkamp, G.* ; Bandinelli, S.* ; Wickremasinghe, A.R.* ; Bharadwaj, D.* ; Koistinen, H.A.* ; Yokota, M.* ; Pramstaller, P.P.* ; Kronenberg, F.* ; Sabanayagam, C.* ; Peters, A. ; Gieger, C. ; Hattersley, A.T.* ; Pedersen, N.L.* ; Cupples, L.A.* ; Langenberg, C.* ; Zeggini, E. ; Kuusisto, J.* ; Laakso, M.* ; Saleheen, D.* ; Jousilahti, P.* ; Salomaa, V.* ; Zhang, J.* ; Deloukas, P.* ; Willer, C.J.* ; Assimes, T.* ; Peloso, G.M.*

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

Genome Biol. 23:268 (2022)
Postprint Research data DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Cholesterol ; Genetics ; Genome-wide Association Study ; Gwas ; Lipids; Genome-wide Association; Cardiovascular Risk-factors; Metabolizing Enzyme; Coding Variants; Low-frequency; Cholesterol; Disease; Discovery; Testosterone; Ugt2b17
Language english
Publication Year 2022
HGF-reported in Year 2022
ISSN (print) / ISBN 1474-760X
e-ISSN 1465-6906
Journal Genome Biology
Quellenangaben Volume: 23, Issue: 1, Pages: , Article Number: 268 Supplement: ,
Publisher BioMed Central
Publishing Place Campus, 4 Crinan St, London N1 9xw, England
Reviewing status Peer reviewed
Institute(s) Institute of Epidemiology (EPI)
Institute of Translational Genomics (ITG)
POF-Topic(s) 30202 - Environmental Health
30205 - Bioengineering and Digital Health
Research field(s) Genetics and Epidemiology
PSP Element(s) G-504091-004
G-506700-001
G-504000-010
Grants NHLBI NIH HHS
DOI 10.1186/s13059-022-02837-1
WOS ID 000927879600003
Scopus ID 85144774123
PubMed ID 36575460
Erfassungsdatum 2023-01-17
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