Implicating Genes, Pleiotropy, and Sexual Dimorphism at Blood Lipid Loci through Multi-Ancestry Meta-Analysis

Citation

Kanoni, Stavroula; Graham, Sarah E.; Wang, Yuxuan; Surakka, Ida; Ramdas, Shweta; Zhu, Xiang; Clarke, Shoa L.; Bhatti, Konain Fatima; Vedantam, Sailaja; & Winkler, Thomas W., et al. (2022). Implicating Genes, Pleiotropy, and Sexual Dimorphism at Blood Lipid Loci through Multi-Ancestry Meta-Analysis. Genome Biology, 23(1), 268. PMCID: PMC9793579

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.

URL

http://dx.doi.org/10.1186/s13059-022-02837-1

Reference Type

Journal Article

Year Published

2022

Journal Title

Genome Biology

Author(s)

Kanoni, Stavroula
Graham, Sarah E.
Wang, Yuxuan
Surakka, Ida
Ramdas, Shweta
Zhu, Xiang
Clarke, Shoa L.
Bhatti, Konain Fatima
Vedantam, Sailaja
Winkler, Thomas W.
Locke, Adam E.
Marouli, Eirini
Zajac, Greg J. M.
Wu, Kuan-Han H.
Ntalla, Ioanna
Hui, Qin
Klarin, Derek
Hilliard, Austin T.
Wang, Zeyuan
Xue, Chao
Thorleifsson, Gudmar
Helgadottir, Anna
Gudbjartsson, Daniel F.
Holm, Hilma
Olafsson, Isleifur
Hwang, Mi Yeong
Han, Sohee
Akiyama, Masato
Sakaue, Saori
Terao, Chikashi
Kanai, Masahiro
Zhou, Wei
Brumpton, Ben M.
Rasheed, Humaira
Havulinna, Aki S.
Veturi, Yogasudha
Pacheco, Jennifer A.
Rosenthal, Elisabeth A.
Lingren, Todd
Feng, QiPing
Kullo, Iftikhar J.
Narita, Akira
Takayama, Jun
Martin, Hilary C.
Hunt, Karen A.
Trivedi, Bhavi
Haessler, Jeffrey
Giulianini, Franco
Bradford, Yuki
Miller, Jason E.
Campbell, Archie
Lin, Kuang
Millwood, Iona Y.
Rasheed, Asif
Hindy, George
Faul, Jessica D.
Zhao, Wei
Weir, David R.
Turman, Constance
Huang, Hongyan
Graff, Mariaelisa
Choudhury, Ananyo
Sengupta, Dhriti
Mahajan, Anubha
Brown, Michael R.
Zhang, Weihua
Yu, Ketian
Schmidt, Ellen M.
Pandit, Anita
Gustafsson, Stefan
Yin, Xianyong
Luan, Jian'an
Zhao, Jing-Hua
Matsuda, Fumihiko
Jang, Hye-Mi
Yoon, Kyungheon
Medina-Gomez, Carolina
Pitsillides, Achilleas
Hottenga, Jouke J.
Wood, Andrew R.
Ji, Yingji
Gao, Zishan
Haworth, Simon
Yousri, Noha A.
Mitchell, Ruth E.
Chai, Jin Fang
Aadahl, Mette
Bjerregaard, Anne A.
Yao, Jie
Manichaikul, Ani
Hwu, Chii-Min
Hung, Yi-Jen
Warren, Helen R.
Ramirez, Julia
Bork-Jensen, Jette
Kårhus, Line L.
Goel, Anuj
Sabater-Lleal, Maria
Noordam, Raymond
Mauro, Pala
Matteo, Floris
McDaid, Aaron F.
Marques-Vidal, Pedro
Wielscher, Matthias
Trompet, Stella
Sattar, Naveed
Møllehave, Line T.
Munz, Matthias
Zeng, Lingyao
Huang, Jianfeng
Yang, Bin
Poveda, Alaitz
Kurbasic, Azra
Lamina, Claudia
Forer, Lukas
Scholz, Markus
Galesloot, Tessel E.
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Mitchell, Jonathan S.
Fuchsberger, Christian
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Vazquez-Moreno, Miguel
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Wang, Zhe
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Huang, Wei
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Wareham, Nicholas J.
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Kuusisto, Johanna
Laakso, Markku
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de Vries, Paul S.
Morrison, Alanna C.
Hazelhurst, Scott
Ramsay, Michèle
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Whitfield, John B.
Abbas, Shahid
Saleheen, Danish
Walters, Robin G.
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Deloukas, Panos
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Peloso, Gina M.

Article Type

Regular

PMCID

PMC9793579

Race/Ethnicity

African Ancestry
South Asian Ancestry
Hispanic Ancestry
European Ancestry

ORCiD

Gordon-Larsen - 0000-0001-5322-4188
Adair - 0000-0002-3670-8073