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AuthorKanoni, Stavroula
AuthorGraham, Sarah E.
AuthorWang, Yuxuan
AuthorSurakka, Ida
AuthorRamdas, Shweta
AuthorZhu, Xiang
AuthorClarke, Shoa L.
AuthorBhatti, Konain Fatima
AuthorVedantam, Sailaja
AuthorWinkler, Thomas W.
AuthorLocke, Adam E.
AuthorMarouli, Eirini
AuthorZajac, Greg J.M.
AuthorWu, Kuan Han H.
AuthorNtalla, Ioanna
AuthorHui, Qin
AuthorKlarin, Derek
AuthorHilliard, Austin T.
AuthorWang, Zeyuan
AuthorXue, Chao
AuthorThorleifsson, Gudmar
AuthorHelgadottir, Anna
AuthorGudbjartsson, Daniel F.
AuthorHolm, Hilma
AuthorOlafsson, Isleifur
AuthorHwang, Mi Yeong
AuthorHan, Sohee
AuthorAkiyama, Masato
AuthorSakaue, Saori
AuthorTerao, Chikashi
AuthorKanai, Masahiro
AuthorZhou, Wei
AuthorBrumpton, Ben M.
AuthorRasheed, Humaira
AuthorHavulinna, Aki S.
AuthorVeturi, Yogasudha
AuthorPacheco, Jennifer Allen
AuthorRosenthal, Elisabeth A.
AuthorLingren, Todd
AuthorFeng, Qi Ping
AuthorKullo, Iftikhar J.
AuthorNarita, Akira
AuthorTakayama, Jun
AuthorMartin, Hilary C.
AuthorHunt, Karen A.
AuthorTrivedi, Bhavi
AuthorHaessler, Jeffrey
AuthorGiulianini, Franco
AuthorBradford, Yuki
AuthorMiller, Jason E.
AuthorCampbell, Archie
AuthorLin, Kuang
AuthorMillwood, Iona Y.
AuthorRasheed, Asif
AuthorHindy, George
AuthorFaul, Jessica D.
AuthorZhao, Wei
AuthorWeir, David R.
AuthorTurman, Constance
AuthorHuang, Hongyan
AuthorGraff, Mariaelisa
AuthorChoudhury, Ananyo
AuthorSengupta, Dhriti
AuthorMahajan, Anubha
AuthorBrown, Michael R.
AuthorZhang, Weihua
AuthorYu, Ketian
AuthorSchmidt, Ellen M.
AuthorPandit, Anita
AuthorGustafsson, Stefan
AuthorYin, Xianyong
AuthorLuan, Jian’an
AuthorZhao, Jing Hua
AuthorMatsuda, Fumihiko
AuthorJang, Hye Mi
AuthorYoon, Kyungheon
AuthorMedina-Gomez, Carolina
AuthorPitsillides, Achilleas
AuthorHottenga, Jouke Jan
AuthorWood, Andrew R.
AuthorJi, Yingji
AuthorGao, Zishan
AuthorHaworth, Simon
AuthorYousri, Noha A.
AuthorMitchell, Ruth E.
AuthorChai, Jin Fang
AuthorAadahl, Mette
AuthorBjerregaard, Anne A.
AuthorYao, Jie
AuthorManichaikul, Ani
AuthorHwu, Chii Min
AuthorHung, Yi Jen
AuthorWarren, Helen R.
AuthorRamirez, Julia
AuthorBork-Jensen, Jette
AuthorKårhus, Line L.
AuthorGoel, Anuj
AuthorSabater-Lleal, Maria
AuthorNoordam, Raymond
AuthorMauro, Pala
Available date2023-09-07T05:29:59Z
Publication Date2022-12-01
Publication NameGenome Biology
Identifierhttp://dx.doi.org/10.1186/s13059-022-02837-1
URIhttps://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85144774123&origin=inward
URIhttp://hdl.handle.net/10576/47316
AbstractBackground: 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.
SponsorGMP, PN, and CW are supported by NHLBI R01HL127564. GMP and PN are supported by R01HL142711. AG acknowledge support from the Wellcome Trust (201543/B/16/Z), European Union Seventh Framework Programme FP7/2007–2013 under grant agreement no. HEALTH-F2-2013–601456 (CVGenes@Target) & the TriPartite Immunometabolism Consortium [TrIC]-Novo Nordisk Foundation’s Grant number NNF15CC0018486. JMM is supported by American Diabetes Association Innovative and Clinical Translational Award 1–19-ICTS-068. SR was supported by the Academy of Finland Center of Excellence in Complex Disease Genetics (Grant No 312062), the Finnish Foundation for Cardiovascular Research, the Sigrid Juselius Foundation, and University of Helsinki HiLIFE Fellow and Grand Challenge grants. EW was supported by the Finnish innovation fund Sitra (EW) and Finska Läkaresällskapet. CNS was supported by American Heart Association Postdoctoral Fellowships 15POST24470131 and 17POST33650016. Charles N Rotimi is supported by Z01HG200362. Zhe Wang, Michael H Preuss, and Ruth JF Loos are supported by R01HL142302. NJT is a Wellcome Trust Investigator (202802/Z/16/Z), is the PI of the Avon Longitudinal Study of Parents and Children (MRC & WT 217065/Z/19/Z), is supported by the University of Bristol NIHR Biomedical Research Centre (BRC-1215–2001) and the MRC Integrative Epidemiology Unit (MC_UU_00011), and works within the CRUK Integrative Cancer Epidemiology Programme (C18281/A19169). Ruth E Mitchell is a member of the MRC Integrative Epidemiology Unit at the University of Bristol funded by the MRC (MC_UU_00011/1). Simon Haworth is supported by the UK National Institute for Health Research Academic Clinical Fellowship. Paul S. de Vries was supported by American Heart Association grant number 18CDA34110116. Julia Ramierz acknowledges support by the People Programme of the European Union’s Seventh Framework Programme grant n° 608765 and Marie Sklodowska-Curie grant n° 786833. Maria Sabater-Lleal is supported by a Miguel Servet contract from the ISCIII Spanish Health Institute (CP17/00142) and co-financed by the European Social Fund. Jian Yang is funded by the Westlake Education Foundation. Olga Giannakopoulou has received funding from the British Heart Foundation (BHF) (FS/14/66/3129). CHARGE Consortium cohorts were supported by R01HL105756. Study-specific acknowledgements are available in the Additional file 32: Supplementary Note. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services.
Languageen
PublisherBioMed Central
SubjectCholesterol
Genetics
Genome-wide association study
GWAS
Lipids
TitleImplicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis
TypeArticle
Issue Number1
Volume Number23
ESSN1474-760X


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