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

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 dru...

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Detalles Bibliográficos
Autores: Kanoni S., Graham S.E., Wang Y., Surakka I., Ramdas S., 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., 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., Matteo F., McDaid A.F., Marques-Vidal P., Wielscher M., Trompet S., Sattar N., Møllehave L.T., Munz M., Zeng L., Huang J., Yang B., Poveda A., Kurbasic A., Lamina C., Forer L., Scholz M., Galesloot T.E., Bradfield J.P., Ruotsalainen S.E., Daw E.W., Zmuda J.M., Mitchell J.S., Fuchsberger C., Christensen H., Brody J.A., Vazquez-Moreno M., Feitosa M.F., Wojczynski M.K., Wang Z., Preuss M.H., Mangino M., Christofidou P., Verweij N., Benjamins J.W., Engmann J., Tsao N.L., Verma A., Slieker R.C., Lo K.S., Zilhao N.R., Le P., Kleber M.E., Delgado G.E., Huo S., Ikeda D.D., Iha H., Demirkan A., Leonard H.L., Marten J., Frank M., Schmidt B., Smyth L.J., Cañadas-Garre M., Wang C., Nakatochi M., Wong A., Hutri-Kähönen N., Sim X., Xia R., Huerta-Chagoya A., Fernandez-Lopez J.C., Lyssenko V., Nongmaithem S.S., Bayyana S., Stringham H.M., Irvin M.R., Oldmeadow C., Kim H.-N., Ryu S., Timmers P.R.H.J., Arbeeva L., Dorajoo R., Lange L.A., Prasad G., Lorés-Motta L., Pauper M., Long J., Theusch E., Takeuchi F., Spracklen C.N., Loukola A., Bollepalli S., Warner S.C., Wang Y.X., Wei W.B., Nutile T., Ruggiero D., Sung Y.J., Chen S., Liu F., Yang J., Kentistou K.A., Banas B., Nardone G.G., Meidtner K., Bielak L.F., Smith J.A., Hebbar P., Farmaki A.-E., Hofer E., Lin M., Concas M.P., Vaccargiu S., van der Most P.J., Pitkänen N., Cade B.E., van der Laan S.W., Chitrala K.N., Weiss S., Bentley A.R., Doumatey A.P., Adeyemo A.A., Lee J.Y., Petersen E.R.B., Nielsen A.A., Choi H.S., Nethander M., Freitag-Wolf S., Southam L., Rayner N.W., Wang C.A., Lin S.-Y., Wang J.-S., Couture C., Lyytikäinen L.-P., Nikus K., Cuellar-Partida G., Vestergaard H., Hidalgo B., Giannakopoulou O., Cai Q., Obura M.O., van Setten J., Li X., Liang J., Tang H., Terzikhan N., Shin J.H., Jackson R.D., Reiner A.P., Martin L.W., Chen Z., Li L., Kawaguchi T., Thiery J., Bis J.C., Launer L.J., Nalls M.A., Raitakari O.T., Ichihara S., Wild S.H., Nelson C.P., Campbell H., Jäger S., Nabika T., Al-Mulla F., Niinikoski H., Braund P.S., Kolcic I., Kovacs P., Giardoglou T., Katsuya T., de Kleijn D., de Borst G.J., Kim E.K., Adams H.H.H., Ikram M.A., Zhu X., Asselbergs F.W., Kraaijeveld A.O., Beulens J.W.J., Shu X.-O., Rallidis L.S., Pedersen O., Hansen T., Mitchell P., Hewitt A.W., Kähönen M., Pérusse L., Bouchard C., Tönjes A., Chen Y.-D.I., Pennell C.E., Mori T.A., Lieb W., Franke A., Ohlsson C., Mellström D., Cho Y.S., Lee H., Yuan J.-M., Koh W.-P., Rhee S.Y., Woo J.-T., Heid I.M., Stark K.J., Zimmermann M.E., Völzke H., Homuth G., Evans M.K., Zonderman A.B., Polasek O., Pasterkamp G., Hoefer I.E., Redline S., Pahkala K., Oldehinkel A.J., Snieder H., Biino G., Schmidt R., Schmidt H., Bandinelli S., Dedoussis G., Thanaraj T.A., Kardia S.L.R., Peyser P.A., Kato N., Schulze M.B., Girotto G., Böger C.A., Jung B., Joshi P.K., Bennett D.A., De Jager P.L., Lu X., Mamakou V., Brown M., Caulfield M.J., Munroe P.B., Guo X., Ciullo M., Jonas J.B., Samani N.J., Kaprio J., Pajukanta P., Tusié-Luna T., Aguilar-Salinas C.A., Adair L.S., Bechayda S.A., de Silva H.J., Wickremasinghe A.R., Krauss R.M., Wu J.-Y., Zheng W., Hollander A.I., Bharadwaj D., Correa A., Wilson J.G., Lind L., Heng C.-K., Nelson A.E., Golightly Y.M., Wilson J.F., Penninx B., Kim H.-L., Attia J., Scott R.J., Rao D.C., Arnett D.K., Hunt S.C., Walker M., Koistinen H.A., Chandak G.R., Mercader J.M., Costanzo M.C., Jang D., Burtt N.P., Villalpando C.G., Orozco L., Fornage M., Tai E.S., van Dam R.M., Lehtimäki T., Chaturvedi N., Yokota M., Liu J., Reilly D.F., McKnight A.J., Kee F., Jöckel K.-H., McCarthy M.I., Palmer C.N.A., Vitart V., Hayward C., Simonsick E., van Duijn C.M., Jin Z.-B., Qu J., Hishigaki H., Lin X., März W., Gudnason V., Tardif J.-C., Lettre G., Hart L.M., Elders P.J.M., Damrauer S.M., Kumari M., Kivimaki M., van der Harst P., Spector T.D., Loos R.J.F., Province M.A., Parra E.J., Cruz M., Psaty B.M., Brandslund I., Pramstaller P.P., Rotimi C.N., Christensen K., Ripatti S., Widén E., Hakonarson H., Grant S.F.A., Kiemeney L.A.L.M., de Graaf J., Loeffler M., Kronenberg F., Gu D., Erdmann J., Schunkert H., Franks P.W., Linneberg A., Jukema J.W., Khera A.V., Männikkö M., Jarvelin M.-R., Kutalik Z., Francesco C., Mook-Kanamori D.O., van Dijk K.W., Watkins H., Strachan D.P., Grarup N., Sever P., Poulter N., Chuang L.-M., Rotter J.I., Dantoft T.M., Karpe F., Neville M.J., Timpson N.J., Cheng C.-Y., Wong T.-Y., Khor C.C., Li H., Sabanayagam C., Peters A., Gieger C., Hattersley A.T., Pedersen N.L., Magnusson P.K.E., Boomsma D.I., Willemsen A.H.M., Cupples L.A., van Meurs J.B.J., Ghanbari M., Gordon-Larsen P., Huang W., Kim Y.J., Tabara Y., Wareham N.J., Langenberg C., Zeggini E., Kuusisto J., Laakso M., Ingelsson E., Abecasis G., Chambers J.C., Kooner J.S., de Vries P.S., Morrison A.C., Hazelhurst S., Ramsay M., North K.E., Daviglus M., Kraft P., Martin N.G., Whitfield J.B., Abbas S., Saleheen D., Walters R.G., Holmes M.V., Black C., Smith B.H., Baras A., Justice A.E., Buring J.E., Ridker P.M., Chasman D.I., Kooperberg C., Tamiya G., Yamamoto M., van Heel D.A., Trembath R.C., Wei W.-Q., Jarvik G.P., Namjou B., Hayes M.G., Ritchie M.D., Jousilahti P., Salomaa V., Hveem K., Åsvold B.O., Kubo M., Kamatani Y., Okada Y., Murakami Y., Kim B.-J., Thorsteinsdottir U., Stefansson K., Zhang J., Chen Y.E., Ho Y.-L., Lynch J.A., Rader D.J., Tsao P.S., Chang K.-M., Cho K., O’Donnell C.J., Gaziano J.M., Wilson P.W.F., Frayling T.M., Hirschhorn J.N., Kathiresan S., Mohlke K.L., Sun Y.V., Morris A.P., Boehnke M., Brown C.D., Natarajan P., Deloukas P., Willer C.J., Assimes T.L., Peloso G.M.
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Institución:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
Repositorio:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
OAI Identifier:oai:iibsantpau.fundanetsuite.com:p15957
Acceso en línea:https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=15957
Access Level:acceso abierto
Palabra clave:lipid
genetic predisposition
genetics
genome-wide association study
human
meta analysis
phenotype
pleiotropy
sexual characteristics
single nucleotide polymorphism
Genetic Pleiotropy
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Lipids
Phenotype
Polymorphism, Single Nucleotide
Sex Characteristics
Descripción
Sumario: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. © 2022, The Author(s).

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