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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Autores: 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., Hiliard, A.T., Wang, Z., Xue, Ch., Thorleidson, G., Helgadottir, A., Gudbjartsson, D. F., Holm, H., Olafsson, I., Hwang, M. Y.: Han, S., Akiyama, M., Sakue, S., Terao, S., Kanai, M., Zhou, W., Brumpton, B. M., Rasheed, H., Havulinna, A. S., Veturi, Y., Ramírez, J.
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Institución:Universidad de Zaragoza
Repositorio:Zaguán. Repositorio Digital de la Universidad de Zaragoza
OAI Identifier:oai:zaguan.unizar.es:123987
Acceso en línea:http://zaguan.unizar.es/record/123987
Access Level:acceso abierto
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spelling Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysisKanoni, 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.Hiliard, A.T.Wang, Z.Xue, Ch.Thorleidson, G.Helgadottir, A.Gudbjartsson, D. F.Holm, H.Olafsson, I.Hwang, M. Y.: Han, S.Akiyama, M.Sakue, S.Terao, S.Kanai, M.Zhou, W.Brumpton, B. M.Rasheed, H.Havulinna, A. S.Veturi, Y.Ramírez, J.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.2022info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://zaguan.unizar.es/record/123987reponame:Zaguán. Repositorio Digital de la Universidad de Zaragozainstname:Universidad de ZaragozaInglésinfo:eu-repo/grantAgreement/EC/FP7/608765info:eu-repo/grantAgreement/EC/H2020/786833This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No H2020 786833-GENESISinfo:eu-repo/grantAgreement/ES/ISCIII/PI17-00142info:eu-repo/semantics/openAccessoai:zaguan.unizar.es:1239872026-05-29T13:59:51Z
dc.title.none.fl_str_mv Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis
title Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis
spellingShingle Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis
Kanoni, S.
title_short Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis
title_full Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis
title_fullStr Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis
title_full_unstemmed Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis
title_sort Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis
dc.creator.none.fl_str_mv 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.
Hiliard, A.T.
Wang, Z.
Xue, Ch.
Thorleidson, G.
Helgadottir, A.
Gudbjartsson, D. F.
Holm, H.
Olafsson, I.
Hwang, M. Y.: Han, S.
Akiyama, M.
Sakue, S.
Terao, S.
Kanai, M.
Zhou, W.
Brumpton, B. M.
Rasheed, H.
Havulinna, A. S.
Veturi, Y.
Ramírez, J.
author Kanoni, S.
author_facet 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.
Hiliard, A.T.
Wang, Z.
Xue, Ch.
Thorleidson, G.
Helgadottir, A.
Gudbjartsson, D. F.
Holm, H.
Olafsson, I.
Hwang, M. Y.: Han, S.
Akiyama, M.
Sakue, S.
Terao, S.
Kanai, M.
Zhou, W.
Brumpton, B. M.
Rasheed, H.
Havulinna, A. S.
Veturi, Y.
Ramírez, J.
author_role author
author2 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.
Hiliard, A.T.
Wang, Z.
Xue, Ch.
Thorleidson, G.
Helgadottir, A.
Gudbjartsson, D. F.
Holm, H.
Olafsson, I.
Hwang, M. Y.: Han, S.
Akiyama, M.
Sakue, S.
Terao, S.
Kanai, M.
Zhou, W.
Brumpton, B. M.
Rasheed, H.
Havulinna, A. S.
Veturi, Y.
Ramírez, J.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
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description 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.
publishDate 2022
dc.date.none.fl_str_mv 2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://zaguan.unizar.es/record/123987
url http://zaguan.unizar.es/record/123987
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv info:eu-repo/grantAgreement/EC/FP7/608765
info:eu-repo/grantAgreement/EC/H2020/786833
This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No H2020 786833-GENESIS
info:eu-repo/grantAgreement/ES/ISCIII/PI17-00142
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv
publisher.none.fl_str_mv
dc.source.none.fl_str_mv reponame:Zaguán. Repositorio Digital de la Universidad de Zaragoza
instname:Universidad de Zaragoza
instname_str Universidad de Zaragoza
reponame_str Zaguán. Repositorio Digital de la Universidad de Zaragoza
collection Zaguán. Repositorio Digital de la Universidad de Zaragoza
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,301603

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