Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis
Graham, Sarah E. (University of Michigan)
Wang, Yuxuan (Boston University School of Public Health)
Surakka, Ida (University of Michigan)
Ramdas, Shweta (University of Pennsylvania)
Zhu, Xiang (Stanford University)
Clarke, Shoa L. (Stanford University School of Medicine)
Bhatti, Konain Fatima (William Harvey Research Institute)
Vedantam, Sailaja (Broad Institute of MIT and Harvard)
Winkler, Thomas W. (University of Regensburg)
Locke, Adam E. (Washington University)
Marouli, Eirini (William Harvey Research Institute)
Zajac, Greg J. M. (University of Michigan)
Wu, Kuan-Han H. (University of Michigan)
Ntalla, Ioanna (William Harvey Research Institute)
Hui, Qin (Atlanta VA Health Care System)
Klarin, Derek (Stanford University School of Medicine)
Hilliard, Austin T. (VA Palo Alto Health Care Systems)
Wang, Zeyuan (Atlanta VA Health Care System)
Xue, Chao (University of Michigan)
Thorleifsson, Gudmar (deCODE Genetics/Amgen)
Helgadottir, Anna (deCODE Genetics/Amgen)
Gudbjartsson, Daniel F. (University of Iceland)
Holm, Hilma (deCODE Genetics/Amgen)
Olafsson, Isleifur (Landspitali - National University Hospital of Iceland)
Hwang, Mi Yeong (National Institute of Health)
Han, Sohee (National Institute of Health)
Akiyama, Masato (Kyushu University)
Sakaue, Saori (The University of Tokyo)
Terao, Chikashi (RIKEN Center for Integrative Medical Sciences)
Kanai, Masahiro (Harvard Medical School)
Zhou, Wei (Massachusetts General Hospital (Boston))
Brumpton, Ben M. (Trondheim University Hospital)
Rasheed, Humaira (University of Oslo)
Havulinna, Aki S. (Finnish Institute for Health and Welfare)
Veturi, Yogasudha (Institute for Biomedical Informatics)
Pacheco, Jennifer Allen (Northwestern University)
Rosenthal, Elisabeth A. (University of Washington)
Lingren, Todd (Cincinnati Children's Hospital Medical Center)
Feng, QiPing (Vanderbilt University Medical Center)
Kullo, Iftikhar J. (Mayo Clinic)
Narita, Akira (Tohoku Medical Megabank Organization)
Takayama, Jun (Tohoku Medical Megabank Organization)
Martin, Hilary C. (Wellcome Trust Sanger Institute (Regne Unit))
Hunt, Karen A. (Queen Mary University of London)
Ramirez, Julia (Universidad de Zaragoza)
Sabater-Lleal, Maria (Institut d'Investigació Biomèdica Sant Pau)
Cañadas-Garre, Marisa (Universidad de Granada)
Universitat Autònoma de Barcelona

Data:	2022
Resum:	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.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca
Matèria:	Cholesterol ; GWAS ; Genetics ; Genome-wide association study ; Lipids
Publicat a:	Genome biology, Vol. 23 (december 2022) , ISSN 1474-760X

42 p, 2.1 MB

El registre apareix a les col·leccions:
Documents de recerca > Documents dels grups de recerca de la UAB > Centres i grups de recerca (producció científica) > Ciències de la salut i biociències > Institut de Recerca Sant Pau
Articles > Articles de recerca
Articles > Articles publicats