Abstract

Lipid levels are important markers for the development of cardio-metabolic diseases. Although hundreds of associated loci have been identified through genetic association studies, the contribution of genetic factors to variation in lipids is not fully understood, particularly in U.S. minority groups. We performed genome-wide association analyses for four lipid traits in over 45,000 ancestrally diverse participants from the Population Architecture using Genomics and Epidemiology (PAGE) Study, followed by a meta-analysis with several European ancestry studies. We identified nine novel lipid loci, five of which showed evidence of replication in independent studies. Furthermore, we discovered one novel gene in a PrediXcan analysis, minority-specific independent signals at eight previously reported loci, and potential functional variants at two known loci through fine-mapping. Systematic examination of known lipid loci revealed smaller effect estimates in African American and Hispanic ancestry populations than those in Europeans, and better performance of polygenic risk scores based on minority-specific effect estimates. Our findings provide new insight into the genetic architecture of lipid traits and highlight the importance of conducting genetic studies in diverse populations in the era of precision medicine.

Date

March 30, 2020

Authors

Yao Hu, Mariaelisa Graff, Jeffrey Haessler, Steven Buyske, Stephanie A Bien, Ran Tao, Heather M Highland, Katherine K Nishimura, Niha Zubair, Yingchang Lu, Marie Verbanck, Austin T Hilliard, Derek Klarin, Scott M Damrauer, Yuk-Lam Ho, VA Million Veteran Program, Peter WF Wilson, Kyong-Mi Chang, Philip S Tsao, Kelly Cho, Christopher J O’Donnell, Themistocles L Assimes, Lauren E Petty, Jennifer E Below, Ozan Dikilitas, Daniel J Schaid, Matthew L Kosel, Iftikhar J Kullo, Laura J Rasmussen-Torvik, Gail P Jarvik, Qiping Feng, Wei-Qi Wei, Eric B Larson, Frank D Mentch, Berta Almoguera, Patrick M Sleiman, Laura M Raffield, Adolfo Correa, Lisa W Martin, Martha Daviglus, Tara C Matise, Jose Luis Ambite, Christopher S Carlson, Ron Do, Ruth JF Loos, Lynne R Wilkens, Loic Le Marchand, Chris Haiman, Daniel O Stram, Lucia A Hindorff, Kari E North, Charles Kooperberg, Iona Cheng, Ulrike Peters

Journal

PLoS genetics

Volume

16

Issue

3

Pages

e1008684

Publisher

Public Library of Science