Minority-centric meta-analyses of blood lipid levels identify novel loci in the Population Architecture using Genomics and Epidemiology (PAGE) study

• Authors: Yao Hu, Fred Hutchinson Cancer Research Center; Mariaelisa Graff, University of North Carolina at Chapel Hill; Jeffrey Haessler, Fred Hutchinson Cancer Research Center; Steven Buyske, Rutgers University–New Brunswick; Stephanie Bien, Fred Hutchinson Cancer Research Center; Ran Tao, Vanderbilt University Medical Center; Heather M. Highland, University of North Carolina at Chapel Hill; Katherine K. Nishimura, Fred Hutchinson Cancer Research Center; Adolfo Correa, Emory University; Peter Wilson, Emory University
• Journal Title: PLoS Genetics
• Volume: Volume 16, Number 3
• Publisher: PLoS | 2020-03-01, Pages e1008684-e1008684
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1371/journal.pgen.1008684
• Subjects: Biology, Genetics; Health Sciences, Nutrition
• Keywords: Databases, Genetic; Female; Genome-Wide Association Study; Genotype; Humans; Lipids; Male; Metagenomics; Minority Groups; Multifactorial Inheritance; Phenotype; Polymorphism, Single Nucleotide; Racial Groups; United States

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.