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

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.Author summary: Blood lipid levels are closely linked to cardio-metabolic diseases, and genetic factors play an important role in their metabolism and regulation. Although over 400 loci have been identified through genetic association studies, the genetic architecture of lipid levels is not fully characterized. The lack of representation of diverse populations in previous studies resulted in a large gap in understanding the genetic background of lipid traits between European and minority populations, including African Americans, Hispanics, Hawaiians, and Native Americans. In our current analyses which included ancestrally diverse populations, we identified nine novel loci, one novel gene, and minority-specific independent signals at eight known loci, and pinpointed potential functional variants at two known loci. We further observed smaller effect sizes of reported lipids-associated loci in African Americans and Hispanics than those in Europeans, and better performance of polygenic risk scores using minority-specific instead of European-derived effect sizes when estimating genetic predisposition in minority populations. Our findings showed the benefits of including multi-ethnic studies in identification and refinement of lipids-associated loci, which will help to reduce the existing disparities and to pave the road to precision medicine.