Strategies for Enriching Variant Coverage in Candidate Disease Loci on a Multiethnic Genotyping Array

Abstract

Investigating genetic architecture of complex traits in ancestrally diverse populations is imperative to understand the etiology of disease. However, the current paucity of genetic research in people of African and Latin American ancestry, Hispanic and indigenous peoples in the United States is likely to exacerbate existing health disparities for many common diseases. The Population Architecture using Genomics and Epidemiology, Phase II (PAGE II), Study was initiated in 2013 by the National Human Genome Research Institute to expand our understanding of complex trait loci in ethnically diverse and well characterized study populations. To meet this goal, the Multi-Ethnic Genotyping Array (MEGA) was designed to substantially improve fine-mapping and functional discovery by increasing variant coverage across multiple ethnicities at known loci for metabolic, cardiovascular, renal, inflammatory, anthropometric, and a variety of lifestyle traits. Studying the frequency distribution of clinically relevant mutations, putative risk alleles, and known functional variants across multiple populations will provide important insight into the genetic architecture of complex diseases and facilitate the discovery of novel, sometimes population-specific, disease associations. DNA samples from 51,650 self-identified African ancestry (17,328), Hispanic/Latino (22,379), Asian/Pacific Islander (8,640), and American Indian (653) and an additional 2,650 participants of either South Asian or European ancestry, and other reference panels have been genotyped on MEGA by PAGE II. MEGA was designed as a new resource for studying ancestrally diverse populations. Here, we describe the methodology for selecting trait-specific content for use in multi-ethnic populations and how enriching MEGA for this content may contribute to deeper biological understanding of the genetic etiology of complex disease.

Fig 1. Enrichment of rarer variation in custom content.

Comparison of minor allele frequency distribution between the MEGA GWAS backbone and the custom content stratified by race. Allele frequencies were calculated in PAGE II study populations.

Fig 2. Improved imputation accuracy found with custom content sites in regions of interest.

Solid lines denote the imputation accuracy of MEGA including the custom content, while dashed lines indicate the performance of MEGA without the custom content. Admixed populations are on the left, with continental populations found on the right.

Fig 3. The functional hypothesis tested (‘Hypothesized Function”) by year for 2,610 variants reported in a functional allelic assay found through literature review.