A blended genome and exome sequencing method captures genetic variation in an unbiased and cost-effective manner

Abstract

Genome-wide association studies (GWAS) have grown exponentially over the past 15 years, rapidly increasing in statistical power to enable the identification of hundreds of thousands of associations between genetic variants and human traits 1 . While these discoveries have been facilitated in part by precipitous drops in sequencing costs, microarrays have been the primary technology used for GWAS to date because of their lower costs. However, by design, they have biased ascertainment of genetic variants; sites that are included on many GWAS arrays, such as the widely used Illumina Global Screening Array (GSA) or Global Diver- sity Array, are most common in European ancestry populations. Previ- ous work has shown that low-coverage sequencing is a cost-effective alternative that can more accurately capture genetic variants across the allele frequency spectrum for variants present in imputation reference panels 2,3. Low-coverage sequencing is especially useful in populations underrepresented in genomics, even compared with GWAS arrays that have been designed to reflect variation within those populations, such as the H3Africa GWAS Array.