Characterization of Exome Variants and Their Metabolic Impact in 6,716 American Indians from the Southwest US

Abstract

Applying exome sequencing to populations with unique genetic architecture has the potential to reveal novel genes and variants associated with traits and diseases. We sequenced and analyzed the exomes of 6,716 individuals from a Southwestern American Indian (SWAI) population with well-characterized metabolic traits. We found that the SWAI population has distinct allelic architecture compared to populations of European and East Asian ancestry, and there were many predicted loss-of-function (pLOF) and nonsynonymous variants that were highly enriched or private in the SWAI population. We used pLOF and nonsynonymous variants in the SWAI population to evaluate gene-burden associations of candidate genes from European genome-wide association studies (GWASs) for type 2 diabetes, body mass index, and four major plasma lipids. We found 19 significant gene-burden associations for 11 genes, providing additional evidence for prioritizing candidate effector genes of GWAS signals. Interestingly, these associations were mainly driven by pLOF and nonsynonymous variants that are unique or highly enriched in the SWAI population. Particularly, we found four pLOF or nonsynonymous variants in APOB, APOE, PCSK9, and TM6SF2 that are private or enriched in the SWAI population and associated with low-density lipoprotein (LDL) cholesterol levels. Their large estimated effects on LDL cholesterol levels suggest strong impacts on protein function and potential clinical implications of these variants in cardiovascular health. In summary, our study illustrates the utility and potential of exome sequencing in genetically unique populations, such as the SWAI population, to prioritize candidate effector genes within GWAS loci and to find additional variants in known disease genes with potential clinical impact.

Keywords: exome sequencing; gene-burden association; isolated founder population; metabolic traits; rare variant.

Figure 1

Summary Statistics and Annotation of Variants Captured by Exome Sequencing of 6,716 SWAI Individuals (A) Site frequency distribution of 1,208,812 autosomal variants according to the predicted functional effect class. (B) The number of variants that are previously reported in gnomAD or dbSNP databases or unreported as a function of alternate allele count. (C) The proportion of variants that are previously reported in gnomAD or dbSNP databases or unreported stratified by predicted functional effect. pLOF, predicted loss-of-function; NONSYN, nonsynonymous; SYN, synonymous.

Figure 2

Comparison of the Distribution and Frequency of pLOF and Nonsynonymous Variants among SWAI, European, and East Asian Exomes (A and B) Comparison of the distribution of pLOF (A) and nonsynonymous (B) variants at different MAC bins among SWAI, European, and East Asian exomes from the SWAI, DiscovEHR, and TAICHI studies, respectively. (C and D) The number and percentage of pLOF (C) and nonsynonymous (D) variants that are enriched in full American Indian exomes from the SWAI study compared to European exomes, East Asian exomes, or both European and East Asian exomes. The analysis is restricted to variants with alternate allele count ≥10 in full American Indians from the SWAI population.

Figure 3

Comparison of the Number of Genes with pLOF Carriers among SWAI, European, and East Asian Exomes (A) The number and percentage of genes among 19,467 annotated autosomal genes with at least X number of heterozygous and homozygous pLOF carriers in the SWAI study alone. (B) The comparison of the number of genes with at least X number of heterozygous (top) and homozygous (bottom) pLOF carriers at fixed sample sizes randomly extracted from the SWAI, European, and East Asian exomes. The analysis was restricted to the consistently covered regions across the three studies.