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 lowdensity 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.

Developing CIRdb as a catalog of natural genetic variation in the Canary Islanders

“…Considering the next steps, CIRdb plans to run WES in all the prioritized samples to efficiently examine the fraction of the genome that includes ~ 85% of all described disease-causing variants 93 . Using WES at population scale, it has been possible to detect an enrichment of risk variants for Panic Disorder in the Faroese population 94 , specific genetic loci associated with longevity in Bulgarian centenarians 95 , or study the metabolic impact of candidate effector genes in Southwestern American Indian population 96 , to name a few. WGS theoretically targets the entire DNA sequence of donors, offering the optimal solution for unbiased genetic studies although at higher costs per sample.…”

Estimating the effective sample size in association studies of quantitative traits

“…For example, we estimated that the ESS multiplier in 68,910 related individuals of British ancestry in the UK Biobank is at most 0.94x. However, the proposed ESS multiplier is likely to have a larger impact in the future for large-scale studies of founder populations ( Kim et al 2020 ) and healthcare studies ( Staples et al 2018 ). Moreover, this work is of immediate interest for all post-GWAS analyses using summary statistics from related individuals, providing guidelines and tools for accurately estimating the ESS.…”

De novogenome assemblies from two Indigenous Americans from Arizona identify new polymorphisms in non-reference sequences

“…Indigenous American people are genetically distinct compared to other populations in the United States, with a significant variation within the group itself [16]. Principal component analysis from a previous study including three ancestral populations from the 1000 Genomes database (European, East Asian, and African ancestries) and our Indigenous American population from Arizona (IAZ) showed a distinct cluster for IAZ on the principal component space [17]. Therefore, exploratory genomics studies using novel methods are warrented in indigenous populations to uncover previously unrecognized genetic variations and capture novel disease associations.…”