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Exome Analysis of Southwestern American Indians Highlights Metabolic Disease-Linked Variants

NEW YORK – A new exome sequencing study has homed in on variants that are more common among Southwestern American Indian individuals and may contribute to metabolic disease. 


Researchers from Regeneron Pharmaceuticals sequenced and analyzed the exomes of more than 6,700 Southwestern American Indian (SWAI) individuals to search for predicted loss-of-function (pLOF) and nonsynonymous variants that might influence type 2 diabetes, body mass index, and plasma lipid levels. Obesity and type 2 diabetes are prevalent among SWAI populations.

In the study, the researchers examined gene-burden associations for candidate genes first identified among European populations and uncovered four variants exclusive to or much more common among SWAI individuals that affect LDL cholesterol levels. The researchers suspected population bottlenecks and isolation experienced by SWAI populations may have shaped the variants present.

"Our study illustrates that exome sequencing applied to founder populations, such as this SWAI population, can uncover additional genetic variants that are associated with clinical and quantitative traits and expand our understanding of the genetic contribution to these traits," Regeneron's Cristopher Van Hout and his colleagues wrote in their paper, which appeared Tuesday in the American Journal of Human Genetics.

The researchers sequenced the exomes of 6,716 SWAI individuals who were enrolled in a longitudinal study of metabolic disease. They identified more than 1.2 million variants, most of which were indels. Following annotation, 16,880 variants were predicted to be loss-of-function variants and 258,306 were non-synonymous variants.

As compared to a cohort of about 29,000 individuals of European ancestry from the DiscovEHR study and a cohort of 13,947 individuals of East Asian ancestry, SWAI individuals harbored fewer ultra-rare pLOFs and non-synonymous variants, but were enriched for moderately rare pLOFs and non-synonymous variants.

Among a set of 1,456 pLOF variants, 38.4 percent were only found among SWAI individuals and 48.3 percent were more than 10 times more enriched among SWAI individuals, as compared to the European and East Asian ancestry cohorts. Likewise, among a set of 32,577 non-synonymous variants, 23.7 percent were only found among SWAI individuals and 36.1 percent were much more common among SWAI populations than among European or East Asian ancestry populations.

In line with the founder effect, the number of genes with heterozygous pLOF carriers was lower among SWAI exomes than European and East Asian exomes and the number of genes with homozygous pLOF carriers was higher, the researchers noted.

The researchers then tested the association of genes previously linked to BMI, type 2 diabetes, and plasma lipid levels among Europeans with those traits among SWAI individuals. Through this gene-burden analysis, they identified variants within 11 genes that were associated with metabolic traits, including, for instance, two variants in MC4R that were associated with BMI and type 2 diabetes, respectively.

In particular, the researchers identified four pLOF or non-synonymous variants that are either found only among SWAI individuals or that are much more common among SWAI individuals in APOB, APOE, PCSK9, and TM6SF2 that influence LDL cholesterol levels.

"Many of these variants were associated with traits with strong effects, warranting further investigation on the clinical implications of these variants in the SWAI population," the researchers wrote.

They further added that additional studies looking into the genetic associations they uncovered could help pinpoint the genetic drivers of metabolic disorders that occur at high prevalence among SWAI individuals.