A stop-gain variant in BTNL9 is associated with atherogenic lipid profiles

Current understanding of lipid genetics has come mainly from studies in European-ancestry populations; limited effort has focused on Polynesian populations, whose unique population history and high prevalence of dyslipidemia may provide insight into the biological foundations of variation in lipid levels. Here we performed an association study to fine map a suggestive association on 5q35 with high-density lipoprotein cholesterol (HDL-C) seen in Micronesian and Polynesian populations. Fine-mapping analyses in a cohort of 2,851 Samoan adults highlighted an association between a stop-gain variant (rs200884524; c.652C>T, p.R218*; posterior probability = 0.9987) in BTNL9 and both lower HDL-C and greater triglycerides (TG). Meta-analysis across this and several other cohorts of Polynesian ancestry from Samoa, American Samoa, and Aotearoa New Zealand confirmed the presence of this association ({beta}HDL-C = -1.60 mg/dL, pHDL-C = 7.63 x 10-10; {beta}TG = 12.00 mg/dL, pTG = 3.82 x 10-7). While this variant appears to be Polynesian-specific, there is also evidence of association from other multi-ancestry analyses in this region. This work provides evidence of a previously unexplored contributor to the genetic architecture of lipid levels and underscores the importance of genetic analyses in understudied populations.