Genome-wide meta-analysis identifies 25 trait-loci associations for cardiometabolic phenotypes in Native Hawaiian and Samoan populationsNative Hawaiian and Samoan DNA study finds new genetic links to diabetes risk

Although genome-wide association studies (GWAS) now routinely reveal genetic associations and biological insights in millions of individuals, underrepresentation of global populations, such as those from Polynesia, continue to persist. These exclusions, often driven by logistical challenges and lack of data, prevent systematic identification of population-enriched associations, such as the association of the missense variant at the CREBRF locus to BMI and type 2 diabetes discovered commonly occurring in Polynesian populations due to its rarity in global populations. Armed with the recently updated TOPMed imputation panel that could benefit studies in diverse populations that previously had poorer imputation performance, we performed the first GWAS of Native Hawaiians and Samoans, the largest to date of Polynesian-ancestry populations (combined N up to 8,461) to identify population-enriched associations for 13 adiposity and cardiometabolic traits available across both cohorts: BMI, fasting glucose, fasting insulin, HDL, height, hip circumference, HOMA-IR, LDL, T2D, total cholesterol, triglycerides, waist circumference, and waist-hip ratio. We found 25 trait-loci associations that met genome-wide significance: 20 previously reported or known associations and 5 putatively new associations via meta-analysis. In particular, with improved statistical power, we were able to confirm the previously suggestive association between the missense CREBRF variant with fasting glucose levels. The remaining 4 potentially novel loci-trait associations for BMI, LDL, and waist-hip ratio, however, were not replicated in All-of-Us. The lack of Polynesian-enriched findings outside of the CREBRF locus informs the bounds of the effect sizes or frequencies of any enriched variants and suggests that further expansion of cohort sizes from this region of the world and improved imputation references specific to these populations are needed to identify more population-enriched associations.