夏威夷原住民与萨摩亚人群 8,000 余人心脏代谢表型遗传关联的荟萃分析
Meta-analysis of over 8,000 individuals from Hawai‘i and Samoa for genetic associations to cardiometabolic phenotypes
一项针对夏威夷原住民与萨摩亚人群的 GWAS 荟萃分析在最多 8,461 名 Polynesian 血统个体中检出 25 个达到全基因组显著性的性状-位点关联，其中 20 个为已知关联、5 个为潜在新关联。研究基于近期更新的 TOPMed 填充面板，覆盖 BMI、空腹血糖、空腹胰岛素、HDL、LDL、T2D、腰围等 13 项肥胖与心脏代谢性状。借助提升的统计效力，研究确认了 CREBRF 错义变异与空腹血糖之间此前仅为提示性的关联；其余 4 个涉及 BMI、LDL 和腰臀比的潜在新位点未能在 All-of-Us 中重复。
来源：PLOS Genetics · journals.plos.org
by Bryan L. Dinh, Xinran Wang, Xin Sheng, Peggy Wan, Amit Kumar Srivastava, Take Naseri, Satupa‘itea Viali, Lynne Wilkens, Loïc Le Marchand, Christopher Haiman, Daniel E. Weeks, Charleston W. K. Chiang, Jenna C. Carlson, The Samoan Obesity, Lifestyle and Genetic Adaptations (OLaGA) Study Group
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.