1 2 Native Hawaiian individuals represent one of the most underserved and understudied populations in US 3 healthcare and medical research. However, this population is one of the fastest growing in the US and faces 4 alarming long-standing health disparities, with approximately 30% higher risk of cardiovascular disease, 100% 5 higher risk of diabetes and gout, and 400% higher risk of stroke compared to White individuals. Obesity and high 6 body mass index (BMI) are known to increase risk for these conditions, and notably, an estimated 41% of Native 7 Hawaiians are obese compared to 21% of White individuals. Native Hawaiians are characterized predominantly 8 by Polynesian, European, and East Asian ancestries, and higher Polynesian ancestries in Native Hawaiians 9 have been linked to higher risk of hypertension, type 2 diabetes, and heart failure, as well as higher BMI and 10 subcutaneous and visceral fat, even after accounting for socioeconomic and smoking status. Despite Native 11 Hawaiians sharing East Asian ancestry with Japanese individuals, the burden of some of these conditions are 12 lower in Japanese Americans. As many of these health disparities are cardiometabolic in nature, the objective 13 of this research is to evaluate circulating metabolomic profiles in Native Hawaiians and Japanese Americans, 14 given their complementary risk profiles, to illuminate the underlying mechanisms contributing to health disparities 15 in these populations. This will be accomplished by establishing a large-scale high throughput metabolomic 16 resource in 2,000 Native Hawaiian and 1,000 Japanese American participants from the Multiethnic Cohort. In 17 Aim 1, we will conduct genome-wide association studies (GWAS) and evaluate genetic ancestry to investigate 18 the contribution of genetics to metabolite variation. In Aim 2, we will conduct metabolome-wide association 19 studies to identify metabolites associated with cardiometabolic and other health-related traits presenting health 20 disparities in Native Hawaiians. In Aim 3, we will investigate potentially causal metabolic mechanisms impacting 21 health-related traits, leveraging the full sample of 5,660 Native Hawaiian and 24,485 Japanese MEC participants 22 with GWAS data, along with GWAS summary statistics from >14,000 Pacific Islander and >214,000 Japanese 23 participants across multiple studies. Findings from this investigation are expected to substantially improve our 24 understanding of the underlying mechanisms contributing to cardiometabolic and other health-related conditions 25 presenting health disparities in Native Hawaiian and Japanese American populations, which will ultimately 26 contribute to novel means to reducing these disparities. This study will also importantly bolster innovative 27 epidemiologic research to address major knowledge gaps and health disparities in populations that are 28 understudied and when included in research, often studied in aggregate, masking the ability...