SUMMARY In this project we will extend our genetic studies of adiposity and related cardiometabolic phenotypes that we began with a genome-wide association study of common variants in a discovery sample of 3,072 Samoans with follow-up validation in 2,512 additional Samoans. As part of the Trans-Omics for Precision Medicine Whole Genome Sequencing Project, 1,295 of the discovery sample Samoans are being sequenced, creating an opportunity to create an unprecedented genomic data set for over 5,000 well-phenotyped Samoans which we will use to explore the genetic architecture of adiposity and cardiometabolic traits. In our first aim we will create a set of Samoan-specific haplotypes from the whole genome sequencing data and will impute genotypes in the remainder of the discovery sample. We will then conduct association studies of our phenotypes and use the results to create custom content to be added to an Illumina HumanCore-24 BeadChip genotyping array. The genotyping array will be used in our second aim to take advantage of the replication sample, first by genotyping with the customized array, followed by imputation and then association testing in concert with the discovery sample. We will then validate the most promising variants by direct genotyping, with additional genotyping in 409 Samoan children to explore the effects of those SNPs on our phenotypes in younger individuals. Finally through active participation in the Whole Genome Sequencing Project we will explore the effects of our variants in other populations, as well as propose and lead other related investigations. By discovering and characterizing Samoan-specific variants that were not on our original SNP chip, we aim to fine-map known loci and are likely to discover and fine-map new association signals. By enabling us to explore our unique well-phenotyped Samoan sample with its unique population history, we are likely to discover risk variants that are undetectable in other, more outbred populations. Our discoveries will help us understand the basic biological underpinnings of obesity and downstream health outcomes as well as identify potential targets for pharmacological interventions.

NARRATIVE This project explores the role of genetics in obesity and related traits by studying Samoans, a Polynesian population with a greater prevalence of obesity than in many other populations worldwide. This study uses the latest technology and methodologies, including whole genome sequencing of a portion of our sample, to determine genetic factors that affect obesity. Our discoveries will help us to understand the basic biology of obesity and downstream health outcomes as well as identify potential targets for drug development.