Assessing the Influence of Structural Variation on Type 2 Diabetes and Cardiometabolic Traits in Samoans

Lauren M. Spor, MPH - Final Dissertation Defense - HUGEN PhD Candidate Department of Human Genetics Doctoral Candidate, Lauren M. Spor, MPH, will defend the following dissertation on “Assessing the Influence of Structural Variation on Type 2 Diabetes and Cardiometabolic Traits in Samoans” COMMITTEE CHAIR: Ryan L. Minster, PhD, MSIS Committee Members: Samantha L. Manna, PhDDaniel E. Weeks, PhDLacey W. Heinsberg, PhD, RNJenna C. Carlson, PhD ABSTRACT: One in four Samoans has type 2 diabetes (T2D), nearly four times the global average, yet they are severely underrepresented in genetic research. To address this disparity, we conducted genome-wide analyses to assess whether genetic variants may be contributing to the high prevalence of T2D in Samoans. In particular, we studied structural variants (SVs), which are large genetic changes (≥ 50 bp) that are oftentimes excluded from genetic research because of their difficulty to call. However, due to their size, SVs may have a larger phenotypic effect than single nucleotide variants (SNVs), warranting their inclusion in genetic research. We analyzed 47,064 SVs across 1,276 Samoans, then combined the data with SNVs called via whole genome sequencing to construct a Samoan-specific reference panel. Using this panel, we reliably imputed around 16 million variants, including over 38,000 SVs, into 3,611 Samoans, dramatically increasing the number of unique sites available for association testing. Compared to imputation with a multi-ancestry reference panel lacking Polynesian representation, our reference panel imputed over 5.5 million more high-quality variants and over 8,000 more high-quality SVs in Samoans, underscoring how purposeful inclusion meaningfully impacts genetic research. Within the combined cohort of 4,887 Samoans, we performed genome-wide association testing for T2D and related metabolic traits: glucose, insulin, and HOMA-IR, an estimate for insulin resistance. Since diab