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, PhD
• Daniel E. Weeks, PhD
• Lacey W. Heinsberg, PhD, RN
• Jenna 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 diabetes can trigger dyslipidemia, we additionally conducted analyses for HDL, LDL, total cholesterol, and triglycerides. Here, we identified three loci associated with metabolic traits and nine loci associated with lipid traits.

          We identified a clinically-actionable, common SV in the haptoglobin gene (HP) for further study: the duplication is associated with increased cardiovascular events in individuals with T2D, which can be mitigated by Vitamin E supplementation. We found that 20% of the Samoan participants were homozygous for the HP duplication and had T2D, and may thus benefit from taking Vitamin E. Additionally, Samoans homozygous for the duplication had 66% higher odds of T2D compared to Samoans without any copies of the duplication.

          Ultimately, this study explores understudied variants, SVs, in an understudied population, Samoans, to better understand the genetic drivers of T2D and related cardiometabolic traits.    

IN-PERSON EVENT - ALL WELCOME