Genetic Architecture of Lipid Traits in Pacific Islander Populations: From Discovery to Function

About this event

Toni-Ann J. Yapp, MPH - Final Dissertation Defense - HUGEN PhD Candidate

Department of Human Genetics Doctoral Candidate, Toni-Ann J. Yapp, MPH , will defend the following dissertation on “Genetic Architecture of Lipid Traits in Pacific Islander Populations: From Discovery to Function ”

COMMITTEE CHAIR: Jenna C. Carlson, PhD

Committee Members:

• Samantha L. Manna, PhD

• Iva Miljkovic, MD, PhD, FAHA

• Wenndy Hernandez, PhD

• Ryan L. Minster, PhD, MSIS

ABSTRACT:

Pacific Islanders have high rates of cardiometabolic disease and are absent from the genomic datasets used to build lipid polygenic scores and expression quantitative trait locus (eQTL) maps. This dissertation asks how well those tools work in Samoans, what adipose regulation looks like in this population, and which genes at Samoan lipid genome-wide association study (GWAS) loci a population-matched map can name. Aim 1 evaluated published multi-ancestry polygenic scores for HDL cholesterol (HDL-C), LDL cholesterol (LDL-C), total cholesterol, and triglycerides in 4,342 adults from five Samoan and American Samoan cohorts (1990–2010). The polygenic scores transferred, but incompletely: those for HDL-C and total cholesterol performed better than those for LDL-C and triglycerides. Variant matching and monomorphic rates differed by trait and genotyping platform, revealing the sensitivity of these methods to variant harmonization. Aim 2 mapped cis-eQTLs in Samoan subcutaneous adipose tissue from N = 90 donors and identified 2,629 genes with at least one significant eQTL variant (eGenes; FDR < 0.05). Most of these eGenes were also GTEx V8 adipose eGenes (90.0%), but they often had a different lead eQTL variant. Aim 3 colocalized the Aim 2 eQTL map with 18 conditionally independent Samoan lipid GWAS signals using SuSiE and FastENLOC after aligning eQTL z-scores to a Samoan-specific LD-panel allele. Seven gene-locus-trait combinations reached gene-level regional colocalization probability (GRCP) &ge; 0.99: GALNT18 (triglycerides), CPNE2 (HDL-C), HERPUD1 (HDL-C), LDAH (LDL-C and total cholesterol), RGL3 (triglycerides and HDL-C). APOB also colocalized at the chr2 LDL-C and total cholesterol signals (GRCP = 0.94). At an HDL-C associated locus on 5q35, BTNL9 had the highest colocalization probability (GRCP = 0.97). At 19q13, which includes APOE, colocalization was near zero, as expected: APOE is not an adipose eGene, suggesting the GWAS locus acts either through a different mechanism and/or in another. Together, these three aims show that European and multi-ancestry resources are a starting point for Samoan lipid genetics, not a substitute for population-matched mapping and colocalization.

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