1468-P: Integrating Whole-Genome Sequence Analysis and eQTL Data from the TOPMed Program Improves Understanding of Type 2 Diabetes Risk Loci in Diverse Populations

Abstract

Type 2 diabetes (T2D) has been well characterized by genetic studies with over 550 risk loci identified in mostly European populations. To better understand the genetic basis of T2D in diverse ancestries, we performed a whole genome sequence association analysis with T2D and related traits of fasting insulin (FI), glucose (FG) and hemoglobin A1c (HbA1c). We then used the colocalization method COLOC to evaluate if the risk locus and expression quantitative trait loci (eQTL) region shared a variant. Four relevant eQTL specific to tissues or cell types were obtained from the NHLBI Trans Omics for Precision Medicine (TOPMed) program, including 6,602 samples for whole blood, 1,265 for peripheral blood mononuclear cells (PBMC), 368 for T cells, and 352 for monocytes. A signal was considered colocalized if the posterior probability of colocalization (PP.coloc) was >0.5. Our analysis included 21,913 prevalent T2D cases, 61,036 controls, and up to 50,201 non-T2D individuals with FG, FI or HbA1c from African, Atlantic Islander, East Asian, European, Hispanic, and Samoan groups. Single variant analysis identified 35 variants in known regions that were significantly associated with T2D or related traits (P < 4.00 × 10−9). Among these regions, we detected six genes (SLC2A2, NKX6-3, KCNQ1, HBB, FN3K, and G6PD) having colocalizing signals in at least one relevant tissue or cell type. For example, variant rs1050828 near G6PD on chromosome X was strongly associated with HbA1c (P <1.0×10−200). Colocalization analysis revealed that rs1050828 also affected the gene expression in various tissues or cell types, including BCAP31 in whole blood, TKTL1 in PBMC, MPP1 in T cell, and RENBP in monocytes. This novel finding, obtained using TOPMed eQTL data from multiple cohorts, suggests a link between risk-associated variation and effector genes, providing insight into potential causal genes and regulatory variants at T2D risk loci in diverse populations. Disclosure N.Wang: None. D.A.Dicorpo: None. Y.Zhang: None. J.Wessel: None. A.Manning: None. Topmed diabetes working group: n/a. Funding National Institute of Diabetes and Digestive and Kidney Diseases (UM1DK078616, R01HL151855)