Risk of developing type 2 diabetes (T2D) is heritable, with over 403 independent genetic variants having been identified primarily through analysis of common variants in European ancestry populations. To further illuminate the genetic architecture of T2D, we conducted a whole genome sequence (WGS) association study (>38x depth) of common, low frequency, and rare variants in 9,663 individuals with T2D and 35,050 controls of diverse ancestry from NHLBI’s Trans-Omics for Precision Medicine (TOPMed) study. We conducted single variant analyses and SKAT tests of rare variants (MAF <1%) annotated with pancreatic islet specific regulatory annotation to define variant sets. In single variant analyses, a total of 15 regions were significantly associated (α=5e-08) with T2D, seven of which are novel associations (in or near ODF2L, LMAN2, KCNV1, CBR1, VLDLR-AS1, LINC01052 and NKX2-5). These new associations were either ancestry specific or rare variants. For instance, a variant not present in other ancestral groups, near KCNV1, was associated with increased risk of T2D (MAF 5.5%, P= 1.57e-08, OR=1.43) in African ancestry. Set based testing of rare variants identified seven regions associated with T2D in at least one ancestry. Six of these were noncoding: in African ancestry CBR1 gene centric variants (cumulative MAC[cMAC]=623, P = 5.85e-09) and an active promoter region in proximity to MRPL46 and MRPS11 (cMAC=3,218, P = 4.89e-07); and in Asian ancestry an enhancer hub containing NXPH3 (cMAC=3,317, P = 3.42e-05) and an active enhancer region linked to RP11-135A1.2 and HES1 (cMAC=57, P = 4.87e-07) were associated with T2D. KLRC4 predicted deleterious coding variants were associated with T2D in the European ancestry group (cMAC=25, P = 3.63e-06). In large scale WGS analyses, we extended our knowledge of the genetic basis of T2D through the inclusion of ancestrally diverse samples, variant typing without imputation, and use of tissue specific regulatory annotation to identify new T2D loci.


H.M. Highland: None. J. Wessel: Employee; Spouse/Partner; Eli Lilly and Company. A. Manning: None.


National Institute of Diabetes and Digestive and Kidney Diseases (5U01DK078616-10, K01DK107836)

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