A Novel Type 2 Diabetes Locus in sub-Saharan Africans, ZRANB3, is Implicated in Beta Cell Proliferation

Abstract

Genome analysis of diverse human populations has contributed to the identification of novel genomic loci for diseases of major clinical and public health impact. Here, we report the largest genome-wide analysis of type 2 diabetes (T2D) in sub-Saharan Africans, an understudied ancestral group. We analyzed ~18 million autosomal SNPs in 5,231 individuals from Nigeria, Ghana and Kenya. TCF7L2 rs7903156 was the most significant locus (p=7.288 x 10-13). We identified a novel genome wide significant locus: ZRANB3 (Zinc Finger RANBP2-Type Containing 3, lead SNP chr2:136064024, T allele frequency=0.034, p=2.831x10-9). Knockdown of the zebrafish ortholog resulted in reduction in pancreatic beta cell number in the developing organism, suggesting a potential mechanism for its effect on glucose hemostasis. We also showed transferability in our study of 32 established T2D loci. Our findings provide evidence of a novel candidate T2D locus and advance understanding of the genetics of T2D in non-European ancestry populations.