ZRANB3 is an African-specific type 2 diabetes locus associated with beta-cell mass and insulin response

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 a genome-wide analysis of type 2 diabetes (T2D) in sub-Saharan Africans, an understudied ancestral group. We analyze ~18 million autosomal SNPs in 5,231 individuals from Nigeria, Ghana and Kenya. We identify a previously-unreported genome-wide significant locus: ZRANB3 (Zinc Finger RANBP2-Type Containing 3, lead SNP p = 2.831 × 10 −9 ). Knockdown or genomic knockout of the zebrafish ortholog results in reduction in pancreatic β-cell number which we demonstrate to be due to increased apoptosis in islets. siRNA transfection of murine Zranb3 in MIN6 β-cells results in impaired insulin secretion in response to high glucose, implicating Zranb3 in β-cell functional response to high glucose conditions. We also show transferability in our study of 32 established T2D loci. Our findings advance understanding of the genetics of T2D in non-European ancestry populations.

Genome-wide analyses disclose the distinctive HLA architecture and the pharmacogenetic landscape of the Somali population

“…Such study should preferably also include neighboring Horn of African populations, including Djibouti and Eritrea, for whom there are no or little genomic data available. To explore mechanisms involving disease alleles or pharmacogenetic variants, approaches recently reported by Adeyemo et al 7 will be useful to employ.…”

Returning incidental findings in African genomics research

“…For example, a recent genome-wide analysis on genetic susceptibility to type 2 diabetes (T2D) in sub-Saharan Africans from Nigeria, Ghana and Kenya, identified a previously-unreported genome-wide significant locus that is specific to African populations (and monomorphic in European and Asians), while the same study showed transferability of 32 established T2D loci. 23 Taken together, the underrepresentation of Africans in international genetic research and variation databases, combined with the greater genetic diversity in African populations, results in some reported variants in genes that are included on the consensus lists may not cause disease in Africans, whilst actual pathogenic variants not yet reported from African populations may not have been considered or included. Also, African genomic studies risk identifying many variants of unknown significance that will likely turn out to be benign.…”

AFF3 and BACH2 are master regulators of metabolic inflexibility, β/α-cell transition, and dedifferentiation in type 2 diabetes

“…We selected 10 candidate MRs for experimental validation based on their activity in T2D-enriched clusters and their association with diabetes susceptibility loci in GWAS studies. They included: AFF3 40 , BACH2 41 , BNC2 42 , GAS7 43 , MYT1L 44 , NFATC3 45 , RFX7 46 , TSHZ2 47 , ZRANB3 48 , and ZNF385D 49 . Critically, their mRNA expression was not significantly different based on scRNA-seq analysis, suggesting that these proteins could not have been identified using more traditional approaches (Supplementary Data 3).…”