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

Adebowale A. Adeyemo, Norann A. Zaghloul, Guanjie Chen, Ayo P. Doumatey, Carmen C. Leitch, Timothy L. Hostelley, Jessica E. Nesmith, Jie Zhou, Amy R. Bentley, Daniel Shriner, Olufemi Fasanmade, Godfrey Okafor, Benjamin Eghan, Kofi Agyenim-Boateng, Settara Chandrasekharappa, Jokotade Adeleye, William Balogun, Samuel Owusu, Albert Amoah, Joseph Acheampong, Thomas Johnson, Johnnie Oli, Clement Adebamowo, Francis Collins, Georgia Dunston and Charles N. Rotimi ()
Additional contact information
Adebowale A. Adeyemo: National Human Genome Research Institute, National Institutes of Health
Norann A. Zaghloul: University of Maryland School of Medicine
Guanjie Chen: National Human Genome Research Institute, National Institutes of Health
Ayo P. Doumatey: National Human Genome Research Institute, National Institutes of Health
Carmen C. Leitch: University of Maryland School of Medicine
Timothy L. Hostelley: University of Maryland School of Medicine
Jessica E. Nesmith: University of Maryland School of Medicine
Jie Zhou: National Human Genome Research Institute, National Institutes of Health
Amy R. Bentley: National Human Genome Research Institute, National Institutes of Health
Daniel Shriner: National Human Genome Research Institute, National Institutes of Health
Olufemi Fasanmade: University of Lagos
Godfrey Okafor: University of Nigeria Teaching Hospital
Benjamin Eghan: University of Science and Technology
Kofi Agyenim-Boateng: University of Science and Technology
Settara Chandrasekharappa: National Human Genome Research Institute, National Institutes of Health
Jokotade Adeleye: College of Medicine, University of Ibadan
William Balogun: College of Medicine, University of Ibadan
Samuel Owusu: University of Ghana Medical School
Albert Amoah: University of Ghana Medical School
Joseph Acheampong: University of Science and Technology
Thomas Johnson: University of Lagos
Johnnie Oli: University of Nigeria Teaching Hospital
Clement Adebamowo: University of Maryland
Francis Collins: National Institutes of Health
Georgia Dunston: National Human Genome Center at Howard University
Charles N. Rotimi: National Human Genome Research Institute, National Institutes of Health

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-10967-7

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