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

Adebowale A. Adeyemo, National Human Genome Research Institute (NHGRI)Follow
Norann A. Zaghloul, University of Maryland School of Medicine
Guanjie Chen, National Human Genome Research Institute (NHGRI)
Ayo P. Doumatey, National Human Genome Research Institute (NHGRI)
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 (NHGRI)
Amy R. Bentley, National Human Genome Research Institute (NHGRI)
Daniel Shriner, National Human Genome Research Institute (NHGRI)
Olufemi Fasanmade, University of Lagos
Godfrey Okafor, University of Nigeria
Benjamin Eghan, Kwame Nkrumah University of Science and Technology
Kofi Agyenim-Boateng, Kwame Nkrumah University of Science and Technology
Settara Chandrasekharappa, National Human Genome Research Institute (NHGRI)
Jokotade Adeleye, University of Ibadan
William Balogun, University of Ibadan
Samuel Owusu, University of Ghana
Albert Amoah, University of Ghana
Joseph Acheampong, Kwame Nkrumah University of Science and Technology
Thomas Johnson, University of Lagos
Johnnie Oli, University of Nigeria
Clement Adebamowo, University of Maryland, Baltimore (UMB)
Ji Chen, Wellcome Sanger Institute
Meng Sun, The Wellcome Centre for Human Genetics
Fraser Pirie, University of KwaZulu-Natal
Tommy Carstensen, University of Cambridge
Cristina Pomilla, Wellcome Sanger Institute
Elizabeth H. Young, University of Cambridge
Manjinder Sandhu, University of Cambridge
Andrew P. Morris, The Wellcome Centre for Human Genetics
Inês Barroso, School of Clinical Medicine
Mark I. McCarthy, The Wellcome Centre for Human Genetics
Anubha Mahajan, The Wellcome Centre for Human Genetics

Document Type

Article

Publication Date

12-1-2019

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.

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