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

被引：74

作者：

Adeyemo, Adebowale A. ^{[1
]}

Zaghloul, Norann A. ^{[2
,3
]}

Chen, Guanjie ^{[1
]}

Doumatey, Ayo P. ^{[1
]}

Leitch, Carmen C. ^{[2
]}

Hostelley, Timothy L. ^{[2
]}

Nesmith, Jessica E. ^{[2
]}

Zhou, Jie ^{[1
]}

Bentley, Amy R. ^{[1
]}

Shriner, Daniel ^{[1
]}

Fasanmade, Olufemi ^{[4
]}

Okafor, Godfrey ^{[5
]}

Eghan, Benjamin, Jr. ^{[6
]}

Agyenim-Boateng, Kofi ^{[6
]}

Chandrasekharappa, Settara ^{[7
]}

Adeleye, Jokotade ^{[8
]}

Balogun, William ^{[8
]}

Owusu, Samuel ^{[9
]}

Amoah, Albert ^{[9
]}

Acheampong, Joseph ^{[6
]}

Johnson, Thomas ^{[4
]}

Oli, Johnnie ^{[5
]}

Adebamowo, Clement ^{[10
,11
,12
]}

Collins, Francis ^{[14
]}

Dunston, Georgia ^{[15
]}

Rotimi, Charles N. ^{[1
]}

Chen, Ji ^{[16
]}

Sun, Meng ^{[17
]}

Pirie, Fraser ^{[18
]}

Carstensen, Tommy ^{[19
]}

Pomilla, Cristina ^{[16
]}

Young, Elizabeth H. ^{[19
]}

Sandhu, Manjinder ^{[19
]}

Morris, Andrew P. ^{[17
,20
]}

Barroso, Ines ^{[21
]}

McCarthy, Mark, I ^{[13
,17
,22
]}

Mahajan, Anubha ^{[17
]}

Wheeler, Eleanor ^{[16
,21
]}

Motala, Ayesha A. ^{[18
]}

机构：

[1] NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20892 USA

[2] Univ Maryland, Dept Med, Sch Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA

[3] Univ Maryland, Program Personalized & Genom Med, Sch Med, Baltimore, MD 21201 USA

[4] Univ Lagos, Lagos, Nigeria

[5] Univ Nigeria, Teaching Hosp, Enugu, Nigeria

[6] Univ Sci & Technol, Kumasi, Ghana

[7] NHGRI, NIH, Bethesda, MD 20892 USA

[8] Univ Ibadan, Coll Med, Ibadan, Nigeria

[9] Univ Ghana, Med Sch, Accra, Ghana

[10] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA

[11] Univ Maryland, Sch Med, Inst Human Virol, Baltimore, MD 21201 USA

[12] Univ Maryland, Sch Med, Greenebaum Comprehens Canc Ctr, Baltimore, MD 21201 USA

[13] Oxford NIHR Biomed Res Ctr, Oxford OX3 7JX, England

[14] NIH, Bldg 10, Bethesda, MD 20892 USA

[15] Howard Univ, Natl Human Genome Ctr, Washington, DC 20059 USA

[16] Wellcome Sanger Inst, Cambridge C310 1SA, England

[17] Univ Oxford, Wellcorne Ctr Human Genet, Roosevelt Dr, Oxford OX3 7BN, England

[18] Univ KwaZulu Natal, Dept Diabet & Endocrinol, ZA-4013 Durban, South Africa

[19] Univ Cambridge, Dept Med, Cambridge CB2 0QQ, England

[20] Univ Liverpool, Dept Biostat, Liverpool L69 3GL, Merseyside, England

[21] Univ Cambridge, Sch Clin Med, MRC Epidemiol Unit, Inst Metab Sci, Cambridge Biomed Campus, Cambridge CB2 0QQ, England

[22] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford OX3 7LE, England

来源：

NATURE COMMUNICATIONS | 2019年 / 10卷 / 1期

基金：

美国国家卫生研究院;

关键词：

GENOME-WIDE ASSOCIATION; GENETIC-VARIANTS; SUSCEPTIBILITY GENES; METAANALYSIS; TRAITS; INDIVIDUALS; GLUCOSE; TCF7L2; IMPACT; RISK;

D O I：

10.1038/s41467-019-10967-7

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 similar to 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 x 10(-9)). Knockdown or genomic knockout of the zebrafish ortholog results in reduction in pancreatic beta-cell number which we demonstrate to be due to increased apoptosis in islets. siRNA transfection of murine Zranb3 in MIN6 beta-cells results in impaired insulin secretion in response to high glucose, implicating Zranb3 in beta-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.

引用

页数：12

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