Genome-wide association study of type 2 diabetes in Africa

Ji Chen¹, Meng Sun², Adebowale Adeyemo³, Fraser Pirie⁴, Tommy Carstensen^{1

5}, Cristina Pomilla^{1

5}, Ayo P Doumatey³, Guanjie Chen³, Elizabeth H Young^{1

5}, Manjinder Sandhu^{1

5}, Andrew P Morris^{2

6}, Inês Barroso^{1

7}, Mark I McCarthy^{2

8

9}, Anubha Mahajan¹⁰, Eleanor Wheeler^{11

12}, Charles N Rotimi¹³, Ayesha A Motala¹⁴

Affiliations

¹ Wellcome Sanger Institute, Hinxton, Cambridge, UK.
² Wellcome Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.
³ Center for Research on Genomics and Global Heath, National Human Genome Research Institute, National Institute of Health, Bethesda, MD, USA.
⁴ Department of Diabetes and Endocrinology, University of KwaZulu-Natal, Durban, 4013, South Africa.
⁵ Department of Medicine, University of Cambridge, Cambridge, UK.
⁶ Department of Biostatistics, University of Liverpool, Liverpool, UK.
⁷ MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK.
⁸ Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.
⁹ Oxford NIHR Biomedical Research Centre, Oxford, UK.
¹⁰ Wellcome Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK. anubha@well.ox.ac.uk.
¹¹ Wellcome Sanger Institute, Hinxton, Cambridge, UK. eleanor.wheeler@mrc-epid.cam.ac.uk.
¹² MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK. eleanor.wheeler@mrc-epid.cam.ac.uk.
¹³ Center for Research on Genomics and Global Heath, National Human Genome Research Institute, National Institute of Health, Bethesda, MD, USA. rotimic@mail.nih.gov.
¹⁴ Department of Diabetes and Endocrinology, University of KwaZulu-Natal, Durban, 4013, South Africa. motala@ukzn.ac.za.

PMID: 31049640
PMCID: PMC6560001
DOI: 10.1007/s00125-019-4880-7

Genome-wide association study of type 2 diabetes in Africa

Ji Chen et al. Diabetologia. 2019 Jul.

. 2019 Jul;62(7):1204-1211.

doi: 10.1007/s00125-019-4880-7. Epub 2019 May 2.

Authors

Affiliations

¹ Wellcome Sanger Institute, Hinxton, Cambridge, UK.
² Wellcome Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.
³ Center for Research on Genomics and Global Heath, National Human Genome Research Institute, National Institute of Health, Bethesda, MD, USA.
⁴ Department of Diabetes and Endocrinology, University of KwaZulu-Natal, Durban, 4013, South Africa.
⁵ Department of Medicine, University of Cambridge, Cambridge, UK.
⁶ Department of Biostatistics, University of Liverpool, Liverpool, UK.
⁷ MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK.
⁸ Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.
⁹ Oxford NIHR Biomedical Research Centre, Oxford, UK.
¹⁰ Wellcome Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK. anubha@well.ox.ac.uk.
¹¹ Wellcome Sanger Institute, Hinxton, Cambridge, UK. eleanor.wheeler@mrc-epid.cam.ac.uk.
¹² MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK. eleanor.wheeler@mrc-epid.cam.ac.uk.
¹³ Center for Research on Genomics and Global Heath, National Human Genome Research Institute, National Institute of Health, Bethesda, MD, USA. rotimic@mail.nih.gov.
¹⁴ Department of Diabetes and Endocrinology, University of KwaZulu-Natal, Durban, 4013, South Africa. motala@ukzn.ac.za.

PMID: 31049640
PMCID: PMC6560001
DOI: 10.1007/s00125-019-4880-7

Abstract

Aims/hypothesis: Genome-wide association studies (GWAS) for type 2 diabetes have uncovered >400 risk loci, primarily in populations of European and Asian ancestry. Here, we aimed to discover additional type 2 diabetes risk loci (including African-specific variants) and fine-map association signals by performing genetic analysis in African populations.

Methods: We conducted two type 2 diabetes genome-wide association studies in 4347 Africans from South Africa, Nigeria, Ghana and Kenya and meta-analysed both studies together. Likely causal variants were identified using fine-mapping approaches.

Results: The most significantly associated variants mapped to the widely replicated type 2 diabetes risk locus near TCF7L2 (p = 5.3 × 10^-13). Fine-mapping of the TCF7L2 locus suggested one type 2 diabetes association signal shared between Europeans and Africans (indexed by rs7903146) and a distinct African-specific signal (indexed by rs17746147). We also detected one novel signal, rs73284431, near AGMO (p = 5.2 × 10^-9, minor allele frequency [MAF] = 0.095; monomorphic in most non-African populations), distinct from previously reported signals in the region. In analyses focused on 100 published type 2 diabetes risk loci, we identified 21 with shared causal variants in African and non-African populations.

Conclusions/interpretation: These results demonstrate the value of performing GWAS in Africans, provide a resource to larger consortia for further discovery and fine-mapping and indicate that additional large-scale efforts in Africa are warranted to gain further insight in to the genetic architecture of type 2 diabetes.

Keywords: Africa; Established loci; Fine-mapping; Genome-wide association study; Type 2 diabetes.

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Figures

**Fig. 1**
Manhattan plot of the type 2 diabetes meta-analysis results. The horizontal grey line corresponds to p=2.5×10⁻⁸ and loci reaching that significance threshold (variants within 500 kb distance of those with p<2.5×10⁻⁸) are shown in red. Gene labels correspond to the nearest/most biologically plausible gene

**Fig. 2**
(a) Associations between the GRSs constructed from the subsets of established type 2 diabetes variants and type 2 diabetes in the Zulu samples. (b) Associations between the GRSs constructed from the subsets of established type 2 diabetes variants and type 2 diabetes in the AADM samples. Please see ESM Table 2 for details of categories

See this image and copyright information in PMC

References

1. NCD Risk Factor Collaboration (NCD-RisC) Worldwide trends in diabetes since 1980: a pooled analysis of 751 population-based studies with 4.4 million participants. Lancet. 2016;387:1513–1530. doi: 10.1016/S0140-6736(16)00618-8. - DOI - PMC - PubMed
1. International Diabetes Federation (2015) Diabetes Atlas (7th Edition). Available from: http://www.diabetesatlas.org
1. Mbanya JC, Motala AA, Sobngwi E, Assah FK, Enoru ST. Diabetes in sub-Saharan Africa. Lancet. 2010;375(9733):2254–2266. doi: 10.1016/S0140-6736(10)60550-8. - DOI - PubMed
1. Morris AP, Voight BF, Teslovich TM, et al. Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes. Nat Genet. 2012;44:981–990. doi: 10.1038/ng.2383. - DOI - PMC - PubMed
1. Scott RA, Scott LJ, Magi R, et al. An expanded genome-wide association study of type 2 diabetes in Europeans. Diabetes. 2017;66(11):2888–2902. doi: 10.2337/db16-1253. - DOI - PMC - PubMed

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Genome-wide association study of type 2 diabetes in Africa

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Genome-wide association study of type 2 diabetes in Africa

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