Abstract
Aims/hypothesisGenome-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.MethodsWe 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.ResultsThe 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/interpretationThese 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.
Highlights
Type 2 diabetes is a major and growing public health problem, with Africa being the region with the fastest growing prevalence [1,2,3]
In a meta-analysis of type 2 diabetes from two African populations, we replicated the widely reported association at Directly detected Locally detected only All detected Not detected All except directly detected All loci
Using direct and local detection, we showed the transferability of 21 established type 2 diabetes signals discovered in non-African ancestry populations to Africans and that causal variants at those loci were shared across ancestries
Summary
Type 2 diabetes is a major and growing public health problem, with Africa being the region with the fastest growing prevalence [1,2,3]. Genetic factors play a major role in susceptibility to type 2 diabetes. Type 2 diabetes genome-wide association studies (GWAS) have uncovered over 400 risk signals, primarily in populations of European [4, 5] and Asian [6,7,8] ancestry, with more limited efforts in Hispanics/Latinos [9,10,11] and African-Americans [12, 13]. Type 2 diabetes genetic studies in populations from Africa, which are genetically and environmentally diverse, have focused on the replication of established loci [14]. We conducted a meta-analysis of type 2 diabetes in up to 4347 African participants to identify genetic risk factors associated with type 2 diabetes in Africans, evaluate previously reported loci and utilise the finer-grained linkage disequilibrium (LD) pattern of African populations to finemap-associated loci
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