Wellcome Sanger Institute, Hinxton, Cambridge, UK.
Wellcome Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.
Diabetologia. 2019 Jul;62(7):1204-1211. doi: 10.1007/s00125-019-4880-7. Epub 2019 May 2.
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.
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.
The most significantly associated variants mapped to the widely replicated type 2 diabetes risk locus near TCF7L2 (p = 5.3 × 10). 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, 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.
目的/假设：2 型糖尿病的全基因组关联研究（GWAS）已经发现了 >400 个风险位点，主要集中在欧洲和亚洲血统的人群中。在这里，我们旨在通过在非洲人群中进行遗传分析来发现额外的 2 型糖尿病风险位点（包括非洲特有的变体）和精细映射关联信号。
我们在来自南非、尼日利亚、加纳和肯尼亚的 4347 名非洲人中进行了两项 2 型糖尿病全基因组关联研究，并对这两项研究进行了荟萃分析。使用精细映射方法来识别可能的因果变体。
最显著相关的变体映射到 TCF7L2 附近广泛复制的 2 型糖尿病风险位点（p=5.3×10）。TCF7L2 基因座的精细映射表明，欧洲人和非洲人之间存在一个 2 型糖尿病关联信号（由 rs7903146 索引）和一个独特的非洲特异性信号（由 rs17746147 索引）。我们还检测到一个位于 AGMO 附近的新信号 rs73284431（p=5.2×10，次要等位基因频率 [MAF]=0.095；在大多数非非洲人群中为单态性），与该区域先前报道的信号不同。在针对 100 个已发表的 2 型糖尿病风险位点的分析中，我们在非洲和非非洲人群中发现了 21 个具有共同因果变异的位点。
结论/解释：这些结果证明了在非洲人中进行 GWAS 的价值，为更大的联盟提供了进一步发现和精细映射的资源，并表明需要在非洲进行更多的大规模努力，以进一步深入了解 2 型糖尿病的遗传结构。
