Evaluation of Genome Wide Association Study Associated Type 2 Diabetes Susceptibility Loci in Sub Saharan Africans

Adebowale A. Adeyemo, Fasil Tekola-Ayele, Ayo P. Doumatey, Amy R. Bentley, Guanjie Chen, Hanxia Huang, Jie Zhou, Daniel Shriner, Olufemi Fasanmade, Godfrey Okafor, Benjamin Eghan, Kofi Agyenim-Boateng, Jokotade Adeleye, Williams Balogun, Abdel Elkahloun, Settara Chandrasekharappa, Samuel Owusu, Albert Amoah, Joseph Acheampong, Thomas Johnson, Johnnie Oli, Clement Adebamowo, Francis Collins, Georgia Dunston, Charles N. Rotimi

Genome wide association studies (GWAS) for type 2 diabetes (T2D) undertaken in European and Asian ancestry populations have yielded dozens of robustly associated loci. However, the genomics of T2D remains largely understudied in sub-Saharan Africa (SSA), where rates of T2D are increasing dramatically and where the environmental background is quite different than in these previous studies. Here, we evaluate 106 reported T2D GWAS loci in continental Africans. We tested each of these SNPs, and SNPs in linkage disequilibrium (LD) with these index SNPs, for an association with T2D in order to assess transferability and to fine map the loci leveraging the generally reduced LD of African genomes. The study included 1775 unrelated Africans (1035 T2D cases, 740 controls; mean age 54 years; 59% female) enrolled in Nigeria, Ghana, and Kenya as part of the Africa America Diabetes Mellitus (AADM) study. All samples were genotyped on the Affymetrix Axiom PanAFR SNP array. Forty-one of the tested loci showed transferability to this African sample (p < 0.05, same direction of effect), 11 at the exact reported SNP and 30 others at SNPs in LD with the reported SNP (after adjustment for the number of tested SNPs). TCF7L2 SNP rs7903146 was the most significant locus in this study (p = 1.61 × 10(-8)). Most of the loci that showed transferability were successfully fine-mapped, i.e., localized to smaller haplotypes than in the original reports. The findings indicate that the genetic architecture of T2D in SSA is characterized by several risk loci shared with non-African ancestral populations and that data from African populations may facilitate fine mapping of risk loci. The study provides an important resource for meta-analysis of African ancestry populations and transferability of novel loci.