Common and distinct genetic architecture of age at diagnosis of diabetes in South Indian and European populations

OBJECTIVE

South Asians are diagnosed with type 2 diabetes (T2D) more than a decade earlier in life than seen in European populations. We hypothesised that studying the genomics of age of diagnosis in these populations may give insight into earlier age diagnosis of T2D among individuals of South Asian descent. 

RESEARCH DESIGN AND METHODS 

We conducted a meta-analysis of GWAS of age at diagnosis of T2D in 34,001 individuals from four independent cohorts of European and South Asian Indians. 

RESULTS 

We identified two signals near the TCF7L2 and CDKAL1 associated with age at the onset of T2D. The strongest genome-wide significant variants at chromosome 10q25·3 in TCF7L2 (rs7903146; p = 2·4 ×10-12, Beta = -0·436; SE = 0·02) and chromosome 6 p22·3 in CDKAL1 (rs9368219; p = 2·29 ×10-8; Beta = -0·053; SE=0·01) were directionally consistent across ethnic groups and present at similar frequencies, however both loci harboured additional independent signals that were only present in the South Indian Cohorts. A genome wide signal was also obtained at chromosome 10q26·12 in WDR11 (rs3011366; p = 3.255 ×10-8; Beta = 1·44; SE=0·25) specifically in the South Indian cohorts. Heritability estimates for the age diagnosis were much stronger in South Indian compared to Europeans, and a polygenic risk score was constructed using a South Indians, which explained about 2% trait variance.

CONCLUSIONS 

Our findings provide a better understanding of ethnic differences in the age at diagnosis and indicate the potential importance of ethnic differences in the genetic architecture underpinning T2D.