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

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 onset in these populations may give insight into earlier age at onset of T2D among individuals of South Asian descent. We conducted a meta-analysis of GWAS of age at diagnosis of T2D in 34,001 individuals from four independent cohorts of European and Asian Indians. We identified two signals near the TCF7L2 and CDKAL1 associated with age at onset of T2D. The strongest genome-wide significant variants at chromosome 10q25.3 in TCF7L2 (lead SNP rs7903146; p = 2.4 x10-12; p-het =0.01; Beta = -0.436; SE = 0.02) and chromosome 6 p22.3 in CDKAL1 (rs9368219; p = 2.29 x10-8; p-het =0.007; 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 Asian cohorts. A genome wide signal was also obtained at chromosome 10q26.12 in WDR11 (rs3011366; p = 2.4 x10-8; p-het =0.25; Beta = 1.44; SE=0.25) specifically in the South Asian Indian cohorts. Our study estimated 17% of heritability (h2) for age onset of T2D among South Indians; higher than the 5% heritability we observed in Europeans suggesting different genetic architectures between these populations. We further estimated the Asian Indian genome-wide polygenic risk score for T2D risk and identified that the variance explained by the Indian specific polygenic risk score (PRS) for age at onset of T2D is substantially higher (2%) in an independent cohort of Asian Indians compared to that seen in White Europeans (<0.1%). This reveals that although variants do exist that are shared between the two population there are also genetic disparities of age onset of T2D between the ethnicities. Author SummaryRecent large multi-ancestry genome-wide meta-analyses have identified over 277 genetic loci associated with type 2 diabetes (T2D). Most association studies for T2D have focused on populations of European ancestry, and the specific genetic architecture of T2D in the South Asian population has not been extensively investigated. Increasing evidence indicates that the prevalence of T2D is higher in South Asians with a strikingly earlier age at diagnosis when compared to Europeans. Genome-wide association studies (GWAS) on age at age at diagnosis of T2D are limited and can help elucidate underlying mechanisms. We conducted the largest meta-analysis to date of genome-wide association studies of age at diagnosis as a surrogate for age of onset of T2D in South Indians and Europeans. Our trans-ancestry meta-analysis identified genetic loci near TCF7L2 and CDKAL1 with substantial ethnic heterogeneity in both allele frequencies and effect sizes in early diagnosis with T2D. Two novel variants near TCF7L2 (rs570193324) and CDKAL1 (rs143316471) were associated with age of diagnosis of T2D only in South Indians and were present at much lower frequency in the European populations. Heritability estimates for age of onset were much stronger in Asian Indians compared to Europeans and a polygenic risk score was constructed using a South Indians, which explained about 2% trait variance compared to European ancestry (<0.1%). Our novel findings provide a better understanding of ethnic differences in the age at onset of T2D and indicate the potential importance of ethnic differences in the genetic architecture underpinning T2D.