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

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posted on 2023-06-12, 22:56 authored by Sundararajan Srinivasan, Samuel Liju, Natarajan Sathish, Moneeza K Siddiqui, Ranjit Mohan Anjana, Ewan R. Pearson, Alexander S.F. Doney, Viswanathan Mohan, Venkatesan Radha, Colin N.A Palmer


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. 


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. 


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.


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.



This work was supported by the National Institute for Health Research using Official Development Assistance (ODA) funding [INSPIRED 16/136/102]. The Wellcome Trust United Kingdom Type 2 Diabetes Case-Control Collection (supporting GoDARTS) was funded by The Wellcome Trust (072960/Z/03/Z, 084726/Z/08/Z, 084727/Z/08/Z, 085475/Z/08/Z, 085475/B/08/Z) and as part of the EU IMI-SUMMIT program. The present study was conducted using the UK Biobank Resource under application No. 20405.