1478-P: Rare Variant Burden of MODY Genes in Type 2 Diabetes Families from Endogamous Ethnic Groups from India

Background: Polygenic risk scores (PRS) derived from genome-wide studies can only partially explain the type 2 diabetes (T2D) risk. Asian Indians have up to six times higher risk of T2D than Europeans. The existence of a high degree of genetic diversity between Indian endogamous ethnic groups (EEGs) offers opportunities to understand the genetic mechanisms of complex disorders like T2D. Here, we evaluated genetic determinants of T2D using family-based cohorts from four distinct EEGs from India.

Methods: Targeted sequencing was performed on 32 families of Punjabi Sikh EEG (n=300). Results were further replicated in 4,602 unrelated Sikhs and 1547 members of 60 families of other Indian EEGs from Rajasthan, Andhra Pradesh, and Tamil Nadu.

Results: We detected several rare variants (RVs) in MODY genes known to cause rare monogenic diabetes in youth. Multiple ultra-rare variants were detected in HNF4A, KCNJ11, and ABCC8 genes cosegregated with late-onset T2D. Gene-burden analysis revealed the highest RV burden contributed by HNF4A (p=0.0003), followed by KCNJ11/ABCC8 (p=0.0061). Some RVs detected in Sikhs were found in families from Rajasthan. Still, they were monomorphic in the other two EEGs from South India. Interestingly, despite carrying a high burden of RVs, these families showed a low PRS, suggesting an oligogenic mode of inheritance.

Conclusions: Our data found an excess of RVs of multiple MODY genes in families with a strong T2D history but with a small common variant burden (low PRS). Sequencing of such endogamous families may uncover new rare sub-forms of T2D and new therapeutic targets.