The contribution of functional HNF1A variants and polygenic susceptibility to risk of type 2 diabetes in ancestrally diverse populations

Aims/hypothesis We examined the contribution of rare HNF1A variants to type 2 diabetes risk and age of diagnosis, and the extent to which their impact is affected by overall genetic susceptibility, across three ancestry groups. Methods Using exome sequencing data of 160,615 individuals of the UK Biobank and 18,797 individuals of the Bio Me Biobank, we identified 746 carriers of rare functional HNF1A variants (minor allele frequency ≤1%), of which 507 carry variants in the functional domains. We calculated polygenic risk scores (PRSs) based on genome-wide association study summary statistics for type 2 diabetes, and examined the association of HNF1A variants and PRS with risk of type 2 diabetes and age of diagnosis. We also tested whether the PRS affects the association between HNF1A variants and type 2 diabetes risk by including an interaction term. Results Rare HNF1A variants that are predicted to impair protein function are associated with increased risk of type 2 diabetes in individuals of European ancestry (OR 1.46, p =0.049), particularly when the variants are located in the functional domains (OR 1.89, p =0.002). No association was observed for individuals of African ancestry (OR 1.10, p =0.60) or Hispanic-Latino ancestry (OR 1.00, p =1.00). Rare functional HNF1A variants were associated with an earlier age at diagnosis in the Hispanic-Latino population (β=−5.0 years, p =0.03), and this association was marginally more pronounced for variants in the functional domains (β=−5.59 years, p =0.03). No associations were observed for other ancestries (African ancestry β=−2.7 years, p =0.13; European ancestry β=−3.5 years, p =0.20). A higher PRS was associated with increased odds of type 2 diabetes in all ancestries (OR 1.61–2.11, p