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

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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 BioMe 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<10−5) and an earlier age at diagnosis in individuals of African ancestry (β=−1.4 years, p=3.7 × 10−6) and Hispanic-Latino ancestry (β=−2.4 years, p<2 × 10−16). Furthermore, a higher PRS exacerbated the effect of the functional HNF1A variants on type 2 diabetes in the European ancestry population (pinteraction=0.037). Conclusions/interpretation: We show that rare functional HNF1A variants, in particular those located in the functional domains, increase the risk of type 2 diabetes, at least among individuals of European ancestry. Their effect is even more pronounced in individuals with a high polygenic susceptibility. Our analyses highlight the importance of the location of functional variants within a gene and an individual’s overall polygenic susceptibility, and emphasise the need for more genetic data in non-European populations. Graphical abstract: [Figure not available: see fulltext.]

OriginalsprogEngelsk
TidsskriftDiabetologia
Vol/bind66
Sider (fra-til)116-126
Antal sider11
ISSN0012-186X
DOI
StatusUdgivet - 2023

Bibliografisk note

Funding Information:
LAS was supported by a grant from the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (DK130576-02). RJFL is supported by grants from the National Institutes of Health (R01DK110113, R01DK107786 and R01DK124097), the Novo Nordisk Foundation (Laureate Research Grant 2020-0059313) and the Danish National Fund for Research (DNRF Chair Grant). ALG is funded by Wellcome (200837) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (U01-DK105535 and UM1DK126185) and the Stanford Diabetes Research Center (NIDDK award P30DK116074).

Publisher Copyright:
© 2022, The Author(s).

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