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. 2023 Jan;66(1):116-126.
doi: 10.1007/s00125-022-05806-2. Epub 2022 Oct 11.

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

Lauren A Stalbow  1   2   3 , Michael H Preuss  1   2   3 , Roelof A J Smit  1   2   3   4 , Nathalie Chami  1   2   3 , Lise Bjørkhaug  5 , Ingvild Aukrust  6   7 , Anna L Gloyn  8   9 , Ruth J F Loos  10   11   12   13
Affiliations

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

Lauren A Stalbow et al. Diabetologia. 2023 Jan.

Abstract

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.

Keywords: Age at diagnosis; Functional domain; HNF1A; Interaction effects; Polygenic risk scores; Risk stratification; Type 2 diabetes.

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Figures

Fig. 1
Fig. 1
Position of functionally damaging HNF1A variants in the HNF1A protein sequence identified in the three ancestry groups: (a) African, (b) European and (c) Hispanic-Latino. The illustrations show the number of carriers of each variant and where in the protein the variant is located. The three functional domains of HNF1A are indicated in orange, green and blue
Fig. 2
Fig. 2
Risk of type 2 diabetes in each ancestry by HNF1A variant (any functionally damaging variant identified, and those within a functional domain of the protein) and PRS in (a) African, (b) European and (c) Hispanic-Latino ancestry groups. The OR was calculated using a logistic regression model, with age, sex, BMI and the first ten ancestry PCs as covariates. In the UK Biobank, centre and chip were included as covariates. The estimates obtained for the specific biobanks were meta-analysed together, and the random-effect ORs are shown. Boxes represent OR; horizontal lines represent 95% CI. T2D, type 2 diabetes
Fig. 3
Fig. 3
Age of type 2 diabetes diagnosis in each ancestry by HNF1A variant (any functionally damaging variant identified, and those within a functional domain of the protein) and PRS in (a) African, (b) European and (c) Hispanic-Latino ancestry groups. The estimates were calculated using a linear regression model, with sex, BMI and the first ten ancestry PCs as covariates. In the UK Biobank, centre and chip were included as covariates. The estimates obtained for the specific biobanks were meta-analysed together, and the random-effect estimates (β) are shown. Boxes represent estimates; horizontal lines represent 95% CI. T2D, type 2 diabetes
Fig. 4
Fig. 4
Risk of type 2 diabetes contributed by rare HNF1A variants in the functional domains and common type 2 diabetes risk strata in the three ancestry groups. Individuals were divided into groups based on their type 2 diabetes PRS quintile (0–20%, 20–40%, 40–60%, 60–80% and 80–100%) and their HNF1A carrier status. The OR was calculated using a logistic regression model, with age, sex, BMI and the first ten ancestry PCs as covariates. In the UK Biobank, centre and chip were included as covariates. The estimates obtained for the specific biobanks were meta-analysed together, and the random-effect ORs are shown. The circles represent the OR in each group. The solid colour represents the HNF1A rare variant carriers, and the shaded circles represent the non-carriers. Non-carriers in the middle quintile (40–60%) served as the reference group for each ancestry
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