ArticleDiabetologia2023
The contribution of functional HNF1A variants and polygenic susceptibility to risk of type 2 diabetes in ancestrally diverse populations.
Article in Diabetologia, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers, 1 of them a synthesis that pooled it.
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Who cites it
5 citing papers in PubMed, 1 synthesis or guideline pooled it, 8 citations in OpenAlex.
- GWAS of CRP response to statins further supports the role of APOE in statin response: A GIST consortium study.Pharmacological research · 2025Pooled it
- Local ancestry-informed rare variant burden testing improves gene discovery in admixed populations.medRxiv : the preprint server for health sciences · 2026Article
- Gene Panel-Based Genotyping of 279 Turkish Maturity-Onset Diabetes of the Young Patients from Eastern Anatolia.Molecular syndromology · 2025Article
- Diabetes mellitus polygenic risk scores: heterogeneity and clinical translation.Nature reviews. Endocrinology · 2025Review
- Current views on etiology, diagnosis, epidemiology and gene therapy of maturity onset diabetes in the young.Frontiers in endocrinology · 2024Review
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Authors and funding
8 authors at 6 institutions in 4 countries.
Funding
Abstract
aims/hypothesisWe 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.
methodsUsing 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.
resultsRare 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 CONCLUSIONS/
interpretationWe 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.
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