The contribution of functional HNF1A variants and polygenic susceptibility to risk of type 2 diabetes in ancestrally diverse populations
Authors' conclusion
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.
Study context
- Population
- Individuals of European, African and Hispanic-Latino ancestry with exome sequencing data in the UK Biobank (160,615) and BioMe Biobank (18,797)746 HNF1A carriers
- Comparison
- Carriers of rare functional HNF1A variants vs non-carriers; higher vs lower PRS
- HNF1A variant carriersn = 746
- Outcome
- Risk of T2D and age of diagnosis
Methodological detailsexome sequencing, UK Biobank and BioMe Biobank, three ancestry groups, polygenic risk scores, interaction analysis
- Exome sequencing
- UK Biobank and BioMe Biobank
- Three ancestry groups
- Polygenic risk scores
- Interaction analysis
Performance
As reported in the abstract
European ancestry, HNF1A variants predicted to impair protein function: OR (p=0.049)
1.46
European ancestry, variants in functional domains: OR (p=0.002)
1.89
African ancestry: no association, OR (p=0.60)
1.10
Further findings
Age at T2D diagnosis with rare functional HNF1A variants, by ancestry
Years
- Hispanic-Latino ancestry: earlier diagnosis, β (p=0.03)
- −5.0
- Hispanic-Latino ancestry, variants in functional domains: β (p=0.03)
- −5.59
- African ancestry: no association, β (p=0.13)
- −2.7
- European ancestry: no association, β (p=0.20)
- −3.5
Higher PRS and T2D risk, all ancestries
- Increased odds of T2D, OR range (p<10-5)
- 1.61-2.11
Higher PRS and age at T2D diagnosis
Years
- African ancestry: earlier diagnosis, β (p=3.7 × 10-6)
- −1.4
- Hispanic-Latino ancestry: earlier diagnosis, β (p<2 × 10-16)
- −2.4
PRS × HNF1A variant interaction on T2D, European ancestry
- Higher PRS exacerbated the effect of functional HNF1A variants on T2D (pinteraction=0.037)
Original publication
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