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Thuesen, A.C.B.* ; Stæger, F.F.* ; Kaci, A.* ; Solheim, M.H.* ; Aukrust, I.* ; Jørsboe, E.* ; Santander, C.G.* ; Andersen, M.K.* ; Li, Z.* ; Gilly, A. ; Stinson, S.E.* ; Gjesing, A.P.* ; Bjerregaard, P.* ; Pedersen, M.L.* ; Larsen, C.V.L.* ; Grarup, N.* ; Jørgensen, M.E.* ; Zeggini, E. ; Bjørkhaug, L.* ; Njølstad, P.R.* ; Albrechtsen, A.* ; Moltke, I.* ; Hansen, T.*

A novel splice-affecting HNF1A variant with large population impact on diabetes in Greenland.

Lancet Reg. Health-Eur. 24:100529 (2023)
Publ. Version/Full Text DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Background: The genetic disease architecture of Inuit includes a large number of common high-impact variants. Identification of such variants contributes to our understanding of the genetic aetiology of diseases and improves global equity in genomic personalised medicine. We aimed to identify and characterise novel variants in genes associated with Maturity Onset Diabetes of the Young (MODY) in the Greenlandic population. Methods: Using combined data from Greenlandic population cohorts of 4497 individuals, including 448 whole genome sequenced individuals, we screened 14 known MODY genes for previously identified and novel variants. We functionally characterised an identified novel variant and assessed its association with diabetes prevalence and cardiometabolic traits and population impact. Findings: We identified a novel variant in the known MODY gene HNF1A with an allele frequency of 1.9% in the Greenlandic Inuit and absent elsewhere. Functional assays indicate that it prevents normal splicing of the gene. The variant caused lower 30-min insulin (β = −232 pmol/L, βSD = −0.695, P = 4.43 × 10−4) and higher 30-min glucose (β = 1.20 mmol/L, βSD = 0.441, P = 0.0271) during an oral glucose tolerance test. Furthermore, the variant was associated with type 2 diabetes (OR 4.35, P = 7.24 × 10−6) and HbA1c (β = 0.113 HbA1c%, βSD = 0.205, P = 7.84 × 10−3). The variant explained 2.5% of diabetes variance in Greenland. Interpretation: The reported variant has the largest population impact of any previously reported variant within a MODY gene. Together with the recessive TBC1D4 variant, we show that close to 1 in 5 cases of diabetes (18%) in Greenland are associated with high-impact genetic variants compared to 1–3% in large populations. Funding: Novo Nordisk Foundation, Independent Research Fund Denmark, and Karen Elise Jensen's Foundation.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Hepatocyte Nuclear Factor-1-alpha; Insulin Sensitivity; Glucose-tolerance; Rare Variants; Low-frequency; Onset; Mutations; Association; Genes; Risk
ISSN (print) / ISBN 2666-7762
e-ISSN 2666-7762
Journal The Lancet Regional Health - Europe
Quellenangaben Volume: 24, Issue: , Pages: , Article Number: 100529 Supplement: ,
Publisher Elsevier
Publishing Place Radarweg 29, 1043 Nx Amsterdam, Netherlands
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Translational Genomics (ITG)
Grants Danmarks Frie Forskningsfond
Novo Nordisk Fonden
Karen Elise Jensens Fond
Københavns Universitet
Sanofi
AstraZeneca