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

Anne Cathrine Baun Thuesen, Frederik Filip Stæger, Alba Kaci, Marie Holm Solheim, Ingvild Aukrust, Emil Jørsboe, Cindy G. Santander, Mette K. Andersen, Zilong Li, Arthur Gilly, Sara Elizabeth Stinson, Anette Prior Gjesing, Peter Bjerregaard, Michael Lynge Pedersen, Christina Viskum Lytken Larsen, Niels Grarup, Marit E. Jørgensen, Eleftheria Zeggini, Lise Bjørkhaug, Pål Rasmus NjølstadAnders Albrechtsen, Ida Moltke, Torben Hansen

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


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.

Original languageEnglish
Article number100529
JournalThe Lancet Regional Health - Europe
StatePublished - Jan 2023
Externally publishedYes


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