A novel splice-affecting HNF1A variant with large population impact on diabetes in Greenland
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A novel splice-affecting HNF1A variant with large population impact on diabetes in Greenland. / Thuesen, Anne Cathrine Baun; Stæger, Frederik Filip; Kaci, Alba; Solheim, Marie Holm; Aukrust, Ingvild; Jørsboe, Emil; Santander, Cindy G.; Andersen, Mette K.; Li, Zilong; Gilly, Arthur; Stinson, Sara Elizabeth; Gjesing, Anette Prior; Bjerregaard, Peter; Pedersen, Michael Lynge; Larsen, Christina Viskum Lytken; Grarup, Niels; Jørgensen, Marit E.; Zeggini, Eleftheria; Bjørkhaug, Lise; Njølstad, Pål Rasmus; Albrechtsen, Anders; Moltke, Ida; Hansen, Torben.
In: The Lancet Regional Health - Europe, Vol. 24, 100529, 2023.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - A novel splice-affecting HNF1A variant with large population impact on diabetes in Greenland
AU - Thuesen, Anne Cathrine Baun
AU - Stæger, Frederik Filip
AU - Kaci, Alba
AU - Solheim, Marie Holm
AU - Aukrust, Ingvild
AU - Jørsboe, Emil
AU - Santander, Cindy G.
AU - Andersen, Mette K.
AU - Li, Zilong
AU - Gilly, Arthur
AU - Stinson, Sara Elizabeth
AU - Gjesing, Anette Prior
AU - Bjerregaard, Peter
AU - Pedersen, Michael Lynge
AU - Larsen, Christina Viskum Lytken
AU - Grarup, Niels
AU - Jørgensen, Marit E.
AU - Zeggini, Eleftheria
AU - Bjørkhaug, Lise
AU - Njølstad, Pål Rasmus
AU - Albrechtsen, Anders
AU - Moltke, Ida
AU - Hansen, Torben
N1 - Publisher Copyright: © 2022 The Author(s)
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
U2 - 10.1016/j.lanepe.2022.100529
DO - 10.1016/j.lanepe.2022.100529
M3 - Journal article
C2 - 36649380
AN - SCOPUS:85145449746
VL - 24
JO - The Lancet Regional Health - Europe
JF - The Lancet Regional Health - Europe
SN - 2666-7762
M1 - 100529
ER -
ID: 331863751