A novel splice-affecting HNF1A variant with large population impact on diabetes in Greenland
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 ch...
Published in: | The Lancet Regional Health - Europe |
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Format: | Article in Journal/Newspaper |
Language: | English |
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2023
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Online Access: | https://curis.ku.dk/portal/da/publications/a-novel-spliceaffecting-hnf1a-variant-with-large-population-impact-on-diabetes-in-greenland(82baefb4-002f-4242-bba3-9122f074ca79).html https://doi.org/10.1016/j.lanepe.2022.100529 https://curis.ku.dk/ws/files/331863755/1_s2.0_S2666776222002253_main.pdf |
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ftcopenhagenunip:oai:pure.atira.dk:publications/82baefb4-002f-4242-bba3-9122f074ca79 2024-06-09T07:46:22+00:00 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 2023 application/pdf https://curis.ku.dk/portal/da/publications/a-novel-spliceaffecting-hnf1a-variant-with-large-population-impact-on-diabetes-in-greenland(82baefb4-002f-4242-bba3-9122f074ca79).html https://doi.org/10.1016/j.lanepe.2022.100529 https://curis.ku.dk/ws/files/331863755/1_s2.0_S2666776222002253_main.pdf eng eng info:eu-repo/semantics/openAccess 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 2023 , ' A novel splice-affecting HNF1A variant with large population impact on diabetes in Greenland ' , The Lancet Regional Health - Europe , vol. 24 , 100529 . https://doi.org/10.1016/j.lanepe.2022.100529 article 2023 ftcopenhagenunip https://doi.org/10.1016/j.lanepe.2022.100529 2024-05-16T11:29:27Z 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, β SD = −0.695, P = 4.43 × 10 −4 ) and higher 30-min glucose (β = 1.20 mmol/L, β SD = 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%, β SD = 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. Article in Journal/Newspaper Greenland greenlandic inuit University of Copenhagen: Research Greenland The Lancet Regional Health - Europe 24 100529 |
institution |
Open Polar |
collection |
University of Copenhagen: Research |
op_collection_id |
ftcopenhagenunip |
language |
English |
description |
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, β SD = −0.695, P = 4.43 × 10 −4 ) and higher 30-min glucose (β = 1.20 mmol/L, β SD = 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%, β SD = 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. |
format |
Article in Journal/Newspaper |
author |
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 |
spellingShingle |
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 A novel splice-affecting HNF1A variant with large population impact on diabetes in Greenland |
author_facet |
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 |
author_sort |
Thuesen, Anne Cathrine Baun |
title |
A novel splice-affecting HNF1A variant with large population impact on diabetes in Greenland |
title_short |
A novel splice-affecting HNF1A variant with large population impact on diabetes in Greenland |
title_full |
A novel splice-affecting HNF1A variant with large population impact on diabetes in Greenland |
title_fullStr |
A novel splice-affecting HNF1A variant with large population impact on diabetes in Greenland |
title_full_unstemmed |
A novel splice-affecting HNF1A variant with large population impact on diabetes in Greenland |
title_sort |
novel splice-affecting hnf1a variant with large population impact on diabetes in greenland |
publishDate |
2023 |
url |
https://curis.ku.dk/portal/da/publications/a-novel-spliceaffecting-hnf1a-variant-with-large-population-impact-on-diabetes-in-greenland(82baefb4-002f-4242-bba3-9122f074ca79).html https://doi.org/10.1016/j.lanepe.2022.100529 https://curis.ku.dk/ws/files/331863755/1_s2.0_S2666776222002253_main.pdf |
geographic |
Greenland |
geographic_facet |
Greenland |
genre |
Greenland greenlandic inuit |
genre_facet |
Greenland greenlandic inuit |
op_source |
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 2023 , ' A novel splice-affecting HNF1A variant with large population impact on diabetes in Greenland ' , The Lancet Regional Health - Europe , vol. 24 , 100529 . https://doi.org/10.1016/j.lanepe.2022.100529 |
op_rights |
info:eu-repo/semantics/openAccess |
op_doi |
https://doi.org/10.1016/j.lanepe.2022.100529 |
container_title |
The Lancet Regional Health - Europe |
container_volume |
24 |
container_start_page |
100529 |
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1801376184271896576 |