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Identification of novel high-impact recessively inherited type 2 diabetes risk variants in the Greenlandic population

AIMS/HYPOTHESIS: In a recent study using a standard additive genetic model, we identified a TBC1D4 loss-of-function variant with a large recessive impact on risk of type 2 diabetes in Greenlanders. The aim of the current study was to identify additional genetic variation underlying type 2 diabetes u...

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Autores principales: Grarup, Niels, Moltke, Ida, Andersen, Mette K., Bjerregaard, Peter, Larsen, Christina V. L., Dahl-Petersen, Inger K., Jørsboe, Emil, Tiwari, Hemant K., Hopkins, Scarlett E., Wiener, Howard W., Boyer, Bert B., Linneberg, Allan, Pedersen, Oluf, Jørgensen, Marit E., Albrechtsen, Anders, Hansen, Torben
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6096637/
https://www.ncbi.nlm.nih.gov/pubmed/29926116
http://dx.doi.org/10.1007/s00125-018-4659-2
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author Grarup, Niels
Moltke, Ida
Andersen, Mette K.
Bjerregaard, Peter
Larsen, Christina V. L.
Dahl-Petersen, Inger K.
Jørsboe, Emil
Tiwari, Hemant K.
Hopkins, Scarlett E.
Wiener, Howard W.
Boyer, Bert B.
Linneberg, Allan
Pedersen, Oluf
Jørgensen, Marit E.
Albrechtsen, Anders
Hansen, Torben
author_facet Grarup, Niels
Moltke, Ida
Andersen, Mette K.
Bjerregaard, Peter
Larsen, Christina V. L.
Dahl-Petersen, Inger K.
Jørsboe, Emil
Tiwari, Hemant K.
Hopkins, Scarlett E.
Wiener, Howard W.
Boyer, Bert B.
Linneberg, Allan
Pedersen, Oluf
Jørgensen, Marit E.
Albrechtsen, Anders
Hansen, Torben
author_sort Grarup, Niels
collection PubMed
description AIMS/HYPOTHESIS: In a recent study using a standard additive genetic model, we identified a TBC1D4 loss-of-function variant with a large recessive impact on risk of type 2 diabetes in Greenlanders. The aim of the current study was to identify additional genetic variation underlying type 2 diabetes using a recessive genetic model, thereby increasing the power to detect variants with recessive effects. METHODS: We investigated three cohorts of Greenlanders (B99, n = 1401; IHIT, n = 3115; and BBH, n = 547), which were genotyped using Illumina MetaboChip. Of the 4674 genotyped individuals passing quality control, 4648 had phenotype data available, and type 2 diabetes association analyses were performed for 317 individuals with type 2 diabetes and 2631 participants with normal glucose tolerance. Statistical association analyses were performed using a linear mixed model. RESULTS: Using a recessive genetic model, we identified two novel loci associated with type 2 diabetes in Greenlanders, namely rs870992 in ITGA1 on chromosome 5 (OR 2.79, p = 1.8 × 10(−8)), and rs16993330 upstream of LARGE1 on chromosome 22 (OR 3.52, p = 1.3 × 10(−7)). The LARGE1 variant did not reach the conventional threshold for genome-wide significance (p < 5 × 10(−8)) but did withstand a study-wide Bonferroni-corrected significance threshold. Both variants were common in Greenlanders, with minor allele frequencies of 23% and 16%, respectively, and were estimated to have large recessive effects on risk of type 2 diabetes in Greenlanders, compared with additively inherited variants previously observed in European populations. CONCLUSIONS/INTERPRETATION: We demonstrate the value of using a recessive genetic model in a historically small and isolated population to identify genetic risk variants. Our findings give new insights into the genetic architecture of type 2 diabetes, and further support the existence of high-effect genetic risk factors of potential clinical relevance, particularly in isolated populations. DATA AVAILABILITY: The Greenlandic MetaboChip-genotype data are available at European Genome-Phenome Archive (EGA; https://ega-archive.org/) under the accession EGAS00001002641. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00125-018-4659-2) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
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spelling pubmed-60966372018-08-24 Identification of novel high-impact recessively inherited type 2 diabetes risk variants in the Greenlandic population Grarup, Niels Moltke, Ida Andersen, Mette K. Bjerregaard, Peter Larsen, Christina V. L. Dahl-Petersen, Inger K. Jørsboe, Emil Tiwari, Hemant K. Hopkins, Scarlett E. Wiener, Howard W. Boyer, Bert B. Linneberg, Allan Pedersen, Oluf Jørgensen, Marit E. Albrechtsen, Anders Hansen, Torben Diabetologia Article AIMS/HYPOTHESIS: In a recent study using a standard additive genetic model, we identified a TBC1D4 loss-of-function variant with a large recessive impact on risk of type 2 diabetes in Greenlanders. The aim of the current study was to identify additional genetic variation underlying type 2 diabetes using a recessive genetic model, thereby increasing the power to detect variants with recessive effects. METHODS: We investigated three cohorts of Greenlanders (B99, n = 1401; IHIT, n = 3115; and BBH, n = 547), which were genotyped using Illumina MetaboChip. Of the 4674 genotyped individuals passing quality control, 4648 had phenotype data available, and type 2 diabetes association analyses were performed for 317 individuals with type 2 diabetes and 2631 participants with normal glucose tolerance. Statistical association analyses were performed using a linear mixed model. RESULTS: Using a recessive genetic model, we identified two novel loci associated with type 2 diabetes in Greenlanders, namely rs870992 in ITGA1 on chromosome 5 (OR 2.79, p = 1.8 × 10(−8)), and rs16993330 upstream of LARGE1 on chromosome 22 (OR 3.52, p = 1.3 × 10(−7)). The LARGE1 variant did not reach the conventional threshold for genome-wide significance (p < 5 × 10(−8)) but did withstand a study-wide Bonferroni-corrected significance threshold. Both variants were common in Greenlanders, with minor allele frequencies of 23% and 16%, respectively, and were estimated to have large recessive effects on risk of type 2 diabetes in Greenlanders, compared with additively inherited variants previously observed in European populations. CONCLUSIONS/INTERPRETATION: We demonstrate the value of using a recessive genetic model in a historically small and isolated population to identify genetic risk variants. Our findings give new insights into the genetic architecture of type 2 diabetes, and further support the existence of high-effect genetic risk factors of potential clinical relevance, particularly in isolated populations. DATA AVAILABILITY: The Greenlandic MetaboChip-genotype data are available at European Genome-Phenome Archive (EGA; https://ega-archive.org/) under the accession EGAS00001002641. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00125-018-4659-2) contains peer-reviewed but unedited supplementary material, which is available to authorised users. Springer Berlin Heidelberg 2018-06-20 2018 /pmc/articles/PMC6096637/ /pubmed/29926116 http://dx.doi.org/10.1007/s00125-018-4659-2 Text en © The Author(s) 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Article
Grarup, Niels
Moltke, Ida
Andersen, Mette K.
Bjerregaard, Peter
Larsen, Christina V. L.
Dahl-Petersen, Inger K.
Jørsboe, Emil
Tiwari, Hemant K.
Hopkins, Scarlett E.
Wiener, Howard W.
Boyer, Bert B.
Linneberg, Allan
Pedersen, Oluf
Jørgensen, Marit E.
Albrechtsen, Anders
Hansen, Torben
Identification of novel high-impact recessively inherited type 2 diabetes risk variants in the Greenlandic population
title Identification of novel high-impact recessively inherited type 2 diabetes risk variants in the Greenlandic population
title_full Identification of novel high-impact recessively inherited type 2 diabetes risk variants in the Greenlandic population
title_fullStr Identification of novel high-impact recessively inherited type 2 diabetes risk variants in the Greenlandic population
title_full_unstemmed Identification of novel high-impact recessively inherited type 2 diabetes risk variants in the Greenlandic population
title_short Identification of novel high-impact recessively inherited type 2 diabetes risk variants in the Greenlandic population
title_sort identification of novel high-impact recessively inherited type 2 diabetes risk variants in the greenlandic population
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6096637/
https://www.ncbi.nlm.nih.gov/pubmed/29926116
http://dx.doi.org/10.1007/s00125-018-4659-2
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