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Effect of tissue-grouped regulatory variants associated to type 2 diabetes in related secondary outcomes

Genome-wide association studies have identified over five hundred loci that contribute to variation in type 2 diabetes (T2D), an established risk factor for many diseases. However, the mechanisms and extent through which these loci contribute to subsequent outcomes remain elusive. We hypothesized th...

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Autores principales: Hemerich, Daiane, Smit, Roelof A. J., Preuss, Michael, Stalbow, Lauren, van der Laan, Sander W., Asselbergs, Folkert W., van Setten, Jessica, Tragante, Vinicius
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9981672/
https://www.ncbi.nlm.nih.gov/pubmed/36864090
http://dx.doi.org/10.1038/s41598-023-30369-6
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author Hemerich, Daiane
Smit, Roelof A. J.
Preuss, Michael
Stalbow, Lauren
van der Laan, Sander W.
Asselbergs, Folkert W.
van Setten, Jessica
Tragante, Vinicius
author_facet Hemerich, Daiane
Smit, Roelof A. J.
Preuss, Michael
Stalbow, Lauren
van der Laan, Sander W.
Asselbergs, Folkert W.
van Setten, Jessica
Tragante, Vinicius
author_sort Hemerich, Daiane
collection PubMed
description Genome-wide association studies have identified over five hundred loci that contribute to variation in type 2 diabetes (T2D), an established risk factor for many diseases. However, the mechanisms and extent through which these loci contribute to subsequent outcomes remain elusive. We hypothesized that combinations of T2D-associated variants acting on tissue-specific regulatory elements might account for greater risk for tissue-specific outcomes, leading to diversity in T2D disease progression. We searched for T2D-associated variants acting on regulatory elements and expression quantitative trait loci (eQTLs) in nine tissues. We used T2D tissue-grouped variant sets as genetic instruments to conduct 2-Sample Mendelian Randomization (MR) in ten related outcomes whose risk is increased by T2D using the FinnGen cohort. We performed PheWAS analysis to investigate whether the T2D tissue-grouped variant sets had specific predicted disease signatures. We identified an average of 176 variants acting in nine tissues implicated in T2D, and an average of 30 variants acting on regulatory elements that are unique to the nine tissues of interest. In 2-Sample MR analyses, all subsets of regulatory variants acting in different tissues were associated with increased risk of the ten secondary outcomes studied on similar levels. No tissue-grouped variant set was associated with an outcome significantly more than other tissue-grouped variant sets. We did not identify different disease progression profiles based on tissue-specific regulatory and transcriptome information. Bigger sample sizes and other layers of regulatory information in critical tissues may help identify subsets of T2D variants that are implicated in certain secondary outcomes, uncovering system-specific disease progression.
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spelling pubmed-99816722023-03-04 Effect of tissue-grouped regulatory variants associated to type 2 diabetes in related secondary outcomes Hemerich, Daiane Smit, Roelof A. J. Preuss, Michael Stalbow, Lauren van der Laan, Sander W. Asselbergs, Folkert W. van Setten, Jessica Tragante, Vinicius Sci Rep Article Genome-wide association studies have identified over five hundred loci that contribute to variation in type 2 diabetes (T2D), an established risk factor for many diseases. However, the mechanisms and extent through which these loci contribute to subsequent outcomes remain elusive. We hypothesized that combinations of T2D-associated variants acting on tissue-specific regulatory elements might account for greater risk for tissue-specific outcomes, leading to diversity in T2D disease progression. We searched for T2D-associated variants acting on regulatory elements and expression quantitative trait loci (eQTLs) in nine tissues. We used T2D tissue-grouped variant sets as genetic instruments to conduct 2-Sample Mendelian Randomization (MR) in ten related outcomes whose risk is increased by T2D using the FinnGen cohort. We performed PheWAS analysis to investigate whether the T2D tissue-grouped variant sets had specific predicted disease signatures. We identified an average of 176 variants acting in nine tissues implicated in T2D, and an average of 30 variants acting on regulatory elements that are unique to the nine tissues of interest. In 2-Sample MR analyses, all subsets of regulatory variants acting in different tissues were associated with increased risk of the ten secondary outcomes studied on similar levels. No tissue-grouped variant set was associated with an outcome significantly more than other tissue-grouped variant sets. We did not identify different disease progression profiles based on tissue-specific regulatory and transcriptome information. Bigger sample sizes and other layers of regulatory information in critical tissues may help identify subsets of T2D variants that are implicated in certain secondary outcomes, uncovering system-specific disease progression. Nature Publishing Group UK 2023-03-02 /pmc/articles/PMC9981672/ /pubmed/36864090 http://dx.doi.org/10.1038/s41598-023-30369-6 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Hemerich, Daiane
Smit, Roelof A. J.
Preuss, Michael
Stalbow, Lauren
van der Laan, Sander W.
Asselbergs, Folkert W.
van Setten, Jessica
Tragante, Vinicius
Effect of tissue-grouped regulatory variants associated to type 2 diabetes in related secondary outcomes
title Effect of tissue-grouped regulatory variants associated to type 2 diabetes in related secondary outcomes
title_full Effect of tissue-grouped regulatory variants associated to type 2 diabetes in related secondary outcomes
title_fullStr Effect of tissue-grouped regulatory variants associated to type 2 diabetes in related secondary outcomes
title_full_unstemmed Effect of tissue-grouped regulatory variants associated to type 2 diabetes in related secondary outcomes
title_short Effect of tissue-grouped regulatory variants associated to type 2 diabetes in related secondary outcomes
title_sort effect of tissue-grouped regulatory variants associated to type 2 diabetes in related secondary outcomes
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9981672/
https://www.ncbi.nlm.nih.gov/pubmed/36864090
http://dx.doi.org/10.1038/s41598-023-30369-6
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