Untangling the genetic link between type 1 and type 2 diabetes using functional genomics

Abstract There is evidence pointing towards shared etiological features between type 1 diabetes (T1D) and type 2 diabetes (T2D) despite both phenotypes being considered genetically distinct. However, the existence of shared genetic features for T1D and T2D remains complex and poorly defined. To bett...

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Autores principales:	Denis M. Nyaga, Mark H. Vickers, Craig Jefferies, Tayaza Fadason, Justin M. O’Sullivan
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f7b1a0eafe5444e09f62694b132ba805
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spelling	oai:doaj.org-article:f7b1a0eafe5444e09f62694b132ba8052021-12-02T16:15:05ZUntangling the genetic link between type 1 and type 2 diabetes using functional genomics10.1038/s41598-021-93346-x2045-2322https://doaj.org/article/f7b1a0eafe5444e09f62694b132ba8052021-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-93346-xhttps://doaj.org/toc/2045-2322Abstract There is evidence pointing towards shared etiological features between type 1 diabetes (T1D) and type 2 diabetes (T2D) despite both phenotypes being considered genetically distinct. However, the existence of shared genetic features for T1D and T2D remains complex and poorly defined. To better understand the link between T1D and T2D, we employed an integrated functional genomics approach involving extensive chromatin interaction data (Hi-C) and expression quantitative trait loci (eQTL) data to characterize the tissue-specific impacts of single nucleotide polymorphisms associated with T1D and T2D. We identified 195 pleiotropic genes that are modulated by tissue-specific spatial eQTLs associated with both T1D and T2D. The pleiotropic genes are enriched in inflammatory and metabolic pathways that include mitogen-activated protein kinase activity, pertussis toxin signaling, and the Parkinson’s disease pathway. We identified 8 regulatory elements within the TCF7L2 locus that modulate transcript levels of genes involved in immune regulation as well as genes important in the etiology of T2D. Despite the observed gene and pathway overlaps, there was no significant genetic correlation between variant effects on T1D and T2D risk using European ancestral summary data. Collectively, our findings support the hypothesis that T1D and T2D specific genetic variants act through genetic regulatory mechanisms to alter the regulation of common genes, and genes that co-locate in biological pathways, to mediate pleiotropic effects on disease development. Crucially, a high risk genetic profile for T1D alters biological pathways that increase the risk of developing both T1D and T2D. The same is not true for genetic profiles that increase the risk of developing T2D. The conversion of information on genetic susceptibility to the protein pathways that are altered provides an important resource for repurposing or designing novel therapies for the management of diabetes.Denis M. NyagaMark H. VickersCraig JefferiesTayaza FadasonJustin M. O’SullivanNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Denis M. Nyaga Mark H. Vickers Craig Jefferies Tayaza Fadason Justin M. O’Sullivan Untangling the genetic link between type 1 and type 2 diabetes using functional genomics
description	Abstract There is evidence pointing towards shared etiological features between type 1 diabetes (T1D) and type 2 diabetes (T2D) despite both phenotypes being considered genetically distinct. However, the existence of shared genetic features for T1D and T2D remains complex and poorly defined. To better understand the link between T1D and T2D, we employed an integrated functional genomics approach involving extensive chromatin interaction data (Hi-C) and expression quantitative trait loci (eQTL) data to characterize the tissue-specific impacts of single nucleotide polymorphisms associated with T1D and T2D. We identified 195 pleiotropic genes that are modulated by tissue-specific spatial eQTLs associated with both T1D and T2D. The pleiotropic genes are enriched in inflammatory and metabolic pathways that include mitogen-activated protein kinase activity, pertussis toxin signaling, and the Parkinson’s disease pathway. We identified 8 regulatory elements within the TCF7L2 locus that modulate transcript levels of genes involved in immune regulation as well as genes important in the etiology of T2D. Despite the observed gene and pathway overlaps, there was no significant genetic correlation between variant effects on T1D and T2D risk using European ancestral summary data. Collectively, our findings support the hypothesis that T1D and T2D specific genetic variants act through genetic regulatory mechanisms to alter the regulation of common genes, and genes that co-locate in biological pathways, to mediate pleiotropic effects on disease development. Crucially, a high risk genetic profile for T1D alters biological pathways that increase the risk of developing both T1D and T2D. The same is not true for genetic profiles that increase the risk of developing T2D. The conversion of information on genetic susceptibility to the protein pathways that are altered provides an important resource for repurposing or designing novel therapies for the management of diabetes.
format	article
author	Denis M. Nyaga Mark H. Vickers Craig Jefferies Tayaza Fadason Justin M. O’Sullivan
author_facet	Denis M. Nyaga Mark H. Vickers Craig Jefferies Tayaza Fadason Justin M. O’Sullivan
author_sort	Denis M. Nyaga
title	Untangling the genetic link between type 1 and type 2 diabetes using functional genomics
title_short	Untangling the genetic link between type 1 and type 2 diabetes using functional genomics
title_full	Untangling the genetic link between type 1 and type 2 diabetes using functional genomics
title_fullStr	Untangling the genetic link between type 1 and type 2 diabetes using functional genomics
title_full_unstemmed	Untangling the genetic link between type 1 and type 2 diabetes using functional genomics
title_sort	untangling the genetic link between type 1 and type 2 diabetes using functional genomics
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/f7b1a0eafe5444e09f62694b132ba805
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Untangling the genetic link between type 1 and type 2 diabetes using functional genomics

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