Increased DNA methylation variability in type 1 diabetes across three immune effector cell types

The incidence of type 1 diabetes (T1D) has substantially increased over the past decade, suggesting a role for non-genetic factors such as epigenetic mechanisms in disease development. Here we present an epigenome-wide association study across 406,365 CpGs in 52 monozygotic twin pairs discordant for...

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Vydané v:	Nature communications Ročník 7; číslo 1; s. 13555 - 11
Hlavní autori:	Paul, Dirk S., Teschendorff, Andrew E., Dang, Mary A.N., Lowe, Robert, Hawa, Mohammed I., Ecker, Simone, Beyan, Huriya, Cunningham, Stephanie, Fouts, Alexandra R., Ramelius, Anita, Burden, Frances, Farrow, Samantha, Rowlston, Sophia, Rehnstrom, Karola, Frontini, Mattia, Downes, Kate, Busche, Stephan, Cheung, Warren A., Ge, Bing, Simon, Marie-Michelle, Bujold, David, Kwan, Tony, Bourque, Guillaume, Datta, Avik, Lowy, Ernesto, Clarke, Laura, Flicek, Paul, Libertini, Emanuele, Heath, Simon, Gut, Marta, Gut, Ivo G, Ouwehand, Willem H., Pastinen, Tomi, Soranzo, Nicole, Hofer, Sabine E., Karges, Beate, Meissner, Thomas, Boehm, Bernhard O., Cilio, Corrado, Elding Larsson, Helena, Lernmark, Åke, Steck, Andrea K., Rakyan, Vardhman K., Beck, Stephan, Leslie, R. David
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	London Nature Publishing Group UK 29.11.2016 Nature Publishing Group Nature Portfolio
Predmet:	631/208/177 631/208/248/144 692/699/2743/137/1418 Biology Cancer Cell cycle Cell division Clinical Medicine College campuses CpG Islands - genetics Diabetes Diabetes Mellitus, Type 1 - genetics Diabetes Mellitus, Type 1 - immunology Disease Disease genetics DNA methylation DNA Methylation - genetics Endocrinology Endocrinology and Diabetes Endokrinologi och diabetes Epigenetics Epigenomics Fetal Blood - metabolism Gene expression Genetic factors Genomes Genomics Health care Humanities and Social Sciences Humans Klinisk medicin Medical and Health Sciences Medicin och hälsovetenskap Medicine Molecular Sequence Annotation multidisciplinary Pathogenesis Pediatrics Science Science (multidisciplinary) Time Factors Twins, Monozygotic - genetics Type 1 diabetes Canada Montreal Quebec Canada Singapore United Kingdom > UK Germany Spain
ISSN:	2041-1723, 2041-1723
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Abstract	The incidence of type 1 diabetes (T1D) has substantially increased over the past decade, suggesting a role for non-genetic factors such as epigenetic mechanisms in disease development. Here we present an epigenome-wide association study across 406,365 CpGs in 52 monozygotic twin pairs discordant for T1D in three immune effector cell types. We observe a substantial enrichment of differentially variable CpG positions (DVPs) in T1D twins when compared with their healthy co-twins and when compared with healthy, unrelated individuals. These T1D-associated DVPs are found to be temporally stable and enriched at gene regulatory elements. Integration with cell type-specific gene regulatory circuits highlight pathways involved in immune cell metabolism and the cell cycle, including mTOR signalling. Evidence from cord blood of newborns who progress to overt T1D suggests that the DVPs likely emerge after birth. Our findings, based on 772 methylomes, implicate epigenetic changes that could contribute to disease pathogenesis in T1D. The incidence of type 1 diabetes is increasing, potentially implicating non-genetic factors. Here the authors conduct an epigenome-wide association study in disease-discordant twins and find increased DNA methylation variability at genes associated with immune cell metabolism and the cell cycle.
AbstractList	The incidence of type 1 diabetes (T1D) has substantially increased over the past decade, suggesting a role for non-genetic factors such as epigenetic mechanisms in disease development. Here we present an epigenome-wide association study across 406,365 CpGs in 52 monozygotic twin pairs discordant for T1D in three immune effector cell types. We observe a substantial enrichment of differentially variable CpG positions (DVPs) in T1D twins when compared with their healthy co-twins and when compared with healthy, unrelated individuals. These T1D-associated DVPs are found to be temporally stable and enriched at gene regulatory elements. Integration with cell type-specific gene regulatory circuits highlight pathways involved in immune cell metabolism and the cell cycle, including mTOR signalling. Evidence from cord blood of newborns who progress to overt T1D suggests that the DVPs likely emerge after birth. Our findings, based on 772 methylomes, implicate epigenetic changes that could contribute to disease pathogenesis in T1D. The incidence of type 1 diabetes is increasing, potentially implicating non-genetic factors. Here the authors conduct an epigenome-wide association study in disease-discordant twins and find increased DNA methylation variability at genes associated with immune cell metabolism and the cell cycle. The incidence of type 1 diabetes (T1D) has substantially increased over the past decade, suggesting a role for non-genetic factors such as epigenetic mechanisms in disease development. Here we present an epigenome-wide association study across 406,365 CpGs in 52 monozygotic twin pairs discordant for T1D in three immune effector cell types. We observe a substantial enrichment of differentially variable CpG positions (DVPs) in T1D twins when compared with their healthy co-twins and when compared with healthy, unrelated individuals. These T1D-associated DVPs are found to be temporally stable and enriched at gene regulatory elements. Integration with cell type-specific gene regulatory circuits highlight pathways involved in immune cell metabolism and the cell cycle, including mTOR signalling. Evidence from cord blood of newborns who progress to overt T1D suggests that the DVPs likely emerge after birth. Our findings, based on 772 methylomes, implicate epigenetic changes that could contribute to disease pathogenesis in T1D. The incidence of type 1 diabetes is increasing, potentially implicating non-genetic factors. Here the authors conduct an epigenome-wide association study in disease-discordant twins and find increased DNA methylation variability at genes associated with immune cell metabolism and the cell cycle. The incidence of type 1 diabetes (T1D) has substantially increased over the past decade, suggesting a role for non-genetic factors such as epigenetic mechanisms in disease development. Here we present an epigenome-wide association study across 406,365 CpGs in 52 monozygotic twin pairs discordant for T1D in three immune effector cell types. We observe a substantial enrichment of differentially variable CpG positions (DVPs) in T1D twins when compared with their healthy co-twins and when compared with healthy, unrelated individuals. These T1D-associated DVPs are found to be temporally stable and enriched at gene regulatory elements. Integration with cell type-specific gene regulatory circuits highlight pathways involved in immune cell metabolism and the cell cycle, including mTOR signalling. Evidence from cord blood of newborns who progress to overt T1D suggests that the DVPs likely emerge after birth. Our findings, based on 772 methylomes, implicate epigenetic changes that could contribute to disease pathogenesis in T1D. This work was funded by the EU-FP7 project BLUEPRINT (282510) and the Wellcome Trust (99148). The incidence of type 1 diabetes (T1D) has substantially increased over the past decade, suggesting a role for non-genetic factors such as epigenetic mechanisms in disease development. Here we present an epigenome-wide association study across 406,365 CpGs in 52 monozygotic twin pairs discordant for T1D in three immune effector cell types. We observe a substantial enrichment of differentially variable CpG positions (DVPs) in T1D twins when compared with their healthy co-twins and when compared with healthy, unrelated individuals. These T1D-associated DVPs are found to be temporally stable and enriched at gene regulatory elements. Integration with cell type-specific gene regulatory circuits highlight pathways involved in immune cell metabolism and the cell cycle, including mTOR signalling. Evidence from cord blood of newborns who progress to overt T1D suggests that the DVPs likely emerge after birth. Our findings, based on 772 methylomes, implicate epigenetic changes that could contribute to disease pathogenesis in T1D.The incidence of type 1 diabetes (T1D) has substantially increased over the past decade, suggesting a role for non-genetic factors such as epigenetic mechanisms in disease development. Here we present an epigenome-wide association study across 406,365 CpGs in 52 monozygotic twin pairs discordant for T1D in three immune effector cell types. We observe a substantial enrichment of differentially variable CpG positions (DVPs) in T1D twins when compared with their healthy co-twins and when compared with healthy, unrelated individuals. These T1D-associated DVPs are found to be temporally stable and enriched at gene regulatory elements. Integration with cell type-specific gene regulatory circuits highlight pathways involved in immune cell metabolism and the cell cycle, including mTOR signalling. Evidence from cord blood of newborns who progress to overt T1D suggests that the DVPs likely emerge after birth. Our findings, based on 772 methylomes, implicate epigenetic changes that could contribute to disease pathogenesis in T1D.
ArticleNumber	13555
Author	Bujold, David Kwan, Tony Leslie, R. David Pastinen, Tomi Elding Larsson, Helena Meissner, Thomas Fouts, Alexandra R. Beck, Stephan Cilio, Corrado Frontini, Mattia Ge, Bing Cheung, Warren A. Gut, Marta Farrow, Samantha Busche, Stephan Simon, Marie-Michelle Paul, Dirk S. Gut, Ivo G Steck, Andrea K. Ramelius, Anita Datta, Avik Karges, Beate Bourque, Guillaume Hofer, Sabine E. Teschendorff, Andrew E. Rehnstrom, Karola Rowlston, Sophia Hawa, Mohammed I. Downes, Kate Rakyan, Vardhman K. Boehm, Bernhard O. Burden, Frances Beyan, Huriya Clarke, Laura Cunningham, Stephanie Dang, Mary A.N. Flicek, Paul Libertini, Emanuele Ecker, Simone Lowe, Robert Heath, Simon Lernmark, Åke Ouwehand, Willem H. Lowy, Ernesto Soranzo, Nicole
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givenname: Warren A. surname: Cheung fullname: Cheung, Warren A. organization: Department of Human Genetics, McGill University, McGill University and Genome Quebec Innovation Centre – sequence: 19 givenname: Bing surname: Ge fullname: Ge, Bing organization: Department of Human Genetics, McGill University, McGill University and Genome Quebec Innovation Centre – sequence: 20 givenname: Marie-Michelle surname: Simon fullname: Simon, Marie-Michelle organization: Department of Human Genetics, McGill University, McGill University and Genome Quebec Innovation Centre – sequence: 21 givenname: David surname: Bujold fullname: Bujold, David organization: Department of Human Genetics, McGill University, McGill University and Genome Quebec Innovation Centre – sequence: 22 givenname: Tony surname: Kwan fullname: Kwan, Tony organization: Department of Human Genetics, McGill University, McGill University and Genome Quebec Innovation Centre – sequence: 23 givenname: Guillaume surname: Bourque fullname: 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BackLink	https://www.ncbi.nlm.nih.gov/pubmed/27898055$$D View this record in MEDLINE/PubMed
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CorporateAuthor	Lunds universitet Profile areas and other strong research environments Department of Clinical Sciences, Malmö Lund University Celiac Disease and Diabetes Unit Diabetes - Immunovirology Strategiska forskningsområden (SFO) Diabetes - immunovirologi EXODIAB: Excellence of Diabetes Research in Sweden Faculty of Medicine Celiaki och diabetes Strategic research areas (SRA) Medicinska fakulteten Pediatrisk endokrinologi Profilområden och andra starka forskningsmiljöer Institutionen för kliniska vetenskaper, Malmö Paediatric Endocrinology
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Snippet	The incidence of type 1 diabetes (T1D) has substantially increased over the past decade, suggesting a role for non-genetic factors such as epigenetic... The incidence of type 1 diabetes is increasing, potentially implicating non-genetic factors. Here the authors conduct an epigenome-wide association study in...
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SubjectTerms	631/208/177 631/208/248/144 692/699/2743/137/1418 Biology Cancer Cell cycle Cell division Clinical Medicine College campuses CpG Islands - genetics Diabetes Diabetes Mellitus, Type 1 - genetics Diabetes Mellitus, Type 1 - immunology Disease Disease genetics DNA methylation DNA Methylation - genetics Endocrinology Endocrinology and Diabetes Endokrinologi och diabetes Epigenetics Epigenomics Fetal Blood - metabolism Gene expression Genetic factors Genomes Genomics Health care Humanities and Social Sciences Humans Klinisk medicin Medical and Health Sciences Medicin och hälsovetenskap Medicine Molecular Sequence Annotation multidisciplinary Pathogenesis Pediatrics Science Science (multidisciplinary) Time Factors Twins, Monozygotic - genetics Type 1 diabetes
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Title	Increased DNA methylation variability in type 1 diabetes across three immune effector cell types
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