Enhanced resolution profiling in twins reveals differential methylation signatures of type 2 diabetes with links to its complications

Colette Christiansen; Louis Potier; Tiphaine C. Martin; Sergio Villicaña; Juan E. Castillo-Fernandez; Massimo Mangino; Cristina Menni; Pei Chien Tsai; Purdey J. Campbell; Shelby Mullin; Juan R. Ordoñana; Olga Monteagudo; Perminder S. Sachdev; Karen A. Mather; Julian N. Trollor; Kirsi H. Pietilainen; Miina Ollikainen; Christine Dalgård; Kirsten Kyvik; Kaare Christensen; Jenny van Dongen; Gonneke Willemsen; Dorret I. Boomsma; Patrik K.E. Magnusson; Nancy L. Pedersen; Scott G. Wilson; Elin Grundberg; Tim D. Spector; Jordana T. Bell

doi:10.1016/j.ebiom.2024.105096

Enhanced resolution profiling in twins reveals differential methylation signatures of type 2 diabetes with links to its complications

Colette Christiansen^*
, Louis Potier
, Tiphaine C. Martin
, Sergio Villicaña
, Juan E. Castillo-Fernandez
, Massimo Mangino
, Cristina Menni
, Pei Chien Tsai
, Purdey J. Campbell
, Shelby Mullin
, Juan R. Ordoñana
, Olga Monteagudo
, Perminder S. Sachdev
, Karen A. Mather
, Julian N. Trollor
, Kirsi H. Pietilainen
, Miina Ollikainen
, Christine Dalgård
, Kirsten Kyvik
, Kaare Christensen

Jenny van Dongen, Gonneke Willemsen, Dorret I. Boomsma, Patrik K.E. Magnusson, Nancy L. Pedersen, Scott G. Wilson, Elin Grundberg, Tim D. Spector, Jordana T. Bell^*

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

Background: Type 2 diabetes (T2D) susceptibility is influenced by genetic and environmental factors. Previous findings suggest DNA methylation as a potential mechanism in T2D pathogenesis and progression. Methods: We profiled DNA methylation in 248 blood samples from participants of European ancestry from 7 twin cohorts using a methylation sequencing platform targeting regulatory genomic regions encompassing 2,048,698 CpG sites. Findings: We find and replicate 3 previously unreported T2D differentially methylated CpG positions (T2D-DMPs) at FDR 5% in RGL3, NGB and OTX2, and 20 signals at FDR 25%, of which 14 replicated. Integrating genetic variation and T2D-discordant monozygotic twin analyses, we identify both genetic-based and genetic-independent T2D-DMPs. The signals annotate to genes with established GWAS and EWAS links to T2D and its complications, including blood pressure (RGL3) and eye disease (OTX2). Interpretation: The results help to improve our understanding of T2D disease pathogenesis and progression and may provide biomarkers for its complications. Funding: Funding acknowledgements for each cohort can be found in the Supplementary Note.

Original language	English
Article number	105096
Pages (from-to)	1-18
Number of pages	18
Journal	Ebiomedicine
Volume	103
Early online date	3 Apr 2024
DOIs	https://doi.org/10.1016/j.ebiom.2024.105096
Publication status	Published - May 2024

Bibliographical note

Publisher Copyright:
© 2024 The Author(s)

Funding

Funding acknowledgements for each cohort can be found in the Supplementary Note. CC was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London and/or the NIHR Clinical Research Facility. This project also received support from the JPI ERA-HDHL DIMENSION project and UK Biological Sciences Research Council (BBSRC, BB/S020845/1 and BB/T019980/1 to JTB). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.

Funders	Funder number
NIHR Sheffield Clinical Research Facility
National Institute for Health and Care Research
Biological Sciences Research Council
Biotechnology and Biological Sciences Research Council	BB/S020845/1, BB/T019980/1

Keywords

DNA methylation
Genetics
Twins
Type 2 diabetes

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10.1016/j.ebiom.2024.105096

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Christiansen, C., Potier, L., Martin, T. C., Villicaña, S., Castillo-Fernandez, J. E., Mangino, M., Menni, C., Tsai, P. C., Campbell, P. J., Mullin, S., Ordoñana, J. R., Monteagudo, O., Sachdev, P. S., Mather, K. A., Trollor, J. N., Pietilainen, K. H., Ollikainen, M., Dalgård, C., Kyvik, K., ... Bell, J. T. (2024). Enhanced resolution profiling in twins reveals differential methylation signatures of type 2 diabetes with links to its complications. Ebiomedicine, 103, 1-18. Article 105096. https://doi.org/10.1016/j.ebiom.2024.105096

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title = "Enhanced resolution profiling in twins reveals differential methylation signatures of type 2 diabetes with links to its complications",

abstract = "Background: Type 2 diabetes (T2D) susceptibility is influenced by genetic and environmental factors. Previous findings suggest DNA methylation as a potential mechanism in T2D pathogenesis and progression. Methods: We profiled DNA methylation in 248 blood samples from participants of European ancestry from 7 twin cohorts using a methylation sequencing platform targeting regulatory genomic regions encompassing 2,048,698 CpG sites. Findings: We find and replicate 3 previously unreported T2D differentially methylated CpG positions (T2D-DMPs) at FDR 5\% in RGL3, NGB and OTX2, and 20 signals at FDR 25\%, of which 14 replicated. Integrating genetic variation and T2D-discordant monozygotic twin analyses, we identify both genetic-based and genetic-independent T2D-DMPs. The signals annotate to genes with established GWAS and EWAS links to T2D and its complications, including blood pressure (RGL3) and eye disease (OTX2). Interpretation: The results help to improve our understanding of T2D disease pathogenesis and progression and may provide biomarkers for its complications. Funding: Funding acknowledgements for each cohort can be found in the Supplementary Note.",

keywords = "DNA methylation, Genetics, Twins, Type 2 diabetes",

author = "Colette Christiansen and Louis Potier and Martin, \{Tiphaine C.\} and Sergio Villica{\~n}a and Castillo-Fernandez, \{Juan E.\} and Massimo Mangino and Cristina Menni and Tsai, \{Pei Chien\} and Campbell, \{Purdey J.\} and Shelby Mullin and Ordo{\~n}ana, \{Juan R.\} and Olga Monteagudo and Sachdev, \{Perminder S.\} and Mather, \{Karen A.\} and Trollor, \{Julian N.\} and Pietilainen, \{Kirsi H.\} and Miina Ollikainen and Christine Dalg{\aa}rd and Kirsten Kyvik and Kaare Christensen and \{van Dongen\}, Jenny and Gonneke Willemsen and Boomsma, \{Dorret I.\} and Magnusson, \{Patrik K.E.\} and Pedersen, \{Nancy L.\} and Wilson, \{Scott G.\} and Elin Grundberg and Spector, \{Tim D.\} and Bell, \{Jordana T.\}",

note = "Publisher Copyright: {\textcopyright} 2024 The Author(s)",

year = "2024",

month = may,

doi = "10.1016/j.ebiom.2024.105096",

language = "English",

volume = "103",

pages = "1--18",

journal = "Ebiomedicine",

issn = "2352-3964",

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Christiansen, C, Potier, L, Martin, TC, Villicaña, S, Castillo-Fernandez, JE, Mangino, M, Menni, C, Tsai, PC, Campbell, PJ, Mullin, S, Ordoñana, JR, Monteagudo, O, Sachdev, PS, Mather, KA, Trollor, JN, Pietilainen, KH, Ollikainen, M, Dalgård, C, Kyvik, K, Christensen, K, van Dongen, J, Willemsen, G, Boomsma, DI, Magnusson, PKE, Pedersen, NL, Wilson, SG, Grundberg, E, Spector, TD & Bell, JT 2024, 'Enhanced resolution profiling in twins reveals differential methylation signatures of type 2 diabetes with links to its complications', Ebiomedicine, vol. 103, 105096, pp. 1-18. https://doi.org/10.1016/j.ebiom.2024.105096

TY - JOUR

T1 - Enhanced resolution profiling in twins reveals differential methylation signatures of type 2 diabetes with links to its complications

AU - Christiansen, Colette

AU - Potier, Louis

AU - Martin, Tiphaine C.

AU - Villicaña, Sergio

AU - Castillo-Fernandez, Juan E.

AU - Mangino, Massimo

AU - Menni, Cristina

AU - Tsai, Pei Chien

AU - Campbell, Purdey J.

AU - Mullin, Shelby

AU - Ordoñana, Juan R.

AU - Monteagudo, Olga

AU - Sachdev, Perminder S.

AU - Mather, Karen A.

AU - Trollor, Julian N.

AU - Pietilainen, Kirsi H.

AU - Ollikainen, Miina

AU - Dalgård, Christine

AU - Kyvik, Kirsten

AU - Christensen, Kaare

AU - van Dongen, Jenny

AU - Willemsen, Gonneke

AU - Boomsma, Dorret I.

AU - Magnusson, Patrik K.E.

AU - Pedersen, Nancy L.

AU - Wilson, Scott G.

AU - Grundberg, Elin

AU - Spector, Tim D.

AU - Bell, Jordana T.

PY - 2024/5

Y1 - 2024/5

N2 - Background: Type 2 diabetes (T2D) susceptibility is influenced by genetic and environmental factors. Previous findings suggest DNA methylation as a potential mechanism in T2D pathogenesis and progression. Methods: We profiled DNA methylation in 248 blood samples from participants of European ancestry from 7 twin cohorts using a methylation sequencing platform targeting regulatory genomic regions encompassing 2,048,698 CpG sites. Findings: We find and replicate 3 previously unreported T2D differentially methylated CpG positions (T2D-DMPs) at FDR 5% in RGL3, NGB and OTX2, and 20 signals at FDR 25%, of which 14 replicated. Integrating genetic variation and T2D-discordant monozygotic twin analyses, we identify both genetic-based and genetic-independent T2D-DMPs. The signals annotate to genes with established GWAS and EWAS links to T2D and its complications, including blood pressure (RGL3) and eye disease (OTX2). Interpretation: The results help to improve our understanding of T2D disease pathogenesis and progression and may provide biomarkers for its complications. Funding: Funding acknowledgements for each cohort can be found in the Supplementary Note.

AB - Background: Type 2 diabetes (T2D) susceptibility is influenced by genetic and environmental factors. Previous findings suggest DNA methylation as a potential mechanism in T2D pathogenesis and progression. Methods: We profiled DNA methylation in 248 blood samples from participants of European ancestry from 7 twin cohorts using a methylation sequencing platform targeting regulatory genomic regions encompassing 2,048,698 CpG sites. Findings: We find and replicate 3 previously unreported T2D differentially methylated CpG positions (T2D-DMPs) at FDR 5% in RGL3, NGB and OTX2, and 20 signals at FDR 25%, of which 14 replicated. Integrating genetic variation and T2D-discordant monozygotic twin analyses, we identify both genetic-based and genetic-independent T2D-DMPs. The signals annotate to genes with established GWAS and EWAS links to T2D and its complications, including blood pressure (RGL3) and eye disease (OTX2). Interpretation: The results help to improve our understanding of T2D disease pathogenesis and progression and may provide biomarkers for its complications. Funding: Funding acknowledgements for each cohort can be found in the Supplementary Note.

KW - DNA methylation

KW - Genetics

KW - Twins

KW - Type 2 diabetes

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UR - https://www.scopus.com/pages/publications/85189532796#tab=citedBy

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DO - 10.1016/j.ebiom.2024.105096

M3 - Article

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AN - SCOPUS:85189532796

SN - 2352-3964

VL - 103

SP - 1

EP - 18

JO - Ebiomedicine

JF - Ebiomedicine

M1 - 105096

ER -

Enhanced resolution profiling in twins reveals differential methylation signatures of type 2 diabetes with links to its complications

Abstract

Bibliographical note

Funding

Keywords

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