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 ChristensenJenny 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 › Journal article › Research › 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
Journal	EBioMedicine
Volume	103
ISSN	2352-3964
DOIs	https://doi.org/10.1016/j.ebiom.2024.105096
Publication status	Published - May 2024

Bibliographical note

Publisher Copyright:
© 2024 The Author(s)

Keywords

DNA methylation
Genetics
Twins
Type 2 diabetes

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Cite this

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, Article 105096. https://doi.org/10.1016/j.ebiom.2024.105096

@article{cf2dff55028a46b8ab1e2fc115da6ec4,

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",

journal = "EBioMedicine",

issn = "2352-3964",

publisher = "Lancet Publishing Group",

}

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. 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

U2 - 10.1016/j.ebiom.2024.105096

DO - 10.1016/j.ebiom.2024.105096

M3 - Journal article

C2 - 38574408

AN - SCOPUS:85189532796

SN - 2352-3964

VL - 103

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

Keywords

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