Epigenome-wide association study on the plasma metabolome suggests self-regulation of the glycine and serine pathway through DNA methylation

Jiafei Wu; Victoria Palasantzas; Sergio Andreu-Sánchez; Torsten Plösch; Sam Leonard; Shuang Li; Marc Jan Bonder; Harm-Jan Westra; Joyce van Meurs; Mohsen Ghanbari; Lude Franke; Alexandra Zhernakova; Jingyuan Fu; Joanne A Hoogerland; Daria V Zhernakova

doi:10.1186/s13148-024-01718-7

Epigenome-wide association study on the plasma metabolome suggests self-regulation of the glycine and serine pathway through DNA methylation

Jiafei Wu, Victoria Palasantzas, Sergio Andreu-Sánchez, Torsten Plösch, Sam Leonard, Shuang Li, Marc Jan Bonder, Harm-Jan Westra, Joyce van Meurs, Mohsen Ghanbari, Lude Franke, Alexandra Zhernakova, Jingyuan Fu, Joanne A Hoogerland^*, Daria V Zhernakova^*

^*Corresponding author for this work

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

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Abstract

BACKGROUND: The plasma metabolome reflects the physiological state of various biological processes and can serve as a proxy for disease risk. Plasma metabolite variation, influenced by genetic and epigenetic mechanisms, can also affect the cellular microenvironment and blood cell epigenetics. The interplay between the plasma metabolome and the blood cell epigenome remains elusive. In this study, we performed an epigenome-wide association study (EWAS) of 1183 plasma metabolites in 693 participants from the LifeLines-DEEP cohort and investigated the causal relationships in DNA methylation-metabolite associations using bidirectional Mendelian randomization and mediation analysis.

RESULTS: After rigorously adjusting for potential confounders, including genetics, we identified five robust associations between two plasma metabolites (L-serine and glycine) and three CpG sites located in two independent genomic regions (cg14476101 and cg16246545 in PHGDH and cg02711608 in SLC1A5) at a false discovery rate of less than 0.05. Further analysis revealed a complex bidirectional relationship between plasma glycine/serine levels and DNA methylation. Moreover, we observed a strong mediating role of DNA methylation in the effect of glycine/serine on the expression of their metabolism/transport genes, with the proportion of the mediated effect ranging from 11.8 to 54.3%. This result was also replicated in an independent population-based cohort, the Rotterdam Study. To validate our findings, we conducted in vitro cell studies which confirmed the mediating role of DNA methylation in the regulation of PHGDH gene expression.

CONCLUSIONS: Our findings reveal a potential feedback mechanism in which glycine and serine regulate gene expression through DNA methylation.

Original language	English
Article number	104
Number of pages	16
Journal	Clinical Epigenetics
Volume	16
DOIs	https://doi.org/10.1186/s13148-024-01718-7
Publication status	Published - 13-Aug-2024

Keywords

Humans
Glycine/blood
Serine/blood
DNA Methylation/genetics
Male
Female
Genome-Wide Association Study/methods
Metabolome/genetics
Epigenesis, Genetic/genetics
Middle Aged
CpG Islands/genetics
Epigenome/genetics
Adult
Aged
Mendelian Randomization Analysis

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Epigenome-wide association study on the plasma metabolome suggests self-regulation of the glycine and serine pathway through DNA methylationFinal publisher's version, 1.56 MBLicence: CC BY-NC-ND

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Wu, J., Palasantzas, V., Andreu-Sánchez, S., Plösch, T., Leonard, S., Li, S., Bonder, M. J., Westra, H.-J., van Meurs, J., Ghanbari, M., Franke, L., Zhernakova, A., Fu, J., Hoogerland, J. A., & Zhernakova, D. V. (2024). Epigenome-wide association study on the plasma metabolome suggests self-regulation of the glycine and serine pathway through DNA methylation. Clinical Epigenetics, 16, Article 104. https://doi.org/10.1186/s13148-024-01718-7

@article{d09bc8ed6ac040db8a691db14bf0d463,

title = "Epigenome-wide association study on the plasma metabolome suggests self-regulation of the glycine and serine pathway through DNA methylation",

abstract = "BACKGROUND: The plasma metabolome reflects the physiological state of various biological processes and can serve as a proxy for disease risk. Plasma metabolite variation, influenced by genetic and epigenetic mechanisms, can also affect the cellular microenvironment and blood cell epigenetics. The interplay between the plasma metabolome and the blood cell epigenome remains elusive. In this study, we performed an epigenome-wide association study (EWAS) of 1183 plasma metabolites in 693 participants from the LifeLines-DEEP cohort and investigated the causal relationships in DNA methylation-metabolite associations using bidirectional Mendelian randomization and mediation analysis.RESULTS: After rigorously adjusting for potential confounders, including genetics, we identified five robust associations between two plasma metabolites (L-serine and glycine) and three CpG sites located in two independent genomic regions (cg14476101 and cg16246545 in PHGDH and cg02711608 in SLC1A5) at a false discovery rate of less than 0.05. Further analysis revealed a complex bidirectional relationship between plasma glycine/serine levels and DNA methylation. Moreover, we observed a strong mediating role of DNA methylation in the effect of glycine/serine on the expression of their metabolism/transport genes, with the proportion of the mediated effect ranging from 11.8 to 54.3%. This result was also replicated in an independent population-based cohort, the Rotterdam Study. To validate our findings, we conducted in vitro cell studies which confirmed the mediating role of DNA methylation in the regulation of PHGDH gene expression.CONCLUSIONS: Our findings reveal a potential feedback mechanism in which glycine and serine regulate gene expression through DNA methylation.",

keywords = "Humans, Glycine/blood, Serine/blood, DNA Methylation/genetics, Male, Female, Genome-Wide Association Study/methods, Metabolome/genetics, Epigenesis, Genetic/genetics, Middle Aged, CpG Islands/genetics, Epigenome/genetics, Adult, Aged, Mendelian Randomization Analysis",

author = "Jiafei Wu and Victoria Palasantzas and Sergio Andreu-S{\'a}nchez and Torsten Pl{\"o}sch and Sam Leonard and Shuang Li and Bonder, {Marc Jan} and Harm-Jan Westra and {van Meurs}, Joyce and Mohsen Ghanbari and Lude Franke and Alexandra Zhernakova and Jingyuan Fu and Hoogerland, {Joanne A} and Zhernakova, {Daria V}",

note = "{\textcopyright} 2024. The Author(s).",

year = "2024",

month = aug,

day = "13",

doi = "10.1186/s13148-024-01718-7",

language = "English",

volume = "16",

journal = "Clinical Epigenetics",

issn = "1868-7075",

publisher = "BMC",

}

Wu, J , Palasantzas, V , Andreu-Sánchez, S , Plösch, T, Leonard, S, Li, S, Bonder, MJ , Westra, H-J, van Meurs, J, Ghanbari, M, Franke, L , Zhernakova, A , Fu, J , Hoogerland, JA & Zhernakova, DV 2024, 'Epigenome-wide association study on the plasma metabolome suggests self-regulation of the glycine and serine pathway through DNA methylation', Clinical Epigenetics, vol. 16, 104. https://doi.org/10.1186/s13148-024-01718-7

TY - JOUR

T1 - Epigenome-wide association study on the plasma metabolome suggests self-regulation of the glycine and serine pathway through DNA methylation

AU - Wu, Jiafei

AU - Palasantzas, Victoria

AU - Andreu-Sánchez, Sergio

AU - Plösch, Torsten

AU - Leonard, Sam

AU - Li, Shuang

AU - Bonder, Marc Jan

AU - Westra, Harm-Jan

AU - van Meurs, Joyce

AU - Ghanbari, Mohsen

AU - Franke, Lude

AU - Zhernakova, Alexandra

AU - Fu, Jingyuan

AU - Hoogerland, Joanne A

AU - Zhernakova, Daria V

PY - 2024/8/13

Y1 - 2024/8/13

N2 - BACKGROUND: The plasma metabolome reflects the physiological state of various biological processes and can serve as a proxy for disease risk. Plasma metabolite variation, influenced by genetic and epigenetic mechanisms, can also affect the cellular microenvironment and blood cell epigenetics. The interplay between the plasma metabolome and the blood cell epigenome remains elusive. In this study, we performed an epigenome-wide association study (EWAS) of 1183 plasma metabolites in 693 participants from the LifeLines-DEEP cohort and investigated the causal relationships in DNA methylation-metabolite associations using bidirectional Mendelian randomization and mediation analysis.RESULTS: After rigorously adjusting for potential confounders, including genetics, we identified five robust associations between two plasma metabolites (L-serine and glycine) and three CpG sites located in two independent genomic regions (cg14476101 and cg16246545 in PHGDH and cg02711608 in SLC1A5) at a false discovery rate of less than 0.05. Further analysis revealed a complex bidirectional relationship between plasma glycine/serine levels and DNA methylation. Moreover, we observed a strong mediating role of DNA methylation in the effect of glycine/serine on the expression of their metabolism/transport genes, with the proportion of the mediated effect ranging from 11.8 to 54.3%. This result was also replicated in an independent population-based cohort, the Rotterdam Study. To validate our findings, we conducted in vitro cell studies which confirmed the mediating role of DNA methylation in the regulation of PHGDH gene expression.CONCLUSIONS: Our findings reveal a potential feedback mechanism in which glycine and serine regulate gene expression through DNA methylation.

AB - BACKGROUND: The plasma metabolome reflects the physiological state of various biological processes and can serve as a proxy for disease risk. Plasma metabolite variation, influenced by genetic and epigenetic mechanisms, can also affect the cellular microenvironment and blood cell epigenetics. The interplay between the plasma metabolome and the blood cell epigenome remains elusive. In this study, we performed an epigenome-wide association study (EWAS) of 1183 plasma metabolites in 693 participants from the LifeLines-DEEP cohort and investigated the causal relationships in DNA methylation-metabolite associations using bidirectional Mendelian randomization and mediation analysis.RESULTS: After rigorously adjusting for potential confounders, including genetics, we identified five robust associations between two plasma metabolites (L-serine and glycine) and three CpG sites located in two independent genomic regions (cg14476101 and cg16246545 in PHGDH and cg02711608 in SLC1A5) at a false discovery rate of less than 0.05. Further analysis revealed a complex bidirectional relationship between plasma glycine/serine levels and DNA methylation. Moreover, we observed a strong mediating role of DNA methylation in the effect of glycine/serine on the expression of their metabolism/transport genes, with the proportion of the mediated effect ranging from 11.8 to 54.3%. This result was also replicated in an independent population-based cohort, the Rotterdam Study. To validate our findings, we conducted in vitro cell studies which confirmed the mediating role of DNA methylation in the regulation of PHGDH gene expression.CONCLUSIONS: Our findings reveal a potential feedback mechanism in which glycine and serine regulate gene expression through DNA methylation.

KW - Humans

KW - Glycine/blood

KW - Serine/blood

KW - DNA Methylation/genetics

KW - Male

KW - Female

KW - Genome-Wide Association Study/methods

KW - Metabolome/genetics

KW - Epigenesis, Genetic/genetics

KW - Middle Aged

KW - CpG Islands/genetics

KW - Epigenome/genetics

KW - Adult

KW - Aged

KW - Mendelian Randomization Analysis

U2 - 10.1186/s13148-024-01718-7

DO - 10.1186/s13148-024-01718-7

M3 - Article

C2 - 39138531

SN - 1868-7075

VL - 16

JO - Clinical Epigenetics

JF - Clinical Epigenetics

M1 - 104

ER -

Epigenome-wide association study on the plasma metabolome suggests self-regulation of the glycine and serine pathway through DNA methylation

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