Differential DNA Methylation of the Serotonin Receptor Signaling and Glutamatergic Synapse Pathways in Adult Twins Born Preterm.

Overview

Authors: Carl Peter Vittrup Rasmussen¹, Marianne Nygaard¹, Morten Frost Nielsen², Mette Soerensen¹, Kaare Christensen¹, Qihua Tan^1,3

ORCID iDs: Marianne Nygaard, Mette Soerensen, Kaare Christensen, Qihua Tan

Epidemiology, Biostatistics and Biodemography, Department of Public Health, Faculty of Health Sciences, University of Southern Denmark, 5230 Odense, Denmark; (C.P.V.R.); (M.N.); (M.S.); (K.C.)
Research Unit of Endocrinology, Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, 5230 Odense, Denmark
Research Unit of Clinical Genetics, Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, 5230 Odense, Denmark

Institutions: University of Southern Denmark (Denmark)

Journal: Genes, volume 17, issue 6, article 683

Dates: received 4 May 2026; accepted 7 June 2026; published online 10 June 2026

Type: Research article · Language: English

License: CC BY

Identifiers: DOI 10.3390/genes17060683 · PMID 42353841 · PMCID PMC13299586 · OpenAlex W7164298803

Open access: gold, a free copy (OpenAlex)

Status: data only (how the code is found and verified)

Categories: genetics / omics (modality), human (organism), other condition (population)

Methods: Statistics, Smoothing, state filtering, decompositions

Keywords: epigenetics, preterm birth, serotonin receptor signaling pathway, glutamatergic synapse pathway

MeSH: DNA Methylation*, Premature Birth*, Receptors, Serotonin*, Synapses*, Adult, Epigenesis, Genetic, Female, Humans, Male, Middle Aged, Neurodevelopment, Receptors, AMPA, Signal Transduction, Twins, Monozygotic (* major topic)

Topic: Epigenetics and DNA Methylation (Molecular Biology, Biochemistry, Genetics and Molecular Biology), according to OpenAlex

Funding: Integrated research on Developmental determinants of Aging and Longevity (IDEAL) (259679)

Citations: not cited yet (Europe PMC); 41 references in the paper

Abstract

Background/Objectives: Early-life environment may influence long-term neurodevelopment through epigenetic regulation. Serotonergic and glutamatergic pathways are central to brain development and have been implicated in DNA methylation changes following prenatal adversity. In this study, we examined whether preterm birth (PTB) in birthweight-discordant twins is associated with differential DNA methylation in the serotonin receptor signaling pathway and the glutamatergic synapse pathway in adult twins. Methods: Genome-wide DNA methylation data were obtained from whole blood samples of 288 individuals (144 monozygotic birthweight-discordant twin pairs), including a younger cohort (140 individuals; mean age 33 years) and an older cohort (148 individuals; mean age 63 years). DNA methylation was measured using the Illumina HumanMethylation450 BeadChip. Linear models were fitted for association testing, adjusting for leukocyte composition and twin pair correlation. Pathway-level differential methylation was assessed using Rotation Gene Set Testing. Results: In the glutamatergic synapse pathway, no consistent directional enrichment of hypo- or hypermethylation was observed. However, gene-level analyses identified consistent hypomethylation of GRIA2 and GRIA4 across cohorts. In the serotonin receptor signaling pathway, the young cohort exhibited a mixed methylation pattern, whereas the old cohort showed significant enrichment of hypermethylation. At the gene level, HTR1A was hypomethylated in the young cohort but hypermethylated in the old cohort, indicating a cohort-dependent effect in the methylation patterns. Conclusions: These findings suggest that PTB is associated with long-term epigenetic variation in neurodevelopmentally relevant pathways, as reflected in blood cells. The results further indicate distinct methylation architectures across pathways, with more consistent pathway-level signals in the serotonergic system and more localized gene-level effects in the glutamatergic pathway.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

The paper links to its data and to no code of its authors: see the Data section.

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Data

Data links

ncbi.nlm.nih.gov/geo, NCBI; found in “Data Availability Statement”

Data Availability Statement

Raw DNA methylation data have been deposited to the NCBI GEO database http://www.ncbi.nlm.nih.gov/geo/ (accessed on 16 January 2026) under accession number GSE61496.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 6 authors, 4 keywords, 14 MeSH terms, 1 funder, 40 references.

Cite

This paper

Rasmussen, C. P. V., Nygaard, M., Nielsen, M. F., Soerensen, M., Christensen, K., & Tan, Q. (2026). Differential DNA Methylation of the Serotonin Receptor Signaling and Glutamatergic Synapse Pathways in Adult Twins Born Preterm. Genes, 17(6), 683. https://doi.org/10.3390/genes17060683

BibTeX

@article{rasmussen2026differential, author = {Rasmussen, Carl Peter Vittrup and Nygaard, Marianne and Nielsen, Morten Frost and Soerensen, Mette and Christensen, Kaare and Tan, Qihua}, title = {{Differential DNA Methylation of the Serotonin Receptor Signaling and Glutamatergic Synapse Pathways in Adult Twins Born Preterm}}, journal = {Genes}, year = {2026}, month = jun, volume = {17}, number = {6}, pages = {683}, publisher = {Multidisciplinary Digital Publishing Institute (MDPI)}, issn = {2073-4425}, doi = {10.3390/genes17060683}, url = {https://doi.org/10.3390/genes17060683}, pmid = {42353841}, pmcid = {PMC13299586} }

RIS

TY - JOUR AU - Rasmussen, Carl Peter Vittrup AU - Nygaard, Marianne AU - Nielsen, Morten Frost AU - Soerensen, Mette AU - Christensen, Kaare AU - Tan, Qihua TI - Differential DNA Methylation of the Serotonin Receptor Signaling and Glutamatergic Synapse Pathways in Adult Twins Born Preterm T2 - Genes J2 - Genes (Basel) PY - 2026 DA - 2026/06/10 VL - 17 IS - 6 SP - 683 SN - 2073-4425 PB - Multidisciplinary Digital Publishing Institute (MDPI) DO - 10.3390/genes17060683 UR - https://doi.org/10.3390/genes17060683 LA - en ER -

CSL-JSON

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