A longitudinal DNA methylation atlas and its link to brain structure and mental health
Epigenetic mechanisms are thought to contribute to neurodevelopmental vulnerability for psychiatric disorders, yet longitudinal evidence linking DNA methylation (DNAm) to brain maturation and psychopathology is limited. Using epigenome-wide DNAm (372,582 CpGs) and whole-brain structural MRI data from the IMAGEN cohort (n = 506, ages 14-19), we identified 18 co-regulated DNAm clusters, ten enriched for brain-expressed genes involved in neuronal development and signalling. The clusters showed consistent longitudinal change and were reproducible in independent adult samples (PPMI, n = 513; ADNI, n = 606). Multivariate analyses revealed coordinated coupling between DNAm change and cortical-subcortical maturation, such that greater DNAm reductions in brain-related clusters associated with greater cortical thinning and subcortical volume changes in the fronto-limbic-striatal axis. Increases in depressive symptoms, and frequency of cannabis use and binge drinking were linked to DNAm changes, with mediation models supporting DNAm as a mechanistic bridge between behaviour and brain change. Two clusters (C1 and C7) were associated with depressive and negative psychotic symptoms across adolescence. Associations of these clusters with depressive symptoms replicated in the PPMI dataset. Their coupling with amygdala-striatal maturation suggests that these DNAm signatures index environmentally shaped affective-motivational neurodevelopment.
Authors
- Sylvane Desrivières (ORCID: https://orcid.org/0000-0002-9120-7060)
- Hugh P Garavan (ORCID: https://orcid.org/0000-0002-8939-1014)
- Rüdiger Brühl (ORCID: https://orcid.org/0000-0003-0111-5996)
- Tobias Banaschewski (ORCID: https://orcid.org/0000-0003-4595-1144)
- Sarah Hohmann (ORCID: https://orcid.org/0000-0002-5175-6698)
- Shitong Xiang (ORCID: https://orcid.org/0000-0002-5513-4714)
- Nathalie E. Holz (ORCID: https://orcid.org/0000-0002-6225-9267)
- Antoine Grigis (ORCID: https://orcid.org/0000-0001-7984-3710)
- Tianye Jia (ORCID: https://orcid.org/0000-0001-5399-2953)
- Hervé Lemaître (ORCID: https://orcid.org/0000-0002-5952-076X)
- Michael N. Smolka (ORCID: https://orcid.org/0000-0001-5398-5569)
- Frauke Nees (ORCID: https://orcid.org/0000-0002-7796-8234)
- Penny Anne Gowland (ORCID: https://orcid.org/0000-0002-4900-4817)
- Eric Artiges A (ORCID: https://orcid.org/0000-0003-4461-7646)
- Nilakshi Vaidya (ORCID: https://orcid.org/0000-0002-4600-7158)
- Andreas Heinz
- Wei Zhang (405)
- Luise Poustka
- Marie-Laure Paillère Martinot
- Robert Whelan
- Henrik Walter
- Jean-Luc Martinot
- Tomáš Paus
- Dimitri Papadopoulos Orfanos
- Di CHEN
- Linbo Wang
- Christian Bäuchl
- Jianfeng Feng
- Herta Flor
- Gunter Schumann
- Arun L. W. Bokde
- Wei Cheng
- Paul M. Thompson
- Xinyang Yu
Institutions
- University of Vermont (US)
- University of Southern California (US)
- Physikalisch-Technische Bundesanstalt (DE)
- CEA CESTA (FR)
- Centre National de la Recherche Scientifique (FR)
- University of Nottingham (GB)
- Université de Bordeaux (FR)
- Inserm (FR)
- Universität Hamburg (DE)
- University of Mannheim (DE)
- King's College London (GB)
- Université Paris Cité (FR)
- Trinity College Dublin (IE)
- Heidelberg University (DE)
- Fudan University (CN)
- Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
- Université Paris-Saclay (FR)
- University Hospital Heidelberg (DE)
- Centre Hospitalier Universitaire Sainte-Justine (CA)
- Humboldt-Universität zu Berlin (DE)
- University of Warwick (GB)
- Sorbonne Université (FR)
- Shanghai Institute for Science of Science (CN)
- Institut des Maladies Neurodégénératives (FR)
- Assistance Publique – Hôpitaux de Paris (FR)
- Central Institute of Mental Health (DE)
- University Medical Center Hamburg-Eppendorf (DE)
- Pitié-Salpêtrière Hospital (FR)
- CEA Paris-Saclay (FR)
- National Institutes for Food and Drug Control (CN)
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE)
- Shanghai Center for Brain Science and Brain-Inspired Technology (CN)
- University of Southampton (GB)
- East China Normal University (CN)
- Technische Universität Dresden (DE)
- Charité - Universitätsmedizin Berlin (DE)
- University of Tübingen (DE)
- Ludwig-Maximilians-Universität München (DE)
Publication Details
- Journal
- Molecular Psychiatry
- Published
- 2026-03-31
- DOI
- https://doi.org/10.1038/s41380-026-03554-y
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 0.00