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DNA methylation signatures of bilateral hippocampal volume, asymmetry and atrophy: a cross-omics analysis in the general population.

EBioMedicine

Authors: Dan Liu, Valentina Talevi, Juliana F Tavares, Ruiqi Wang, Mohammed A Imtiaz, Konstantinos Melas, Alexander Teumer, Katharina Wittfeld, Robert F Hillary, Dina Vojinovic, Marian Beekman, Nicola J Armstrong, Santiago Estrada, Henry Völzke, Robin Bülow, Natalie A Royle, Joanna M Wardlaw, Wei Wen, Perminder S Sachdev, Karen A Mather, P Eline Slagboom, Simon R Cox, Hans Jörgen Grabe, Qiong Yang, N Ahmad Aziz, Monique M B Breteler

BACKGROUND: Left-right hippocampal volumetric asymmetry and atrophy are implicated in neurodegenerative and neuropsychiatric disorders, yet their molecular basis in healthy adults remains poorly understood.

METHODS: We conducted a meta-analysis of epigenome-wide association studies across six population-based cohorts (n = 8156; 53% women; mean age = 60.7 years) to identify DNA methylation signatures associated with left and right hippocampal volumes (LHCV, RHCV) and hippocampal asymmetry (i.e, differences between left and right volumes divided by their sums).

FINDINGS: We identified five CpGs and 262 differentially methylated regions associated with LHCV, nine CpGs and 246 regions with RHCV, one CpG and 16 regions with asymmetry. Cross-omics integration uncovered 15 LHCV-related and 13 RHCV-related methylation-gene expression pairs, with five overlapping genes primarily involved in immune regulation. LHCV-specific genes were involved in cellular signalling, and Mendelian randomisation (MR) analyses supported a potential causal association between brain expression of DIP2C and increased risk of major depressive disorder. RHCV-specific genes were involved in neuronal differentiation pathways, with MR analyses suggesting that brain-tissue expression of BAIAP2, MACF1, SLC16A5, and CORO1B was associated with neuropsychiatric disorders. We also identified sex-specific patterns with hippocampal asymmetry. Notably, baseline methylation at these sites predicted hippocampal atrophy rates, explaining >10% of the variation. Associations with multiple healthy dietary patterns suggest modifiable influences on hippocampal structure.

INTERPRETATION: These findings highlight distinct methylation profiles as potential biomarkers or therapeutic targets for neuropsychiatric and neurodegenerative conditions.

FUNDING: Institutional funds, Federal Ministry of Education and Research of Germany, Alzheimer's Association.

Copyright © 2026 The Authors. Published by Elsevier B.V. All rights reserved.

PMID: 42114417

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