Integrative cross-omics analysis identifies DNA methylation signatures associated with bilateral hippocampal volume, asymmetry and atrophy rate in the general population
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The hippocampus exhibits volumetric differences between the left and right hemispheres (LHCV and RHCV) and asymmetry, yet the molecular mechanisms underlying these features remain unclear. In this study, we performed a meta-analysis of epigenome-wide association studies (EWAS) across six population-based cohorts (n=8,156; 53% women; mean age: 60.7 years) to identify blood-based methylation signatures associated with LHCV, RHCV, and hippocampal asymmetry. Integrative cross-omics analyses using individual-level genetic, methylation, and gene expression data (n > 2,624 participants from the Rhineland Study) revealed 15 CpG/DMR-gene expression pairs linked to LHCV and 18 pairs to RHCV, implicating pathways involved in neuronal differentiation and immune processes. Notably, baseline methylation at these loci predicted bilateral hippocampal atrophy rates, explaining over 10% of the variation. Four CpGs were consistently associated with hippocampal asymmetry cross-sectionally and longitudinally, exhibiting sex-specific differences. Additionally, adherence to healthy dietary patterns was associated with these methylation signatures, highlighting modifiable influences on hippocampal health and atrophy.
