# Profiling of 5-hydroxymethylcytosine in blood reveals preferential enrichment at exon-intron junctions and predictive value for Parkinson’s disease

## TL;DR

This study shows that 5-hydroxymethylcytosine levels in blood are lower in Parkinson’s disease patients and may serve as a potential biomarker.

## Contribution

The study identifies 5hmC as a predictive biomarker for Parkinson’s disease and reveals its enrichment near exon-intron junctions.

## Key findings

- Global 5hmC levels are significantly reduced in PD patients compared to controls.
- Differentially methylated and hydroxymethylated regions are enriched within introns and near exon-intron junctions.
- Global 5hmC levels combined with age and sex can predict Parkinson’s disease status.

## Abstract

5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) are epigenetic modifications increasingly recognized for their roles in Parkinson’s disease (PD). In this study, we profiled 5mC and 5hmC in blood samples from individuals with PD to explore their relevance to disease status and progression. We observed significantly reduced global 5hmC levels in peripheral blood mononuclear cells (PBMCs) from PD cases compared to controls. Using the Illumina EPIC BeadArray, we conducted genome-wide analyses of 5mC and 5hmC in a subset of PD cases and controls to explore methylation and hydroxymethylation patterns. We identified differentially methylated and hydroxymethylated positions and regions enriched within introns, with both types of regions showing a marked concentration near exon-intron junctions. Positional analysis relative to exon–intron junctions revealed that proximal and distal regions mapped to partially different functional themes, suggesting that genomic context provides additional biological insight. Functional enrichment analyses also highlighted distinct biological roles for 5mC and 5hmC, with associated genes implicated in neurodevelopment, vascular remodeling, and neuroimmune signaling. Additionally, we demonstrate that global 5hmC levels, in combination with age and sex, are predictive of disease status, highlighting the potential of 5hmC as a blood-based biomarker for PD.