Building epigenetic risk scores of opioid use disorder: Insights from human postmortem brain data

Opioid use disorder (OUD) poses significant global health and socioeconomic burden. While epigenetic mechanisms, particularly DNA methylation (5mC), have been implicated in OUD, recent work from our group has revealed an important role of DNA hydroxymethylation (5hmC). Building on prior work, we aimed to construct epigenetic risk scores as tools to help predict OUD. Methylation and hydroxymethylation risk scores (MRS/hMRS) were calculated and evaluated for their predictive ability, variance explained, and functional significance. Our results revealed that hMRS outperforms MRS in predicting OUD, with a variance explained of 33.5%. The combined MRS and hMRS explained 34.5% of the variance in OUD. Functional analysis revealed enrichment for Wnt signaling and embryonic development. Gene interaction networks implicated genes involved in opioid signaling pathway and unveiled potential novel gene candidates. This study further supports the importance of distinguishing between 5mC and 5hmC to further understand the epigenetic landscape of OUD. The higher predictive accuracy of hMRS along with hMRS's functional pathways and networks provide valuable insights into the molecular underpinnings of OUD.