Neuronal-specific methylome and hydroxymethylome analysis reveal significant loci associated with alcohol use disorder

• DOI: 10.3389/fgene.2024.1345410
• Publication Date: 2024-04-03T04:26:11Z
• Authors: Diego E. Andrade-...; Diana L. Núñez-Ríos; José Jaime Martín...; Sheila T. Nagamatsu; Gregory Rompala; Lea Zillich; Stephanie H. Witt; Shaunna L. Clark; Maria C. Lattig; Janitza L. Montal...
• Keywords: Alcohol use disorder; Differentially methylated regions; CpG site

Background: Alcohol use disorder (AUD) is a complex condition associated with adverse health consequences that affect millions of individuals worldwide. Epigenetic modifications, including DNA methylation (5 mC), have been AUD and other alcohol-related traits. Epigenome-wide association studies (EWAS) identified differentially methylated genes in human peripheral brain tissue. More recently, epigenetic also evaluated hydroxymethylation hmC) the brain. However, most work postmortem tissue has examined bulk In this study, we investigated neuronal-specific 5 mC hmC alterations at CpG sites orbitofrontal cortex (OFC). Methods: Neuronal nuclei from OFC were 34 samples (10 AUD, 24 non-AUD). Reduced representation oxidative bisulfite sequencing was used to assess genome-wide level. Differential using methylKit R package significance set false discovery rate < 0.05 differential > 2. Functional enrichment analyses performed, gene-level convergence an independent dataset assessed cortical Results: We 417 363 5hmC significant 59% gene promoters. Some previously implicated alcohol consumption, SYK, DNMT3A for mC, GAD1, DLX1, DLX2, GATA4 both. Convergence previous study observed 28 genes. 35 regions hmC, respectively. Lastly, GWAS analysis showed Discussion: This reveals methylome hydroxymethylome dysregulation identifying both reported potentially novel associations AUD. Our findings provide new insights into epigenomic