Dual methylation and hydroxymethylation study in blood and brain identifies BAIAP2 as a mediator of gene expression differences associated with alcohol use disorder

Background: Using a three-stage, multi-tissue design we sought to characterize methylation and hydroxymethylation changes in blood and brain associated with alcohol use disorder (AUD). Methods: In the discovery stage, we used epigenomic deconvolution to perform cell-type specific methylome-wide association studies within subpopulations of granulocytes/T-cells/B-cells/monocytes in 1,132 blood samples. Blood findings were examined for overlap with AUD-related methylation and hydroxymethylation in 50 human post-mortem brain samples in the brain overlap stage. Follow-up analyses investigated if overlapping findings mediated AUD-associated transcription changes in the same brain samples in the final stage. Results: Cell-type specific analyses in blood identified methylome-wide significant associations in monocytes and T-cells. One of the top genic findings is located in PLA2G4A, a gene required for monocyte chemotaxis. Alcohol inhibits monocyte chemotaxis, thereby contributing to alcohol-induced inflammation. The monocyte findings were significantly enriched for AUD-related methylation and hydroxymethylation in brain. Hydroxymethylation in BAIAP2 was found to mediate AUD-associated transcription in the same brain samples. BAIAP2 regulates dendritic spine density and is linked to cognitive deficits that are clinical features of advanced AUD. Conclusions: As part of the most comprehensive methylation study of AUD to date, this work involved the first cell-type specific methylation study of AUD conducted in blood, identifying methylation sites that are involved in alcohol-induced inflammation. In this first study to consider the role of hydroxymethylation in AUD, we found evidence for a novel mechanism for AUD brain-related impairments. Our results suggest promising new avenues for AUD research.