Journal
ADDICTION BIOLOGY
Volume 27, Issue 2, Pages -Publisher
WILEY
DOI: 10.1111/adb.13114
Keywords
alcohol use disorder; hydroxymethylation; methylation
Categories
Funding
- National Institutes of Health [R01MH099110, 1R01MH104576, 1R01AA026057]
- VCU CTSA from the National Institutes of Health's National Center for Advancing Translation Science [UL1TR002649]
- CCTR Endowment Fund of the Virginia Commonwealth University
- NARSAD Young Investigator Grant from the Brain and Behavior Research Foundation
- Geestkracht program of the Netherlands Organisation for Health Research and Development (ZonMw) [10-000-1002]
- National Institute of Alcohol Abuse and Alcoholism of the National Institutes of Health [R28AA012725]
- VU University Medical Center
- GGZ inGeest
- Leiden University Medical Center
- Leiden University
- GGZ Rivierduinen
- University Medical Center Groningen
- Lentis
- GGZ Friesland
- GGZ Drenthe
- Rob Giel Onderzoekscentrum
- University of Groningen
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This study characterized methylation and hydroxymethylation changes associated with alcohol use disorder (AUD) in blood and brain using an integrative, multi-tissue design. Cell-type-specific analyses in blood identified significant associations in monocytes and T-cells, with the monocyte findings significantly enriched for AUD-related methylation and hydroxymethylation in the brain. The study also discovered a novel mechanism for cognitive deficits associated with AUD and suggested promising new avenues for research in this area.
Using an integrative, multi-tissue design, we sought to characterize methylation and hydroxymethylation changes in blood and brain associated with alcohol use disorder (AUD). First, we used epigenomic deconvolution to perform cell-type-specific methylome-wide association studies within subpopulations of granulocytes/T-cells/B-cells/monocytes in 1132 blood samples. Blood findings were then examined for overlap with AUD-related associations with methylation and hydroxymethylation in 50 human post-mortem brain samples. Follow-up analyses investigated if overlapping findings mediated AUD-associated transcription changes in the same brain samples. Lastly, we replicated our blood findings in an independent sample of 412 individuals and aimed to replicate published alcohol methylation findings using our results. Cell-type-specific analyses in blood identified methylome-wide significant associations in monocytes and T-cells. The monocyte findings were significantly enriched for AUD-related methylation and hydroxymethylation in brain. Hydroxymethylation in specific sites mediated AUD-associated transcription in the same brain samples. 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 and replicating a finding in DLGAP1 that may be a blood-based biomarker of AUD. In this first study to consider the role of hydroxymethylation in AUD, we found evidence for a novel mechanism for cognitive deficits associated with AUD. Our results suggest promising new avenues for AUD research.
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