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Dual methylation and hydroxymethylation study of alcohol use disorder

By Shaunna L Clark, Robin F Chan, Min Zhao, William E. Copeland, Lin Y Xie, Brenda WJH Penninx, Karolina A. Aberg, Edwin J.C.G. van den Oord

Posted 18 Sep 2020
medRxiv DOI: 10.1101/2020.09.16.20194639

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 1,132 blood samples. Blood findings were then examined for overlap with AUD-related associations in 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 involved in AUD-related brain impairment. 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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