Epigenome-wide Association Study of Alcohol Use Disorder in Five Brain Regions

Zillich, Lea; Frank, Josef; Streit, Fabian; Friske, Marion M; Foo, Jerome C.; Sirignano, Lea; Dukal, Helene; Degenhardt, Franziska; Hoffmann, Per; Hansson, Anita C.; Nöthen, Markus M.; Rietschel, Marcella; Spanagel, Rainer; Witt, Stephanie H.

doi:10.1101/2021.08.01.21261118

Cited by 2 publications

(8 citation statements)

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“…DNA extraction, methylation profiling, and QC was performed as described in Zillich et al 15 . In brief, DNA was extracted using the DNeasy extraction kit (Qiagen, Hilden, Germany); the Illumina HumanMethylation EPIC BeadChip and the Illumina HiScan array scanning system (Illumina, San Diego, CA) were used to determine DNA-methylation levels.…”

Section: Methodsmentioning

confidence: 99%

“…We used an updated and customized version of the CPACOR pipeline to extract beta values from raw intensities 19 . Criteria for the removal of samples and probes can be found in Zillich et al 15 . In the present analyses, DNA methylation data was included from all subjects from whom gene expression data was available after QC.…”

Section: Methodsmentioning

confidence: 99%

“…To identify genes both DE and differentially methylated, we analyzed the overlap of DE genes (FDR<0.25) with the results of an EWAS (p<0.001) in the same sample 15 . We prioritized CpG-sites based on their functional relevance in gene expression regulation.…”

Section: Methodsmentioning

confidence: 99%

“…Effect sizes and p values for CpG sites were used from the EWAS results as presented in the original publication 15 . In brief, the EWAS model was based on methylation M-values as the dependent variable and AUD status as the predictor.…”

Section: Differential Methylation Analysismentioning

confidence: 99%

“…In a recent EWAS of AUD in postmortem brain tissue, we identified differentially methylated CpG-sites and regions in the ventral and dorsal striatum 15 . Previous studies have shown the utility of integrating epigenetic and transcriptomic data in postmortem brain tissue of SUDs using weighted correlation network analysis (WGCNA) 16 .…”

Section: Introductionmentioning

confidence: 99%

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Multi-Omics Signatures of Alcohol Use Disorder in the Dorsal and Ventral Striatum

Zillich

Poisel

Frank

et al. 2021

Preprint

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Alcohol Use Disorder (AUD) is a major contributor to global mortality and morbidity. Postmortem human brain tissue enables the investigation of molecular mechanisms of AUD in the neurocircuitry of addiction. We aimed to identify differentially expressed (DE) genes in the ventral and dorsal striatum between individuals with AUD and controls, and to integrate the results with findings from genome- and epigenome-wide association studies (GWAS/EWAS) to identify functionally relevant molecular mechanisms of AUD. DNA-methylation and gene expression (RNA-seq) data was generated from postmortem brain samples of 48 individuals with AUD and 51 controls from the ventral striatum (VS) and the dorsal striatal regions caudate nucleus (CN) and putamen (PUT). We identified DE genes using DESeq2, performed gene-set enrichment analysis (GSEA), and tested enrichment of DE genes in results of GWASs using MAGMA. Weighted correlation network analysis (WGCNA) was performed for DNA-methylation and gene expression data and gene overlap was tested. In the dorsal striatum, we discovered differential expression (FDR<0.05) for a total of 50 genes. In the VS, DE genes at FDR<0.25 were overrepresented in a recent GWAS of problematic alcohol use. The ARHGEF15 gene was upregulated in all three brain regions. GSEA in CN and VS pointed towards cell-structure associated GO-terms and in PUT towards immune pathways. The WGCNA modules most strongly associated with AUD showed strong enrichment for immune response and inflammation pathways. Our integrated analysis of multi-omics data sets provides further evidence for the importance of immune-and inflammation-related processes in AUD.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Differential Methylation Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Multi-Omics Signatures of Alcohol Use Disorder in the Dorsal and Ventral Striatum

Zillich

Poisel

Frank

et al. 2021

Preprint

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DNA Methylation in Cocaine Use Disorder – An Epigenome-wide Approach in the Human Prefrontal Cortex

Poisel

Zillich

Streit

et al. 2022

Preprint

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Cocaine use disorder (CUD) is characterized by a loss of control over drug intake and is associated with structural, functional, and molecular alterations in the brain. At the molecular level, epigenetic alterations are hypothesized to contribute to the higher-level functional and structural brain changes as observed in CUD. Most evidence of cocaine-associated epigenetic changes comes from animal studies while only a few studies have been performed using human tissue. We investigated epigenome-wide DNA methylation signatures of CUD in human postmortem brain tissue of Brodmann Area 9 (BA9). A total of N = 42 BA9 brain samples were obtained from N = 21 individuals with CUD and N = 21 individuals without a CUD diagnosis. We performed an epigenome-wide association study and analyzed CUD-associated differentially methylated regions (DMRs). To assess the functional role of CUD-associated differential methylation, we performed Gene Ontology enrichment analyses and characterized co-methylation networks using a weighted correlation network analysis. We further investigated epigenetic age in CUD using epigenetic clocks for the assessment of biological age. While no CpG site was associated with CUD at epigenome-wide significance in BA9, we detected a total of 20 CUD-associated DMRs. After annotation of DMRs to genes, we identified NPFFR2 and KALRN for which a previous role in the behavioral response to cocaine in rodents is known. Three of the four identified CUD-associated co-methylation modules were functionally related to neurotransmission and neuroplasticity. Protein-protein interaction networks derived from module hub genes revealed several addiction-related genes as highly connected nodes such as CACNA1C, NR3C1, and JUN. In BA9, we observed a trend toward epigenetic age acceleration in individuals with CUD remaining stable even after adjustment for covariates. Results from our study highlight that CUD is associated with epigenome-wide differences in DNA methylation levels in BA9 particularly related to synaptic signaling and neuroplasticity. This supports findings from previous studies that report on the strong impact of cocaine on neurocircuits in the human prefrontal cortex. Further studies are needed to follow up on the role of epigenetic alterations in CUD focusing on the integration of epigenetic signatures with transcriptomic and proteomic data.

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Epigenome-wide Association Study of Alcohol Use Disorder in Five Brain Regions

Cited by 2 publications

References 62 publications

Multi-Omics Signatures of Alcohol Use Disorder in the Dorsal and Ventral Striatum

Multi-Omics Signatures of Alcohol Use Disorder in the Dorsal and Ventral Striatum

DNA Methylation in Cocaine Use Disorder – An Epigenome-wide Approach in the Human Prefrontal Cortex

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