Alcohol abuse and cigarette smoking are associated with global DNA hypermethylation: Results from the German Investigation on Neurobiology in Alcoholism (GINA)

Semmler, Alexander; Heese, Peter; Stoffel‐Wagner, Birgit; Muschler, Marc; Heberlein, Annemarie; Bigler, Laurent; Prost, Jean-Christophe; Frieling, Helge; Kornhuber, Johannes; Banger, Markus; Hillemacher, Thomas; Linnebank, Michael

doi:10.1016/j.alcohol.2015.01.004

Cited by 29 publications

(13 citation statements)

References 28 publications

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“…It has been hypothesized that such alcohol-associated decreases in global DNAm are attributed to the lack of methionine adenosyl transferase regulation in AD patients 14, 52 . However, in contrast, earlier studies have postulated that due to the higher homocysteine levels in AD patients, global DNAm patterns should be elevated 53 , although such associations have not been confirmed 54 . The lack of consensus in regard to alterations in alcohol-related global DNAm measures highlights the need for further investigation into the biological mechanisms underlying global DNAm patterns in AD patients.…”

Section: Discussionmentioning

confidence: 72%

DNA methylation signatures of chronic alcohol dependence in purified CD3+ T-cells of patients undergoing alcohol treatment

Brückmann

Islam

MacIsaac

et al. 2017

Sci Rep

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Several studies have shown an association of alcohol dependence with DNA methylation (DNAm), suggesting that environmentally-induced changes on epigenomic variation may play an important role in alcohol dependence. In the present study, we analysed genome-wide DNAm profiles of purified CD3+ T-cells from pre- and post-treatment alcohol dependent patients, as well as closely matched healthy controls. We identified 59 differentially methylated CpG sites comparing patients prior to treatment with healthy controls and were able to confirm 8 of those sites in additional analyses for differentially methylated regions. Comparing patients before and after a 3-week alcohol treatment program we revealed another unique set of 48 differentially methylated CpG sites. Additionally, we found that the mean global DNAm was significantly lower in patients prior to treatment compared to controls, but reverted back to levels similar to controls after treatment. We validated top-ranked hits derived from the epigenome-wide analysis by pyrosequencing and further replicated two of them in an independent cohort and confirmed differential DNAm of HECW2 and SRPK3 in whole blood. This study is the first to show widespread DNAm variation in a disease-relevant blood cell type and implicates HECW2 and SRPK3 DNAm as promising blood-based candidates to follow up in future studies.

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Section: Discussionmentioning

confidence: 72%

DNA methylation signatures of chronic alcohol dependence in purified CD3+ T-cells of patients undergoing alcohol treatment

Brückmann

Islam

MacIsaac

et al. 2017

Sci Rep

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“…In drugs of abuse, DNA methylation changes have been reported at particular genes of interest in response to cocaine, for example, [52], but there has not yet been a genome-wide mapping of such regulation. Alcohol abuse and cigarette smoking have certainly been associated with altered DNA methylation, including global DNA hypermethylation [53, 54]. …”

Section: Relevant Environmental Factors and Dna Methylationmentioning

confidence: 99%

DNA methylation in Huntington’s disease: Implications for transgenerational effects

Thomas

2016

Neuroscience Letters

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Huntington’s disease (HD) is a devastating, neurodegenerative disorder caused by a CAG repeat mutation in the HTT gene. A growing body of evidence suggests that epigenetic modifications play a key role in HD pathogenesis. Expression of the disease protein, huntingtin, leads to extensive transcriptional dysregulation due to disruption of histone-modifying complexes and altered interactions with chromatin-related factors. Such epigenetic mechanisms also readily respond to environmental factors, which are now thought to influence the risk, onset and progression of neurodegenerative disorders, including HD. DNA methylation is an epigenetic modification that has been studied intensively, however, its role in HD is just emerging. In this review, DNA methylation differences associated with HD will be summarized, as well as the role of environmental factors to alter DNA methylation in a manner that could alter disease phenotypes. Further, transgenerational epigenetic inheritance will be discussed in the context of relevant environmental factors and their potential links to HD. The study of epigenetic states in HD presents an opportunity to gain new insights into risk factors and pathogenic mechanisms associated with HD, as well as to inform about treatment options.

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“…25,26 A recent study specifically investigating the role of homocysteine in altered DNA methylation in 363 alcohol dependent patients also found no correlation between homocysteine and global DNA methylation. 42 Further studies are therefore necessary to clarify the relationship between homocysteine levels and GDAP1 DNA methylation.…”

Section: Control Individualsmentioning

confidence: 99%

Validation of differential GDAP1 DNA methylation in alcohol dependence and its potential function as a biomarker for disease severity and therapy outcome

et al. 2016

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Alcohol dependence is a severe disorder contributing substantially to the global burden of disease. Despite the detrimental consequences of chronic alcohol abuse and dependence, effective prevention strategies as well as treatment options are largely missing to date. Accumulating evidence suggests that gene-environment interactions, including epigenetic mechanisms, play a role in the etiology of alcohol dependence. A recent epigenome-wide study reported widespread alterations of DNA methylation patterns in alcohol dependent patients compared to control individuals. In the present study, we validate and replicate one of the top findings from this previous investigation in an independent cohort: the hypomethylation of GDAP1 in patients. To our knowledge, this is the first independent replication of an epigenome-wide finding in alcohol dependence. Furthermore, the AUDIT as well as the GSI score were negatively associated with GDAP1 methylation and we found a trend toward a negative association between GDAP1 methylation and the years of alcohol dependency, pointing toward a potential role of GDAP1 hypomethylation as biomarker for disease severity. In addition, we show that the hypomethylation of GDAP1 in patients reverses during a short-term alcohol treatment program, suggesting that GDAP1 DNA methylation could also serve as a potential biomarker for treatment outcome. Our data add to the growing body of knowledge on epigenetic effects in alcohol dependence and support GDAP1 as a novel candidate gene implicated in this disorder. As the role of GDAP1 in alcohol dependence is unknown, this novel candidate gene should be followed up in future studies.

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Alcohol abuse and cigarette smoking are associated with global DNA hypermethylation: Results from the German Investigation on Neurobiology in Alcoholism (GINA)

Cited by 29 publications

References 28 publications

DNA methylation signatures of chronic alcohol dependence in purified CD3+ T-cells of patients undergoing alcohol treatment

DNA methylation signatures of chronic alcohol dependence in purified CD3+ T-cells of patients undergoing alcohol treatment

DNA methylation in Huntington’s disease: Implications for transgenerational effects

Validation of differential GDAP1 DNA methylation in alcohol dependence and its potential function as a biomarker for disease severity and therapy outcome

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