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Epigenetic Signatures of Smoking in Five Brain Regions.

ABSTRACT: (1) Background: Epigenome-wide association studies (EWAS) in peripheral blood have repeatedly found associations between tobacco smoking and aberrant DNA methylation (DNAm), but little is known about DNAm signatures of smoking in the human brain, which may contribute to the pathophysiology of addictive behavior observed in chronic smokers. (2) Methods: We investigated the similarity of DNAm signatures in matched blood and postmortem brain samples (n = 10). In addition, we performed EWASs in five brain regions belonging to the neurocircuitry of addiction: anterior cingulate cortex (ACC), Brodmann Area 9, caudate nucleus, putamen, and ventral striatum (n = 38-72). (3) Results: cg15925993 within the LOC339975 gene was epigenome-wide significant in the ACC. Of 16 identified differentially methylated regions, two (PRSS50 and LINC00612/A2M-AS1) overlapped between multiple brain regions. Functional enrichment was detected for biological processes related to neuronal development, inflammatory signaling and immune cell migration. Additionally, our results indicate the association of the well-known AHRR CpG site cg05575921 with smoking in the brain. (4) Conclusion: The present study provides further evidence of the strong relationship between aberrant DNAm and smoking.

SUBMITTER: Zillich L

PROVIDER: S-EPMC9029407 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Epigenetic Signatures of Smoking in Five Brain Regions.

Zillich Lea L Poisel Eric E Streit Fabian F Frank Josef J Fries Gabriel R GR Foo Jerome C JC Friske Marion M MM Sirignano Lea L Hansson Anita C AC Nöthen Markus M MM Witt Stephanie H SH Walss-Bass Consuelo C Spanagel Rainer R Rietschel Marcella M

Journal of personalized medicine 20220402 4

(1) Background: Epigenome-wide association studies (EWAS) in peripheral blood have repeatedly found associations between tobacco smoking and aberrant DNA methylation (DNAm), but little is known about DNAm signatures of smoking in the human brain, which may contribute to the pathophysiology of addictive behavior observed in chronic smokers. (2) Methods: We investigated the similarity of DNAm signatures in matched blood and postmortem brain samples (<i>n</i> = 10). In addition, we performed EWASs ...[more]

PMID: 35455681

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Project description:BackgroundMultiple studies have made robust associations between differential DNA methylation and exposure to cigarette smoke. But whether a DNA methylation phenotype is established immediately upon exposure, or only after prolonged exposure is less well-established. Here, we assess DNA methylation patterns from peripheral blood samples in current smokers in response to dose and duration of exposure, along with the effects of smoking cessation on DNA methylation in former smokers.MethodsDimensionality reduction was applied to DNA methylation data at 90 previously identified smoking-associated CpG sites for over 4900 individuals in the Generation Scotland cohort. K-means clustering was performed to identify clusters associated with current and never smoker status based on these methylation patterns. Cluster assignments were assessed with respect to duration of exposure in current smokers (years as a smoker), time since smoking cessation in former smokers (years), and dose (cigarettes per day).FindingsTwo clusters were specified, corresponding to never smokers (97·5% of whom were assigned to Cluster 1) and current smokers (81·1% of whom were assigned to Cluster 2). The exposure time point from which >50% of current smokers were assigned to the smoker-enriched cluster varied between 5 and 9 years in heavier smokers and between 15 and 19 years in lighter smokers. Low-dose former smokers were more likely to be assigned to the never smoker-enriched cluster in the first year following cessation. In contrast, a period of at least two years was required before the majority of former high-dose smokers were assigned to the never smoker-enriched cluster.InterpretationOur findings suggest that smoking-associated DNA methylation changes are a result of prolonged exposure to cigarette smoke, and can be reversed following cessation. The length of time in which these signatures are established and recovered is dose dependent. Should DNA methylation-based signatures of smoking status be predictive of smoking-related health outcomes, our findings may provide an additional criterion on which to stratify risk.

Project description:Recent advances in genome-wide DNA methylation (DNAm) profiling for smoking behaviour have given rise to a new, molecular biomarker of smoking exposure. It is unclear whether a smoking-associated DNAm (epigenetic) score has predictive value for ageing-related health outcomes which is independent of contributions from self-reported (phenotypic) smoking measures. Blood DNA methylation levels were measured in 895 adults aged 70 years in the Lothian Birth Cohort 1936 (LBC1936) study using the Illumina 450K assay. A DNA methylation score based on 230 CpGs was used as a proxy for smoking exposure. Associations between smoking variables and health outcomes at age 70 were modelled using general linear modelling (ANCOVA) and logistic regression. Additional analyses of smoking with brain MRI measures at age 73 (n?=?532) were performed. Smoking-DNAm scores were positively associated with self-reported smoking status (P?<?0.001, eta-squared ?2?=?0.63) and smoking pack years (r?=?0.69, P?<?0.001). Higher smoking DNAm scores were associated with variables related to poorer cognitive function, structural brain integrity, physical health, and psychosocial health. Compared with phenotypic smoking, the methylation marker provided stronger associations with all of the cognitive function scores, especially visuospatial ability (P?<?0.001, partial eta-squared ?p2?=?0.022) and processing speed (P?<?0.001, ?p2?=?0.030); inflammatory markers (all P?<?0.001, ranges from ?p2?=?0.021 to 0.030); dietary patterns (healthy diet (P?<?0.001, ?p2?=?0.052) and traditional diet (P?<?0.001, ?p2?=?0.032); stroke (P?=?0.006, OR 1.48, 95% CI 1.12, 1.96); mortality (P?<?0.001, OR 1.59, 95% CI 1.42, 1.79), and at age 73; with MRI volumetric measures (all P?<?0.001, ranges from ?p2?=?0.030 to 0.052). Additionally, education was the most important life-course predictor of lifetime smoking tested. Our results suggest that a smoking-associated methylation biomarker typically explains a greater proportion of the variance in some smoking-related morbidities in older adults, than phenotypic measures of smoking exposure, with some of the accounted-for variance being independent of phenotypic smoking status.

Project description:Neuropathic pain is a chronic debilitating condition with a high comorbidity with depression. Clinical reports and animal studies have suggested that both the medial prefrontal cortex (mPFC) and the anterior cingulate cortex (ACC) are critically implicated in regulating the affective symptoms of neuropathic pain. Neuropathic pain induces differential long-term structural, functional, and biochemical changes in both regions, which are thought to be regulated by multiple waves of gene transcription. However, the differences in the transcriptomic profiles changed by neuropathic pain between these regions are largely unknown. Furthermore, women are more susceptible to pain and depression than men. The molecular mechanisms underlying this sexual dimorphism remain to be explored. Here, we performed RNA sequencing and analyzed the transcriptomic profiles of the mPFC and ACC of female and male mice at 2 weeks after spared nerve injury (SNI), an early time point when the mice began to show mild depressive symptoms. Our results showed that the SNI-induced transcriptomic changes in female and male mice were largely distinct. Interestingly, the female mice exhibited more robust transcriptomic changes in the ACC than male, whereas the opposite pattern occurred in the mPFC. Cell type enrichment analyses revealed that the differentially expressed genes involved genes enriched in neurons, various types of glia and endothelial cells. We further performed gene set enrichment analysis (GSEA), which revealed significant de-enrichment of myelin sheath development in both female and male mPFC after SNI. In the female ACC, gene sets for synaptic organization were enriched, and gene sets for extracellular matrix were de-enriched after SNI, while such signatures were absent in male ACC. Collectively, these findings revealed region-specific and sexual dimorphism at the transcriptional levels induced by neuropathic pain, and provided novel therapeutic targets for chronic pain and its associated affective disorders.

Dataset Information

Epigenetic Signatures of Smoking in Five Brain Regions.

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Epigenetic Signatures of Smoking in Five Brain Regions.

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