Epigenetic Signatures of Smoking in Five Brain Regions

Zillich, Lea; Poisel, Eric; Streit, Fabian; Frank, Josef; Fries, Gabriel R.; Foo, Jerome C.; Friske, Marion M; Sirignano, Lea; Hansson, Anita C.; Nöthen, Markus M.; Witt, Stephanie H.; Walss‐Bass, Consuelo; Spanagel, Rainer; Rietschel, Marcella

doi:10.3390/jpm12040566

Cited by 6 publications

(8 citation statements)

References 40 publications

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“…Importantly, effects of smoking on DNA methylation in brain cells have been hypothesized to contribute to addiction [3], but it is largely unknown to what extent addiction-related DNA methylation dynamics are captured in other tissues such as blood. Nicotinic receptors are especially abundant in the central and peripheral nervous system, but are also present in other tissues.…”

Section: Discussionmentioning

confidence: 99%

“…Based on comparison with loci identified in large genome-wide association studies (GWAS), differentially methylated sites were significantly enriched in genes implicated in well-established smoking-associated diseases, such as cancer, cardiovascular disease, inflammatory disease and lung disease, as well as in genes associated with schizophrenia and educational attainment[2]. It has been hypothesized that smoking-induced methylation changes might also contribute to the addictive effect of smoking[3].…”

Section: Introductionmentioning

confidence: 99%

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Genome-wide DNA methylation profiles in smoking discordant and concordant monozygotic twin pairs

Dongen

Willemsen

Geus

et al. 2022

Preprint

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Smoking-associated DNA methylation levels identified through epigenome-wide association studies (EWAS) are generally ascribed to smoking-reactive mechanisms, but the contribution of a shared genetic predisposition to smoking and DNA methylation levels is typically not accounted for. We exploited a strong within-family design, i.e., the discordant monozygotic twin design, to study reactiveness of DNA methylation in blood cells to smoking and reversibility of methylation patterns upon quitting smoking. Illumina HumanMethylation450 BeadChip data were available for 769 monozygotic twin pairs (mean age=36 years,range=18-78, 70% female), including pairs discordant or concordant for current or former smoking. In pairs discordant for current smoking, 13 differentially methylated CpGs were found between current smoking twins and their genetically identical co-twin who never smoked. Top sites include multiple CpGs in CACNA1D and GNG12, which encode subunits of a calcium voltage-gated channel and G protein, respectively. These proteins interact with the nicotinic acetylcholine receptor, suggesting that methylation levels at these CpGs might be reactive to nicotine exposure. All 13 CpGs have been previously associated with smoking in unrelated individuals and data from monozygotic pairs discordant for former smoking indicated that methylation patterns are to a large extent reversible upon smoking cessation. We further showed that differences in smoking level exposure for monozygotic twins who are both current smokers but differ in the number of cigarettes they smoke are reflected in their DNA methylation profiles. In conclusion, by analysing data from monozygotic twins, we robustly demonstrate that DNA methylation level in human blood cells is reactive to cigarette smoking.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Genome-wide DNA methylation profiles in smoking discordant and concordant monozygotic twin pairs

Dongen

Willemsen

Geus

et al. 2022

Preprint

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“…AHRR methylation in blood and saliva can predict smoking status (Current versus Former and Never) and has been proposed as an objective tool to assess smoking status (Philibert et al 2020, Grieshober et al 2020. In one comprehensive study, Christensen et al performed a genome wide methylation analysis in several tissues including brain tissue but in a very small sample of brains (N=12) and blood (N=15) and not from the same subjects making it impossible to perform within subject comparisons of tissue specific alterations associated with smoking (Christensen et al 2009).A larger EWAS study of five brain regions (anterior cingulate cortex, Brodmann Area 9, caudate nucleus, putamen, and ventral striatum) ranging from 38 to 72 samples per region identified 16 differentially methylated regions and a strong correlation between in matched brain and blood samples in a small (N=10) subsample (Zillich et al 2022).…”

Section: Discussionmentioning

confidence: 99%

“…However, very little is understood about long-term gene expression effects of nicotine in the NAcc in the human brain. Postmortem investigations have been conducted across brain regions, particularly in areas implicated in the addiction neurocircuitry (e.g., cortical, striatal, and limbic regions) (Zillich et al 2022, Webb et al 2015, Markunas et al 2021, Sey et al 2022, Quach et al 2020, Barrie et al 2017). However, relatively few studies used RNA-seq to analyze the NAcc, a key area associated with addiction and a target of deep brain stimulation (DBS) for treatment-resistant substance abuse including tobacco (Navarro et al 2022, Chang et al 2022).…”

Section: Introductionmentioning

confidence: 99%

Overexpression of Cancer- and Neurotransmitter-Associated Genes in the Nucleus Accumbens of Smokers

Mamdani

Bunney

Cartagena

et al. 2022

Preprint

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The effects of smoking in the human brain were explored at the molecular level in the nucleus accumbens (NAcc), a key brain region involved in tobacco addiction. Gene expression data from post-mortem NAcc were analyzed according to smoking habits: Never smokers, Former smokers and Current smokers at the time of death. The effect of smoking was determined using an ANCOVA model, controlling for potential confounders (psychiatric diagnosis, gender, age, post-mortem interval, and brain pH) followed by pair-wise post-hoc comparisons. Q-values (false discovery rate adjusted p-values) < 0.05 were used in combination with afold change of > ±1.3 to identify the most relevant genes. The greatest number of differentially expressed genes (DEGs) were found in subjects with a recent history of smoking (Current smokers) compared to either Former or Never smokers. Only two genes were differentially expressed between Former and Never smokers, suggesting that the effects of smoking on gene expression in the brain may be transient. Ingenuity Pathway Analysis (IPA) of DEGs identified a significant over-representation of neurotransmitter system genes (glutamate, GABA) in Current smokers. IPA also revealed many genes associated with cancer in Current smokers compared to Former and Never smokers despite no known cancer in any subjects. Genes associated with neoplasms, glioblastoma, gliomas and tumor regulations are among the top 10 transcripts. Our findings show that active smokers have a significant increase in cancer-related genes and alterations in glutamate and GABA neurotransmitter systems in the NAcc. To our knowledge this is the first study to identify cancer-related genes in the NAcc in Current smokers who have no evidence of cancer.

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“…Based on comparison with loci identified in large genome-wide association studies (GWASs), differentially methylated sites were significantly enriched in genes implicated in well-established smoking-associated diseases, such as cancer, cardiovascular disease, inflammatory disease, and lung disease, as well as in genes associated with schizophrenia and educational attainment ( Joehanes et al, 2016 ). It has been hypothesized that smoking-induced methylation changes might also contribute to the addictive effect of smoking ( Zillich et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

Effects of smoking on genome-wide DNA methylation profiles: A study of discordant and concordant monozygotic twin pairs

van Dongen,

Willemsen,

de Geus

et al. 2023

eLife

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Background: Smoking-associated DNA methylation levels identified through epigenome-wide association studies (EWAS) are generally ascribed to smoking-reactive mechanisms, but the contribution of a shared genetic predisposition to smoking and DNA methylation levels is typically not accounted for.Methods: We exploited a strong within-family design, i.e., the discordant monozygotic twin design, to study reactiveness of DNA methylation in blood cells to smoking and reversibility of methylation patterns upon quitting smoking. Illumina HumanMethylation450 BeadChip data were available for 769 monozygotic twin pairs (mean age=36 years,range=18-78, 70% female), including pairs discordant or concordant for current or former smoking.Results: In pairs discordant for current smoking, 13 differentially methylated CpGs were found between current smoking twins and their genetically identical co-twin who never smoked. Top sites include multiple CpGs in CACNA1D and GNG12, which encode subunits of a calcium voltage-gated channel and G protein, respectively. These proteins interact with the nicotinic acetylcholine receptor, suggesting that methylation levels at these CpGs might be reactive to nicotine exposure. All 13 CpGs have been previously associated with smoking in unrelated individuals and data from monozygotic pairs discordant for former smoking indicated that methylation patterns are to a large extent reversible upon smoking cessation. We further showed that differences in smoking level exposure for monozygotic twins who are both current smokers but differ in the number of cigarettes they smoke are reflected in their DNA methylation profiles.Conclusions: In conclusion, by analysing data from monozygotic twins, we robustly demonstrate that DNA methylation level in human blood cells is reactive to cigarette smoking.Funding: We acknowledge funding from the National Institute on Drug Abuse grant DA049867, the Netherlands Organization for Scientific Research (NWO): Biobanking and Biomolecular Research Infrastructure (BBMRI–NL, NWO 184.033.111) and the BBRMI-NL-financed BIOS Consortium (NWO 184.021.007), NWO Large Scale infrastructures X-Omics (184.034.019), Genotype/phenotype database for behavior genetic and genetic epidemiological studies (ZonMw Middelgroot 911-09-032); Netherlands Twin Registry Repository: researching the interplay between genome and environment (NWO-Groot 480-15-001/674); the Avera Institute, Sioux Falls (USA) and the National Institutes of Health (NIH R01 HD042157-01A1, MH081802, Grand Opportunity grants 1RC2 MH089951 and 1RC2 MH089995); epigenetic data were generated at the Human Genomics Facility (HuGe-F) at ErasmusMC Rotterdam. Cotinine assaying was sponsored by the Neuroscience Campus Amsterdam. DIB acknowledges the Royal Netherlands Academy of Science Professor Award (PAH/6635).

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Epigenetic Signatures of Smoking in Five Brain Regions

Cited by 6 publications

References 40 publications

Genome-wide DNA methylation profiles in smoking discordant and concordant monozygotic twin pairs

Genome-wide DNA methylation profiles in smoking discordant and concordant monozygotic twin pairs

Overexpression of Cancer- and Neurotransmitter-Associated Genes in the Nucleus Accumbens of Smokers

Effects of smoking on genome-wide DNA methylation profiles: A study of discordant and concordant monozygotic twin pairs

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