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Predictors of Alcohol Misuse: Role of MAOA Genotype, Methylation, Transcription, and Negative and Positive Environmental factors
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Center for Clinical Research, Uppsala University, Västerås, Sweden. (Science for Life Laboratory)
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Alcohol misuse is a risk factor for alcohol use disorder (AUD). Gene-environment interactions contribute to the risk or resilience for AUD. A functional polymorphism in the promoter of the monoamine oxidase A gene (MAOA-uVNTR), in interaction with negative environment (Eneg), is associated with alcohol misuse and AUD. Men carrying short (MAOA-S), and women carrying long (MAOA-L), MAOA-uVNTR alleles who experienced maltreatment or poor parent-child relationships are at increased susceptibility to alcohol misuse and AUD. This thesis assessed whether the association of MAOAxEneg with the risk of AUD is moderated by MAOA methylation or positive environment and whether MAOA methylation-associated changes in MAOA expression in the stress- and reward-related brain regions is an underlying mechanism.

The thesis reveals that the association of MAOAxEneg with alcohol misuse is moderated by MAOA methylation in men, but not in women. In the clinical sample, men carrying MAOA-S allele who experienced maltreatment and had low MAOA methylation displayed higher alcohol-related problems than those without maltreatment or MAOA-L carriers with and without maltreatment. Furthermore, the quality of the parent–child relationship moderated the association of MAOAxEneg with alcohol misuse in a sex- and AUD stage-dependent manner. In the non-clinical sample of adolescents, girls carrying MAOA-L allele who experienced maltreatment and poor parent–child relationship displayed higher alcohol consumption, whereas those with average or good parent–child relationship had lower alcohol consumption. In the clinical sample of adolescents, however, no such association was observed. These results suggest that a good parent–child relationship protects MAOA susceptibility genotype carriers exposed to maltreatment during the early stages of alcohol use. The preclinical studies revealed that the male rats exposed to Eneg and alcohol had higher CpG-specific Maoa promoter methylation, which was associated with lower Maoa expression in the nucleus accumbens than the control rats. Thus, MAOA methylation-associated changes in MAOA expression in the nucleus accumbens might mediate the effect of environment on alcohol use.

The thesis contributes to the understanding of biological mechanisms underlying MAOAxEnvironment effect and the critical role of MAOA methylation and positive environment in moderating risk and resilience for AUD. Also, the identification of subgroups may benefit from personalised interventions for AUD.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2019. , p. 115
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1602
Keywords [en]
Alcohol, AUD, MAOA, methylation, expression, early-life stress, maltreatment, parent–child relationship, gene–environment interactions.
National Category
Medical and Health Sciences
Research subject
Medical Science
Identifiers
URN: urn:nbn:se:uu:diva-393306ISBN: 978-91-513-0769-5 (print)OAI: oai:DiVA.org:uu-393306DiVA, id: diva2:1358785
Public defence
2019-11-27, Aulan, 21, Västmanlands Hospital, Västerås, 13:15 (English)
Opponent
Supervisors
Available from: 2019-11-06 Created: 2019-10-08 Last updated: 2019-11-27
List of papers
1. Associations Between MAOA-uVNTR Genotype, Maltreatment, MAOA Methylation, and Alcohol Consumption in Young Adult Males
Open this publication in new window or tab >>Associations Between MAOA-uVNTR Genotype, Maltreatment, MAOA Methylation, and Alcohol Consumption in Young Adult Males
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2018 (English)In: Alcoholism: Clinical and Experimental Research, ISSN 0145-6008, E-ISSN 1530-0277, Vol. 42, no 3, p. 508-519Article in journal (Refereed) Published
Abstract [en]

Background

Epigenetic mechanisms are candidate moderators of the effect of maltreatment on brain and behavior. Interactions between maltreatment and the monoamine oxidase A upstream variable number tandem repeat genotype (MAOA-uVNTR) are associated with alcohol-related problems. However, presently it is not known whether DNA methylation moderates this association. The study focused on 53 young adult males and aimed to determine whether MAOA methylation moderated the association of alcohol-related problems with the interaction of MAOA-uVNTR and maltreatment, and whether alcohol consumption moderated the association of MAOA methylation with the interaction of MAOA-uVNTR and maltreatment.

Methods

MAOA-uVNTR genotypes with 3 and > 3 repeats were categorized as short (S) and long (L), respectively. Data on maltreatment were obtained retrospectively, using self-reported questionnaires. DNA methylation of 16 candidate CpGs within part of the MAOA first exon and intron was assessed and grouped based on principal component analyses. Alcohol-related problems were assessed using the Alcohol Use Disorders Identification Test (AUDIT). Alcohol consumption was measured using AUDIT-C. Moderation effects were assessed and probed using the moderated moderation model and Johnson-Neyman's method, respectively.

Results

Carriers of the S allele, who experienced maltreatment and displayed lower Component 1 (mean of CpGs 13-16 in the first intron) MAOA methylation levels, reported higher AUDIT score in contrast to L-allele carriers. Carriers of the S allele, who reported higher AUDIT-C score and experienced maltreatment, displayed lower Component 3 (mean of CpGs 2-6 in the first exon) MAOA methylation levels than L-allele carriers.

Conclusions

Intronic methylation moderated the association of alcohol-related problems with the interaction of MAOA-uVNTR and maltreatment. Alcohol consumption moderated the association of exonic methylation with the interaction of MAOA-uVNTR and maltreatment. These results suggest that epigenetic factors as well as genotype and maltreatment play a role in the development of alcohol misuse among young adult males.

Keywords
Alcohol, DNA Methylation, Gene by Environment, MAOA-, uVNTR, Maltreatment
National Category
Psychiatry
Identifiers
urn:nbn:se:uu:diva-351264 (URN)10.1111/acer.13578 (DOI)000426489600005 ()29222910 (PubMedID)
Funder
Swedish Research Council, VR: 2015-00495
Available from: 2018-06-11 Created: 2018-06-11 Last updated: 2019-10-08Bibliographically approved
2. Effect of voluntary alcohol consumption on Maoa expression in the mesocorticolimbic brain of adult male rats previously exposed to prolonged maternal separation.: Maoa,ELS and alcohol
Open this publication in new window or tab >>Effect of voluntary alcohol consumption on Maoa expression in the mesocorticolimbic brain of adult male rats previously exposed to prolonged maternal separation.: Maoa,ELS and alcohol
2015 (English)In: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 5, article id e690Article in journal (Refereed) Published
Abstract [en]

Discordant associations between monoamine oxidase A (MAOA) genotype and high alcohol drinking have been reported in human and non-human primates. Environmental influences likely moderate genetic susceptibility. The biological basis for this interplay remains elusive, and inconsistencies call for translational studies in which conditions can be controlled and brain tissue is accessible. The present study investigated whether early life stress and subsequent adult episodic alcohol consumption affect Maoa expression in stress- and reward-related brain regions in the rat. Outbred Wistar rats were exposed to rearing conditions associated with stress (prolonged maternal separation) or no stress during early life, and given free choice between alcohol and/or water in adulthood. Transcript levels of Maoa were assessed in the ventral tegmental area, nucleus accumbens (NAc), medial prefrontal cortex, cingulate cortex, amygdala and dorsal striatum (DS). Blood was collected to assess corticosterone levels. After alcohol consumption, lower blood corticosterone and Maoa expression in the NAc and DS were found in rats exposed to early life stress compared with control rats. An interaction between early life stress and voluntary alcohol intake was found in the NAc. Alcohol intake before death correlated negatively with Maoa expression in DS in high alcohol-drinking rats exposed to early life stress. Maoa expression is sensitive to adulthood voluntary alcohol consumption in the presence of early life stress in outbred rats. These findings add knowledge of the molecular basis of the previously reported associations between early life stress, MAOA and susceptibility to alcohol misuse.

National Category
Medical and Health Sciences Psychiatry
Identifiers
urn:nbn:se:uu:diva-271230 (URN)10.1038/tp.2015.186 (DOI)000367666900002 ()26645625 (PubMedID)
Funder
Swedish Research Council, K2012-61X-22090-01-3Lars Hierta Memorial Foundation
Available from: 2016-01-07 Created: 2016-01-07 Last updated: 2019-10-08Bibliographically approved
3. Early life stress and voluntary alcohol consumption in relation to Maoa methylation in male rats.
Open this publication in new window or tab >>Early life stress and voluntary alcohol consumption in relation to Maoa methylation in male rats.
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2019 (English)In: Alcohol, ISSN 0741-8329, E-ISSN 1873-6823, Vol. 79, p. 7-16Article in journal (Refereed) Published
Abstract [en]

Early life stress (ELS) or alcohol consumption can influence DNA methylation and affect gene expression. The monoamine oxidase A (Maoa) encodes the enzyme that metabolizes monoaminergic neurotransmitters crucial for the stress response, alcohol reward, and reinforcement. Previously, we reported lower Maoa expression in the nucleus accumbens and dorsal striatum of male rats exposed to ELS during the first three postnatal weeks, and to voluntary alcohol consumption in adulthood, compared with controls. The present study continued to investigate the effect of ELS and alcohol consumption on Maoa methylation, and its relation to Maoa expression in these animals. We selected candidate CpGs after performing next-generation bisulfite sequencing of the Maoa promoter, intron 1-5, exons 5 and 6, together comprised of 107 CpGs, in a subgroup of rats. Pyrosequencing was used to analyse the methylation of ten candidate CpGs in the promoter and intron 1 in the entire sample. ELS and alcohol displayed an interaction effect on CpG-specific methylation in the dorsal striatum. CpG-specific methylation correlated with Maoa expression, corticosterone levels, and alcohol consumption in a brain region-specific manner. CpG-specific methylation in the Maoa promoter was a potential moderator of the interaction of ELS with alcohol consumption on Maoa expression in the NAc. However, the findings were sparse, did not survive correction for multiple testing, and the magnitude of differences in methylation levels was small. In conclusion, CpG-specific Maoa methylation in the promoter and intron 1 may associate with ELS, alcohol consumption and Maoa expression in reward-related brain regions.

Keywords
Alcohol, DNA methylation, Gene expression, Maoa, Maternal separation, Stress
National Category
Psychiatry Neurosciences
Identifiers
urn:nbn:se:uu:diva-368636 (URN)10.1016/j.alcohol.2018.11.001 (DOI)000483450600002 ()30414913 (PubMedID)
Funder
Forte, Swedish Research Council for Health, Working Life and Welfare, 2011-0627Fredrik och Ingrid Thurings StiftelseLars Hierta Memorial FoundationThe Swedish Brain Foundation, PS2013-0052Swedish Research Council, K2012-61X-22090-01-3Swedish Research Council, VR: 2015-00495EU, FP7, Seventh Framework Programme, INCA 600398Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Available from: 2018-12-06 Created: 2018-12-06 Last updated: 2019-10-17Bibliographically approved
4. The Interaction of MAOA-uVNTR Genotype, Maltreatment, and Positive Parent-child relationship Predicts Adolescent Alcohol Drinking in a Sex-Dependent Manner
Open this publication in new window or tab >>The Interaction of MAOA-uVNTR Genotype, Maltreatment, and Positive Parent-child relationship Predicts Adolescent Alcohol Drinking in a Sex-Dependent Manner
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(English)Manuscript (preprint) (Other academic)
Keywords
MAOA, Maltreatment, Alcohol, Parent-child relationship
National Category
Medical and Health Sciences
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-393297 (URN)
Available from: 2019-09-19 Created: 2019-09-19 Last updated: 2019-10-08

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