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. 2015 Jun;172(6):543-52.
doi: 10.1176/appi.ajp.2014.14030382. Epub 2015 May 18.

Association of Protein Phosphatase PPM1G With Alcohol Use Disorder and Brain Activity During Behavioral Control in a Genome-Wide Methylation Analysis

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Association of Protein Phosphatase PPM1G With Alcohol Use Disorder and Brain Activity During Behavioral Control in a Genome-Wide Methylation Analysis

Barbara Ruggeri et al. Am J Psychiatry. .
Free PMC article

Abstract

Objective: The genetic component of alcohol use disorder is substantial, but monozygotic twin discordance indicates a role for nonheritable differences that could be mediated by epigenetics. Despite growing evidence associating epigenetics and psychiatric disorders, it is unclear how epigenetics, particularly DNA methylation, relate to brain function and behavior, including drinking behavior.

Method: The authors carried out a genome-wide analysis of DNA methylation of 18 monozygotic twin pairs discordant for alcohol use disorder and validated differentially methylated regions. After validation, the authors characterized these differentially methylated regions using personality trait assessment and functional MRI in a sample of 499 adolescents.

Results: Hypermethylation in the 3'-protein-phosphatase-1G (PPM1G) gene locus was associated with alcohol use disorder. The authors found association of PPM1G hypermethylation with early escalation of alcohol use and increased impulsiveness. They also observed association of PPM1G hypermethylation with increased blood-oxygen-level-dependent response in the right subthalamic nucleus during an impulsiveness task.

Conclusions: Overall, the authors provide first evidence for an epigenetic marker associated with alcohol consumption and its underlying neurobehavioral phenotype.

Figures

Figure 1
Figure 1. Association of PPM1G Methylation With Drinking Escalation (N=352) and Trait Impulsiveness (N=399) in Adolescentsa
aAs shown in panel A, PPM1G methylation is positively associated with an increase in amount of daily drinking (corrected p=0.024). PPM1G methylation at age 14 predicts an increase in daily drinking between ages 14 and 16. In panel B, an increase in amount of daily drinking is positively associated with impulsiveness in 16-year-old adolescents (corrected p=0.041). In panel C, PPM1G methylation is positively associated with impulsiveness (corrected p=0.032). All graphs represent data for each individual and have linear fit lines. In panels A and B, escalation of daily drinking is measured as the difference between age 14 and age 16 on an item on amount of daily drinking from the European School Survey Project on Alcohol and Other Drugs questionnaire (on a five-level ordinal scale). In panels B and C, impulsiveness is represented by a sum score of five items (on a five-level ordinal scale) of the Substance Use Risk Profile Scale.
Figure 2
Figure 2. Association of PPM1G Methylation and Activation of the Subthalamic Nucleus During a Stop Signal Task in Adolescents (N=393)a
aAs shown in panel A, PPM1G methylation is positively associated with blood-oxygen-level-dependent (BOLD) activation in the right subthalamic nucleus in 14-year-olds (corrected p=0.038). The graph depicts the percentage of PPM1G methylation and averaged beta values of activation of the right subthalamic nucleus for each individual; a linear fit line was added. In panel B, a coronal section shows methylation differences in activation of the right subthalamic nucleus (t value of activation, with a lighter color indicating a stronger activation) during successful inhibition, indicating an association between PPM1G methylation and activation of the right subthalamic nucleus (coordinates: x=10, y=−15, z=−5).

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