Epigenetic Marker May ID Future Alcohol-Use Disorder

Gene PPM1G hypermethylation is associated with alcohol use disorder
Gene PPM1G hypermethylation is associated with alcohol use disorder
Hypermethylation in gene PPM1G is associated with behaviors that increase risk in adolescents for future alcohol-related problems.

TORONTO — The first evidence for an epigenetic marker associated with alcohol consumption and its underlying neurobehavioral phenotype has been uncovered, according to research presented at the American Psychiatric Association Annual Meeting.

“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,” explained Barbara Ruggeri, PhD, of Kings College in London, United Kingdom, and colleagues in the American Journal of Psychiatry, where the study was simultaneously released online.

“Early escalation of alcohol use among adolescents is a risk factor for future alcohol use disorders and is associated with externalizing disorders.”

To investigate the relationship between nongenetic influences and alcohol consumption, the investigators carried out a genome-wide analysis of DNA methylation of 18 monozygotic twin pairs discordant for alcohol use disorder and validated differentially methylated regions. 

Following validation, the investigators characterized the differentially methylated regions using personality trait assessment and functional MRI in a sample of 499 adolescents enrolled in the IMAGEN study. Among the 499 adolescents, 352 reported drinking between ages 14 and 16.

Seventy-seven differentially methylated regions that exhibit an alcohol use disorder-associated differential methylation were identified. The majority (68%) of these regions were hypermethylated in the affected twin, which is consistent with previous findings showing an association between DNA hypermethylation and alcohol use disorder, according to the researchers.

Hypermethylation in the 3:-protein phosphatase-1G (PPM1G) gene locus was linked with alcohol use disorder. An association of PPM1G hypermethylation with early escalation of alcohol use and increased impulsiveness was observed as well as an association of PPM1G hypermethylation with increased blood-oxygen level-dependent response in the right subthalamic nucleus during an impulsiveness task.

“We identified a differentially methylated region in the PPM1G gene associated with alcohol use disorders in adults, and we provide evidence for its association with brain mechanisms and behaviors that underlie risk in adolescents for future alcohol-related problems,” concluded the researchers.

“Our data indicate that methylation of PPM1G may influence behavioral inhibition by altering activity of the right subthalamic nucleus, which integrates neural signals necessary for behavioral control.”


Ruggeri B, et al. Association of Protein Phosphatase PPM1G With Alcohol Use Disorder and Brain Activity During Behavioral Control in a Genome-Wide Methylation Analysis. Am J Psych. 2015; doi: 10.1176/appi.ajp.2014.14030382.