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Hypermethylation of PPM1G gene site may be linked to alcohol abuse

The hypermethylation of an area of the PPM1G gene appears to be linked to alcohol abuse disorders in adults, and may also play a role in brain mechanisms related to impulse control in adolescents, according to recent findings.

In the study, researchers identified 18 pairs of monozygotic twins from the population-based Finn Twin 16 study. These participants were evaluated at the age of 16, and followed up with surveys at ages 17, 18.5 and 24. The twin pairs were discordant for alcohol dependency or abuse. DNA was extracted from serum samples taken at the age 24 assessment, and a genome-wide methylation analysis was conducted. The researchers evaluated methylated sites in the following genes: PPM1G, INS-IGF2, FMN1, SEPHS2, SLC6A3, AIM1, OPRL1 and PIPOX.

After validating these sites, the researchers further investigated the methylation characteristics of the PPM1G gene in 499 adolescents aged 14 years who were enrolled in IMAGEN, a European, multicenter, imaging genetic/epigenetic study.

The researchers assessed this sample to determine whether the differentially methylated site of PPM1G was related to the extent of alcohol exposure at age 14.

They found that in the twin pairs discordant for alcohol abuse, most of the 77 differentially methylated sites of PPM1G (68%) demonstrated hypermethylation in the twin affected by alcohol dependency or abuse. Among twins with alcohol-related disorders, there were significant percent increases in methylation of the CpG site in the 3:UTR of PPM1G (P = .005, mean delta = 2.4%) and in a CpG region within the OPRL1 probe (P = .017, mean delta = 3.6%), which corroborated microarray findings. A possible link was identified between increased daily drinking between the ages of 14 and 16 and hypermethylated PP1MG. The researchers also found that PPM1G hypermethylation was correlated with an elevation in blood-oxygen level-dependent response in the subthalamic nucleus during a task involving behavioral inhibition.

According to the researchers, the increased activity of the subthalamic nucleus in those with PPM1G hypermethylation suggests that these individuals may require greater effort in order to successfully inhibit their behavior. These data may be useful in predicting future alcohol disorders in adolescents, the researchers wrote.

“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,” they wrote. “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.” – by Jennifer Byrne

Disclosure: Ruggeri reports no relevant financial disclosures. Please see the full study for a list of all other authors’ relevant financial disclosures.