A Gene That Controls Dopamine Breakdown Showed Epigenetic Links to Teen Substance Use | Research

The takeaway

Methylation of the COMT gene promoter was associated with smoking in adolescents, and a specific gene-epigenetic interaction influenced high-frequency cannabis use.

Read this if you want to understand how genetics and epigenetics interact to influence teen substance use.

Met/Met genotype + high COMT methylation was protective against frequent cannabis use

What the researchers found

In 463 adolescents (mean age 16), methylation of the membrane-bound COMT (MB-COMT) promoter was associated with non-daily smoking (OR=1.82, p=0.03), but not with daily smoking or alcohol use.

A gene-epigenetic interaction was found for cannabis use: adolescents with the Met/Met genotype (associated with higher dopamine levels) and high MB-COMT promoter methylation were less likely to be high-frequency cannabis users compared to those with Val/Val or Val/Met genotypes. This suggests that the combination of high dopamine availability (Met/Met) and additional epigenetic reduction of COMT expression may be protective against frequent cannabis use.

Soluble COMT (S-COMT) promoter methylation was not associated with any substance use measure.

Why it matters

This study bridges genetics and epigenetics in adolescent substance use, showing that it is not just which gene variants you carry but how those genes are regulated (through methylation) that influences substance use risk. This more nuanced view of genetic risk could eventually inform personalized prevention.

The numbers in context

463 adolescents, mean age 16. MB-COMT methylation associated with non-daily smoking (OR=1.82, p=0.03). Met/Met genotype + high methylation: protective against high-frequency cannabis use. S-COMT methylation: no associations.

How the study worked

In 463 adolescents from the TRAILS longitudinal study (mean age 16, 50.8% girls), substance use (cigarettes, alcohol, cannabis) was assessed by self-report questionnaires. From blood samples, COMT Val108/158Met genotype and methylation rates of both membrane-bound and soluble COMT promoters were measured. Logistic regression tested associations between methylation, genotype, and substance use.

What this study cannot tell us

This was a cross-sectional analysis that cannot determine whether methylation changes preceded or resulted from substance use. Blood methylation may not reflect brain methylation patterns. The sample size was moderate, and the cannabis finding involved a subgroup analysis. The TRAILS study is Dutch, and findings may not generalize across populations.

How to read the evidence

This is a cross-sectional epigenetic study with a moderate sample size. The findings are preliminary and the causal direction is unclear.

When this study was published

Published in 2014. Epigenetic research on substance use has expanded substantially since, though clinical applications remain distant.

The bigger picture

Epigenetic research is revealing that genetic predisposition to substance use is more complex than previously thought. The COMT gene sits at a critical junction in dopamine metabolism, and this study shows that both the genetic sequence and its epigenetic regulation contribute to substance use patterns in adolescents.

Questions still open

Does substance use itself alter COMT methylation, or do pre-existing methylation patterns predict substance use? Would longitudinal data clarify the causal direction? Can epigenetic markers be used to identify at-risk adolescents?

Common questions

What is COMT?

Catechol-O-methyltransferase (COMT) is an enzyme that breaks down dopamine in the brain. The Val/Met polymorphism affects how quickly dopamine is cleared: Met/Met carriers have slower clearance and higher dopamine levels, while Val/Val carriers have faster clearance.

What is DNA methylation?

It is an epigenetic modification where methyl groups are added to DNA, typically at gene promoters. Higher methylation usually reduces gene expression. Unlike genetic sequence changes, methylation patterns can change over a person's lifetime in response to environmental factors.

Read the original research

Catechol-O-methyltransferase gene methylation and substance use in adolescents: the TRAILS study.

Genes, brain, and behavior, 13(7), 618-25

View on PubMed ↗Publisher’s paper ↗

Citation

van der Knaap, L J; Schaefer, J M; Franken, I H A; Verhulst, F C; van Oort, F V A; Riese, H. (2014). Catechol-O-methyltransferase gene methylation and substance use in adolescents: the TRAILS study.. Genes, brain, and behavior, 13(7), 618-25. https://doi.org/10.1111/gbb.12147