2014 › Trails



Genetic studies: Catechol-O-methyltransferase gene methylation and substance use in adolescents. The TRAILS study

Authors: LJ van der Knaap, JM Schaefer, IHA Franken, FC Verhulst, FVA van Oort, H Riese

 Substance use often starts in adolescence and poses a major problem for society and individual health. The dopamine system plays a role in substance use, and catechol-O-methyltransferase (COMT) is an important enzyme that degrades dopamine. The Val(108/158) Met polymorphism modulates COMT activity and thus dopamine levels, and has been linked to substance use. COMT gene methylation, on the other hand, may affect expression and thus indirectly COMT activity. We investigated whether methylation of the COMT gene was associated with adolescents' substance use. Furthermore, we explored whether the COMT Val(108/158) Met polymorphism interacts with COMT gene methylation in association with substance use. In 463 adolescents (mean age=16, 50.8% girls), substance use (cigarette smoking, alcohol and cannabis use) was assessed with self-report questionnaires. From blood samples, COMT Val(108/158) Met genotype and methylation rates of membrane bound (MB) and soluble (S) COMT promoters were assessed. MB-COMT promoter methylation was associated with non-daily smoking [odds ratio (OR)=1.82, P=0.03], but not with daily smoking (OR=1.20, P=0.34), MB-COMT promoter methylation was not associated with alcohol use. Adolescents with the Met/Met genotype and high rates of MB-COMT promoter methylation were less likely to be high-frequent cannabis users than adolescents with the Val/Val or Val/Met genotype. S-COMT promoter methylation was not associated with substance use. These results indicate that there is an association between substance use and COMT gene methylation. Although this association is complex, combining genetic and epigenetic variation of the COMT gene may be helpful in further elucidating the influence of the dopamine system on substance use in adolescence.

© 2014 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

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Genetic studies: Glucocorticoid receptor gene (NR3C1) methylation following stressful events between birth and adolescence. The TRAILS study

Authors: Van der Knaap, L.J., Riese H., Hudziak J.J., Verbiest M.M.P.J., Verhulst F.C., Oldehinkel A.J., van Oort F.V.A

Stress early in life is a known risk factor for the development of affective disorders later in life. Epigenetic mechanisms, such as DNA methylation, may have an important role in mediating that risk. Recent epigenetic research reported on the long-term relationship between traumatic stress in childhood and DNA methylation in adulthood. In this study, we examined the impact of various types of stress (perinatal stress, stressful life events (SLEs) and traumatic youth experiences) on methylation of the glucocorticoid receptor gene (NR3C1) in the blood of a population sample of 468 adolescents (50.4% female, mean age 16.1 years). Second, we determined whether stress at different ages was associated with higher NR3C1 methylation. NR3C1 methylation rates were higher after exposure to SLEs and after exposure to traumatic youth experiences. NR3C1 methylation in adolescence was not higher after exposure to perinatal stress. Experience of SLEs in adolescence was associated with a higher NR3C1 methylation, independently of childhood SLEs. We demonstrate that not only traumatic youth experiences but also (more common) SLEs are associated with higher NR3C1 methylation. In addition, our findings underline the relevance of adolescent stress for epigenetic changes in the NR3C1 gene.

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Genetic studies: The Interplay Between Peer Rejection and Acceptance in Preadolescence and Early Adolescence, Serotonin Transporter Gene, and Antisocial Behavior in Late Adolescence: The TRAILS Study

Authors: Kretschmer T., Sentse M., Dijkstra J.K., Veenstra R.

Gene-environment studies on adolescents' peer contexts are important for understanding the interplay between biological and social antecedents of adolescent psychopathology. To this end, this study examined the roles of serotonin transporter (5-HTTLPR) and preadolescent and early adolescent peer rejection and acceptance, as well as the interaction between genotype and environment as predictors of antisocial behavior. Longitudinal data from TRAILS (TRacking Adolescents' Individual Lives Survey), a Dutch cohort study into adolescent development that includes peer reports of rejection and acceptance assessed at 11.1 and 13.6 years and self-reported antisocial behavior at 19.1 years was used. The interaction between 5-HTTLPR and preadolescent peer rejection predicted antisocial behavior with carriers of the 5-HTTLPR short-short variant most strongly affected. No main or interaction effects were found for early adolescent rejection or interactions involving peer acceptance. Our results extend the gene-environment interaction literature by focusing on peer relationship experiences.

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