INTERACTION OF MAOA GENOTYPE, DNA METHYLATION AND STRESSFUL LIFE EVENTS IN RELATION TO ALCOHOL MISUSE

Epigenetic mechanisms are candidate mediators of the effects of stressful life events (SLEs) on the brain. Stress, especially during critical developmental periods, might render an individual vulnerable to alcohol misuse later in life. Previous studies report sex-dependent interactions of Monoamine Oxidase A upstream variable number tandem repeat genotype (MAOA-uVNTR) and SLEs in association with alcohol misuse, however whether DNA methylation moderates this effect is unknown. The aim of the present longitudinal study was to investigate whether the interaction between MAOA-uVNTR genotype, promoter DNA methylation and SLEs associates with alcohol misuse in 56 males and 78 females whom as adolescents had sought treatment for substance misuse in Sweden. The functional MAOA-uVNTR polymorphism, consisting of a 30-bp repeated sequence present in 2, 3, 3.5, 4, or 5 copies, was genotyped. Alleles with less or more than 3 copies were grouped into short (S) and long (L) alleles, respectively. Methylation analysis of 16 candidate CpGs within the MAOA promoter (Chr.X: 43515544 - 43515991) was performed. Data on SLEs (i.e. physical abuse by parents, sexual abuse and experience of victimization by peers) was obtained from a self-report questionnaire. Alcohol misuse at the time of first contact with the clinic and after five years was assessed using the Alcohol Use Disorder Identification Test (AUDIT). The general linear model with type III sum of square was used to analyze interaction effects. In males but not females, an interaction effect between MAOA-uVNTR genotype, DNA methylation and sexual or physical abuse was observed on follow-up AUDIT scores. Sexually or physically abused males carrying the S allele and lower DNA methylation reported higher AUDIT scores whereas the opposite effect was observed in non-sexually or non-physically abused males. On the other hand, irrespective of exposure to sexual or physical abuse, L allele male carriers with lower DNA methylation display