Gene environment interactions with a novel variable Monoamine Oxidase A transcriptional enhancer are associated with antisocial personality disorder

Abstract

Monoamine Oxidase A (MAOA) is a critical enzyme in the catabolism of monoaminergic neurotransmitters. MAOA transcriptional activity is thought to be regulated by a well characterized 30 base pair (bp) variable nucleotide repeat (VNTR) that lies approximately ~1000 bp upstream of the transcriptional start site (TSS). However, clinical associations between this VNTR genotype and behavioral states have been inconsistent. Herein, we describe a second, 10 base pair VNTR that lies ~1500 bp upstream of the TSS. We provide in vitro and in silico evidence that this new VNTR region may be more influential in regulating MAOA transcription than the more proximal VNTR and that methylation of this CpG-rich VNTR is genotype dependent in females. Finally, we demonstrate that genotype at this new VNTR interacts significantly with history of child abuse to predict antisocial personality disorder (ASPD) in women and accounts for variance in addition to that explained by the prior VNTR.

Genetic determinants of aggression and impulsivity in humans

“…Recently, Philibert et al (2011) identified a new polymorphic VNTR in the promoter region of MAOA located 1.5 kb upstream from the start ATG codon and consisting of 10-bp tandem repeats. This VNTR enhances the transcription of MAOA, and its regulatory effect is much more sound than that of the 30 bp-VNTR.…”

Potential biomarkers in personality disorders: current state and future research

“…It is known that a reduction of the activity of the platelet MAO-A is related with impulsivity and PD and that it is also associated with 5-HAA in LCR, thus presenting an inverse correlation with rates at scales that search for sensations and impulsivity (Schalling, Asberg, Edman, & Oreland, 1987). In addition, recent studies have replicated of gene x environment (G x E) interactions involving the MAO-A, indicating that activity MAO-A genetic variant who were more associated to PD traits like as hostility and impulsivity (Fergusson, Boden, Horwood, Miller, & Kennedy, 2011;Philibert et al, 2011;Reti et al, 2011) …”

Modulation of monoamine oxidase (MAO) expression in neuropsychiatric disorders: genetic and environmental factors involved in type A MAO expression

“…An association between low affinity allele mao-a polymorphisms in women with a history of childhood sexual abuse and the later development of alcoholism and antisocial personal disorders has been reported (Ducci et al 2008). A novel 10 bp VNTR *1,500 bp upstream of the transcriptional site has been associated with antisocial personality disorder in female children with a history of child abuse (Philibert et al 2011). In female patients with panic disorder, longer, higher activity mao-a promoter alleles were significantly more frequently found than in control females (Deckert et al 1999).…”