Excess of High Activity Monoamine Oxidase A Gene Promoter Alleles in Female Patients with Panic Disorder

Abstract

A genetic contribution to the pathogenesis of panic disorder has been demonstrated by clinical genetic studies. Molecular genetic studies have focused on candidate genes suggested by the molecular mechanisms implied in the action of drugs utilized for therapy or in challenge tests. One class of drugs effective in the treatment of panic disorder is represented by monoamine oxidase A inhibitors. Therefore, the monoamine oxidase A gene on chromosome X is a prime candidate gene. In the present study we investigated a novel repeat polymorphism in the promoter of the monoamine oxidase A gene for association with panic disorder in two independent samples (German sample, n = 80; Italian sample, n = 129). Two alleles (3 and 4 repeats) were most common and constituted >97% of the observed alleles. Functional characterization in a luciferase assay demonstrated that the longer alleles (3a, 4 and 5) were more active than allele 3. Among females of both the German and the Italian samples of panic disorder patients (combined, n = 209) the longer alleles (3a, 4 and 5) were significantly more frequent than among females of the corresponding control samples (combined, n = 190, chi2 = 10.27, df = 1, P = 0.001). Together with the observation that inhibition of monoamine oxidase A is clinically effective in the treatment of panic disorder these findings suggest that increased monoamine oxidase A activity is a risk factor for panic disorder in female patients.

Serotonin Function in Panic Disorder: Important, But Why?

“…The transcriptionally more active longer alleles and genotypes of a functional polymorphism of the MAO-A gene, uVNTR, demonstrated a significant association with PD in female but not male patients (Deckert et al, 1999). We found a similar gender-dependent association with longer allele genotypes in female PD patients with agoraphobia (Maron et al, 2005a).…”

MAOA, maltreatment, and gene–environment interaction predicting children's mental health: new evidence and a meta-analysis

“…31 In terms of expression, all studies agree on the functional classification of the two most common alleles, that is, 3-repeats (low activity), and 4-repeats (high activity). Of rare alleles, both Sabol et al 4 and Deckert et al 50 assayed the 3.5-repeat with the same result (high activity), whereas a discrepancy resulted for the 5-repeat. We chose the classification of Sabol et al 4 (i.e., 5-repeat equals low activity) as they assayed three cell lines as opposed to one.…”

Nature and Nurture Predispose to Violent Behavior: Serotonergic Genes and Adverse Childhood Environment

“…MAOA-uVNTR and the 5-HTTLPR were genotyped using previously published protocols (Deckert et al, 1999;Lesch et al, 1996). PCR of the DAT VNTR was carried out in a 25 ml volume containing 20 ng genomic DNA and 0.4 mM primers.…”

“…A repeat length polymorphism (MAOAuVNTR (MAOA-variable number of tandem repeats)) in the promoter region consisting of a 30-bp repeat element with 3, 3.5, 4, 5 or (rare) 6 copies was described (Sabol et al, 1998). The 3-repeat allele results in significantly decreased expression of MAO-A as compared to longer alleles (Deckert et al, 1999); the latter also resulting in higher cerebrospinal fluid (CSF) homovanillic acid levels, arguing for functional metabolic consequences of this polymorphism (Zalsman et al, 2005). For association studies, hence, MAOA-uVNTR has been dichotomized in short low-activity (3-allele) and long high-activity (3.5, 4, 5-allele) variants.…”