A functional polymorphism in the MAOA gene promoter (MAOA-LPR) predicts central dopamine function and body mass index

Abstract

Variation in brain monoaminergic activity is heritable and modulates risk of alcoholism and other addictions, as well as food intake and energy expenditure. Monoamine oxidase A deaminates the monoamine neurotransmitters serotonin, dopamine (DA), and noradrenalin. The monoamine oxidase A (MAOA) gene (Xp11.5) contains a length polymorphism in its promoter region (MAOA-LPR) that putatively affects transcriptional efficiency. Our goals were to test (1) whether MAOA-LPR contributes to interindividual variation in monoamine activity, assessed using levels of cerebrospinal fluid (CSF) monoamine metabolites; and (2) whether MAOA-LPR genotype influences alcoholism and/or body mass index (BMI). Male, unrelated criminal alcoholics (N = 278) and controls (N = 227) were collected from a homogeneous Finnish source population. CSF concentration of 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) were available from 208 participants. Single allele, hemizygous genotypes were grouped according to inferred effect of the MAOA alleles on transcriptional activity. MAOA-LPR genotypes had a significant effect on CSF HVA concentration (P = 0.01) but explained only 3% of the total variance. There was a detectable but nonsignificant genotype effect on 5-HIAA and no effects on MHPG. Specifically, the genotype conferring high MAOA activity was associated with lower HVA levels in both alcoholics and controls, a finding that persisted after accounting for the potential confounds of alcoholism, BMI, height, and smoking. MAOA-LPR genotype predicted BMI (P < 0.005), with the high-activity genotype being associated with lower BMI. MAOA-LPR genotypes were not associated with alcoholism or related psychiatric phenotypes in this data set. Our results suggest that MAOA-LPR allelic variation modulates DA turnover in the CNS, but does so in a manner contrary to our prior expectation that alleles conferring high activity would predict higher HVA levels in CSF. Our results are consistent with an emerging literature that suggests greater complexity in how variation in MAOA expression alters monoaminergic function. Finally, our work suggests that MAOA may be involved in the regulation of BMI. Independent samples are necessary to confirm this preliminary finding.

A Non-Additive Interaction of a Functional MAO-A VNTR and Testosterone Predicts Antisocial Behavior

“…As reported previously in this same sample (Virkkunen et al, 1994), individuals with ASPD had higher levels of CSF testosterone but there was no significant predictive effect of MAOALPR genotype alone (Ducci et al, 2006). The main finding of the present study is that testosterone (assessed in CSF) and MAOA genotype interact to predict ASPD as well as lifetime aggression and antisocial behavior measured on the Brown-Goodwin Scale.…”

“…As reported previously (Ducci et al, 2006) there were no significant differences in MAOA allele frequencies between cases and controls.…”

“…As has been reported elsewhere, the effects of these confounding variables in this sample were significant (Ducci et al, 2006). The correlation between smoking and MHPG was negative and the correlations between BMI and height and MHPG were positive.…”

“…CSF testosterone level also tended to be positively correlated with Brown-Goodwin Lifetime Aggression, although this trend was non-significant (linear regression, b ¼ 1.27, P ¼ 0.09). As reported previously (Ducci et al, 2006), MAOA genotype itself does not predict ASPD in this population (see Table 1). …”

A Functional Polymorphism of the MAOA Gene Is Associated with Neural Responses to Induced Anger Control

“…A variable number tandem repeat polymorphism in the promoter of this gene (MAOA-uVNTR) affects gene expression (Sabol, Hu, & Hamer, 1998). Individuals with the low-expression allele (MAOA-L) are at risk for increased aggression relative to individuals with the high-expression allele (MAOA-H; Raine, 2008;Caspi et al, 2002;Manuck, Flory, Ferrell, Mann, & Muldoon, 2000;Brunner, Nelen, Breakefield, Ropers, & Van Oost, 1993; but for nonreplications, see Sjöberg et al, 2008;Ducci et al, 2006).…”