Monoamine oxidase A genotype predicts human serotonin 1A receptor availability in vivo.
The serotonergic system, including the serotonin 1A (5-HT(1A)) receptor, has been implicated in the pathophysiology of a number of neuropsychiatric disorders. Current data show substantial interindividual variation in the regional concentration of this receptor site, the source of which is unclear. Monoamine oxidase A (MAO-A) is a key regulator of serotonin metabolism, and polymorphic variation in the X-linked MAO-A gene influences its expression. We hypothesized that polymorphism in the MAO-A gene would be associated with sex-specific variation in 5-HT(1A) receptor expression. We used positron emission tomography and [(11)C]WAY-100635 to quantify 5-HT(1A) receptors in a group of 31 healthy and unmedicated depressed individuals. The same individuals were genotyped for an upstream variable number tandem repeat polymorphism in the promoter of the MAO-A gene. ANOVA of 5-HT(1A) receptor availability demonstrated a significant effect of MAO-A genotype in the raphe nuclei, medial and inferior temporal cortex, insula, medial prefrontal cortex, and anterior cingulate (p < 0.05). The effect persisted when age, race, body mass index, and diagnosis were included in the model. Genotypes with greater putative MAO-A activity were associated with greater 5-HT(1A) receptor availability in women, but not in men. Genotype predicted a substantial 42-74% of the variance in receptor availability in women, depending on the brain region (p < 0.05). Depression diagnosis was not associated with MAO-A genotype or 5-HT(1A) receptor availability in these regions. These results demonstrate a sex-specific interaction between two key molecules of the human serotonergic system, and suggest a neurobiological basis for sexual dimorphism in serotonin-modulated phenotypes.
The Journal of neuroscience : the official journal of the Society for Neuroscience
October 29, 2008
Agency: NCRR NIH HHS, Id: M01 RR000042
Agency: NCRR NIH HHS, Id: M01 RR000042-441387
Agency: NCRR NIH HHS, Id: M01 RR000042-441440
Agency: NIMH NIH HHS, Id: P01 MH042251
Agency: NIMH NIH HHS, Id: P01 MH042251-160013
Agency: NIMH NIH HHS, Id: P01 MH42251
Agency: NIMH NIH HHS, Id: R25 MH6374
Agency: NCRR NIH HHS, Id: RR00042
Agency: Intramural NIH HHS, Id: Z01 AA000306-02
Predictive Value of Tests
Receptor, Serotonin, 5-HT1A
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