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.
Mickey
Brian J
BJ
Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, Michigan 48109-0720, USA.
Ducci
Francesca
F
Hodgkinson
Colin A
CA
Langenecker
Scott A
SA
Goldman
David
D
Zubieta
Jon-Kar
JK
D000328:Adult; D001933:Brain Stem / Q000737:chemistry / Q000378:metabolism; D003866:Depressive Disorder / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D008995:Monoamine Oxidase / Q000235:genetics* / Q000378:metabolism*; D011110:Polymorphism, Genetic / Q000502:physiology; D011237:Predictive Value of Tests; D016548:Prosencephalon / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D044282:Receptor, Serotonin, 5-HT1A / Q000235:genetics* / Q000378:metabolism*; D012727:Sex Characteristics
D044282:Receptor, Serotonin, 5-HT1A; D008995:Monoamine Oxidase