Evidence that the methylation state of the monoamine oxidase A (MAOA) gene predicts brain activity of MAO A enzyme in healthy men

Abstract

Human brain function is mediated by biochemical processes, many of which can be visualized and quantified by positron emission tomography (PET). PET brain imaging of monoamine oxidase A (MAO A)-an enzyme metabolizing neurotransmitters-revealed that MAO A levels vary widely between healthy men and this variability was not explained by the common MAOA genotype (VNTR genotype), suggesting that environmental factors, through epigenetic modifications, may mediate it. Here, we analyzed MAOA methylation in white blood cells (by bisulphite conversion of genomic DNA and subsequent sequencing of cloned DNA products) and measured brain MAO A levels (using PET and [(11)C]clorgyline, a radiotracer with specificity for MAO A) in 34 healthy non-smoking male volunteers. We found significant interindividual differences in methylation status and methylation patterns of the core MAOA promoter. The VNTR genotype did not influence the methylation status of the gene or brain MAO A activity. In contrast, we found a robust association of the regional and CpG site-specific methylation of the core MAOA promoter with brain MAO A levels. These results suggest that the methylation status of the MAOA promoter (detected in white blood cells) can reliably predict the brain endophenotype. Therefore, the status of MAOA methylation observed in healthy males merits consideration as a variable contributing to interindividual differences in behavior.

Figure 1. MAOA genomic locus and region analyzed in the study. (A) X-chromosome ideogram with the MAOA position indicated in red; (B) overview of the MAOA promoter and its epigenetic features; (C) Amplicon overview (red arrows indicate its position relatively to the MAOA gene) represents the methylation status of individual CpG sites, averaged across the samples (shades of gray correspond to the methylation percentage). Green dashed box shows colocalization of the CpG11 and CpG12 with nucleosome exclusion region.

Figure 3. Interindividual variability of the MAOA methylation states. (A) Methylation statuses of CpG sites in individual samples (sorted by age) are compiled as methylation map. (B) Average methylation for the amplicon calculated for individual genomic samples is plotted against the respective brain MAOA levels (λk₃ values). (C) Experiment-wide average (percentile) and range (± s.d.) of site-specific methylation. (D) Graphical representation of Pearson’s similarity between the methylation values of individual CpG sites.

Figure 2. Variability in brain MAOA levels observed in healthy males. Parametric images of the model term which is a function of MAOA activity for two healthy individuals show the same planes of the brain. Brain λk₃ for those individuals are 0.27 mL_plasma(mL_brain)⁻¹min⁻¹ and 0.4 mL_plasma(mL_brain)⁻¹min⁻¹ (top and bottom panels, respectively). A rainbow color scale is used where red represents the highest λk₃ values.