MAOA methylation is associated with nicotine and alcohol dependence in women

Abstract

In recent years, the role of epigenetic phenomenon, such as methylation, in mediating vulnerability to behavioral illness has become increasingly appreciated. One prominent locus at which epigenetic phenomena are thought to be in play is the monoamine oxidase A (MAOA) locus. In order to examine the role of methylation at this locus, we performed quantitative methylation analysis across the promoter region of this gene in lymphoblast lines derived from 191 subjects participating in the Iowa Adoption Studies (IAS). We analyzed the resulting data with respect to genotype and lifetime symptom counts for the more common major behavioral disorders in the IAS, antisocial personality disorder (ASPD), and substance use disorders (alcohol (AD) and nicotine dependence (ND)). We found that methylation status was significantly associated with lifetime symptom counts for ND (P < 0.001) and AD (P < 0.008) in women, but not men. Furthermore, a trend was found for women homozygous for the 3,3 allele to have a higher degree of overall methylation than women homozygous for the 4,4 allele (P < 0.10). We conclude that methylation of MAOA may play a significant role in common psychiatric illness and that further examination of epigenetic processes at this locus is in order.

Figure 1

The sequence and structure of the MAOA promoter region. The first CpG island begins at bp 43398975 and contains 18 CpG residues. A second CpG island begins at bp 43399493 and contains 70 CpG residues. The position of each of the CpG residues is noted in the figure. The first exon of MAOA is denoted by small blue letters and is wholly contained within the second island. The positions of the primers used to amplify the MAOA VNTR are denoted by boxed letters. The transcription start site (TSS) is at bp43400353 between CpG residues 64 and 65.

Figure 2

The average methylation ratios (methyl CpG/total CpG) at each CpG residue for each sex. The bp position on the X chromosome is given on the X axis and corresponds to the position of each of the residues in Figure 1. The average values for female subjects are depicted by blue squares, while the average values for males are depicted by red circles. The position of MAOA exon 1 is denoted by the box with the direction of transcription being indicated by the line with arrows.

Figure 3

The relationship of MAOA VNTR genotype to methylation in females (above) and males (below). There was a trend for association for female 3,3 homozygotes to have higher average methylation (methyl CpG/total CpG) than female 4,4 homozygotes (43.3% ± 3.8 vs 40.9% ± 5.2; p<0.10). There was no significant difference between males hemizygous for the 3 repeat allele as compared to those with the 4 allele although the arithmetic difference was in the same direction (9.0 ± 3.7 vs 8.3 ± 2.6; p<0.32).