Associations of age, sex, sexual abuse, and genotype with monoamine oxidase a gene methylation

Abstract

Epigenome-wide studies report higher methylation among women than men with decreasing levels with age. Little is known about associations of sex and age with methylation of monoamine oxidase A (MAOA). Methylation of the first exonic and partial first intronic region of MAOA has been shown to strengthen associations of interactions of MAOA-uVNTR genotypes and adversity with aggression and substance misuse. Our study examined associations of sex and age with MAOA first exon and intron methylation levels in 252 women and 157 men aged 14–73 years. Participants included adolescents recruited at a substance misuse clinic, their siblings and parents, and healthy women. Women showed ~ 50% higher levels of exonic, and ~ 15% higher intronic, methylation than men. Methylation levels were similar between younger (M = 22.7 years) and older (M = 46.1 years) participants, and stable across age. Age modified few associations of methylation levels with sex. MAOA genotypes modified few associations of methylation with sex and age. Higher methylation levels among women were not explained by genotype, nor interaction of genotype and sexual abuse. Findings were similar after adjusting for lifetime diagnoses of substance dependence (women = 24.3%; men = 34.2%). Methylation levels were higher among women who experienced sexual abuse than women who did not. Results extend on prior studies by showing that women display higher levels of methylation than men within first intronic/exonic regions of MAOA, which did not decrease with age in either sex. Findings were not conditioned by genotype nor interactions of genotype and trauma, and indicate X-chromosome inactivation.

MAOA‐LPR polymorphism and math anxiety: A marker of genetic susceptibility to social influences in girls?

“…Most consistently, males with the MAOA‐L/– genotype experiencing early childhood adverse experiences are susceptible to externalizing disorders, including impulsivity, aggressiveness, and antisocial behavior 48 . In contrast, stress‐induced methylation of the MAOA gene promoter has been associated with depression 44,84 and anxiety 49 in females.…”

“…In addition to chemical environmental influences, 40 sex-dimorphic effects of early infancy/childhood adverse experiences (e.g., neglect; physical and sexual abuse) have also been reported on several psychological characteristics, such as antisocial and anxiety traits. 10,[40][41][42][43][44][45][46][47][48][49] Over the last few years, knowledge of the intricacy of the metabolic 2020 mechanisms involving MAOs is growing. 50 In the first step of the metabolic pathways, MAOs convert their metabolites into aldehydes.…”

“…Therefore, epigenetic influences also play a role in MAO regulation. In addition to chemical environmental influences, 40 sex‐dimorphic effects of early infancy/childhood adverse experiences (e.g., neglect; physical and sexual abuse) have also been reported on several psychological characteristics, such as antisocial and anxiety traits 10,40–49 …”

Effect ofMAOADNA methylation on humanin vivoprotein expression measured by [11C]harmine PET in healthy and depressed individuals

“…Changes to DNA methylation within the MAOA gene have been observed in affective disorders (12), anxiety (13, 14), OCD (15) and post-traumatic stress disorder (16), among others (17). MAOA DNA methylation is mediated both by risk factors for (18, 19) – as well as treatment of (14, 20) – various psychiatric disorders, suggestive of its role as an intermediate between environment and neurobiology (21). In vitro studies demonstrate a negative association between peripheral blood MAOA promoter / intron I / exon I methylation and protein function (14, 22).…”

Effect ofMAOADNA Methylation on Human in Vivo Protein Expression Measured by [11C]harmine Positron Emission Tomography

“…Changes to DNA methylation within the MAOA gene have been observed in multiple psychiatric conditions ( Domschke et al, 2012 ; Peng et al, 2018 ; Schiele et al, 2018 , 2020 ; Ziegler and Domschke, 2018 ; Ziegler et al, 2018 ). They are mediated both by risk factors for ( Checknita et al, 2018 , 2021 )—as well as treatment of ( Ziegler et al, 2016 ; Schiele et al, 2018 )—these diseases, suggestive of a role of MAOA gene methylation as an intermediary between environment and neurobiology. In vitro studies demonstrate a negative association between peripheral blood MAOA promoter/intron I/exon I methylation and protein function ( Checknita et al, 2015 ; Schiele et al, 2018 ).…”