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

David Checknita,Jari Tiihonen,Kent W Nilsson,Sheilagh Hodgins

doi:10.1007/s00702-021-02403-2

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.

Highlights

Methylation of DNA at cytosine–guanine dinucleotides (CpGs) across the genome is a dynamic biological process influenced by environmental and biological factors, that in turn impacts gene activity and the subsequent regulation of biological systems (Xiao et al 2018; Pagiatakis et al 2019)
Methylation in the monoamine oxidase A (MAOA) ROI was assessed in five ways: individual CpGs; mean levels across the ROI; mean levels within intronic and exonic regions, since promotor and first exon methylation associates with suppressed gene expression, while intronic and gene body methylation associates with elevated gene expression (Brenet et al 2011; Jones 2012; Moore et al 2013); empirically derived components of CpG methylation levels
We previously found that MAOA-uVNTR and sexual abuse, but not their interaction, were each associated with higher methylation of the MAOA ROI and current diagnosis of depression in a smaller sample of the young women included in the present study (Checknita et al 2020)

Summary

Introduction

Methylation of DNA at cytosine–guanine dinucleotides (CpGs) across the genome is a dynamic biological process influenced by environmental and biological factors, that in turn impacts gene activity and the subsequent regulation of biological systems (Xiao et al 2018; Pagiatakis et al 2019). Together, these factors contribute to the high degree of inter-individual variation in CpG methylation across the genome associated with mental and physical disorders (Han et al 2019; Pagiatakis et al 2019). Polymorphisms of MAOA have been implicated in treatment response to mirtazapine among individuals with depression (Tzeng et al 2009), further highlighting the gene’s clinical importance to understanding etiology and treatment

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