Monoamine Oxidase A Genotype Research Articles

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

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.

Monoamine oxidase A (MAOA) interaction with parenting practices on callous-unemotional traits in preschoolers

Background and ObjectivesFrom a gene-by-environment perspective, parenting in interaction with the polymorphism in the Monoamine oxidase A (MAOA) gene (MAOA-uVNTR) might also be associated with increased callous-unemotional traits (CU) in preschoolers. MAOA-uVNTR results in differential enzyme activity, so that high-activity alleles (MAOA-H) are linked to reduced dopamine, serotonin, and norepinephrine availability in comparison to low-activity allele (MAOA-L). As MAOA-uVNTR has been previously described to moderate the relationship between childhood parental maltreatment and aggressive and antisocial behavior, it may also play a role in CU traits etiology. MethodsData was collected through questionnaires answered by parents and teachers. MAOA-uVNTR was genotyped in 368 Caucasian children from a community sample (51.9% male). Multiple linear regression analyses were conducted to analyze the interaction effect of MAOA genotypes and both positive parenting and punitive parenting practices on CU traits at two different periods (3 and 5 years old) and separately by sex. ResultsNo significant interactions were found for boys. Among girls, a significant interaction effect was found for MAOA-LL carriers, who showed higher CU traits at age 5 when exposed to higher punitive or positive parenting at age 3. ConclusionsOur study provides the first evidence for significant MAOA × early parenting effects on CU traits in preschoolers, specifically among female MAOA-LL carriers. This suggests that the MAOA-LL genotype for girls is associated with higher sensitivity to both positive and punitive parenting in girls, so that MAOA-LL emerges as a genotype that confers higher vulnerability to parental influences.

Sex-Dimorphic Interactions of MAOA Genotype and Child Maltreatment Predispose College Students to Polysubstance Use.

Polysubstance use (PSU) is highly prevalent among college students. Recent evidence indicates that PSU is based on gene x environment (G×E) interactions, yet the specific biosocial factors underlying this problem remain elusive. We recently reported that lifetime use of tobacco and cannabis in college students is influenced by the interaction of the X-linked MAOA (monoamine oxidase A) gene and child maltreatment. Building on these premises, here we evaluated whether the same G×E interaction may also predict PSU in this population. Students of a large Midwestern university (n = 470; 50.9% females) took part in a computer survey for substance use, as well as childhood trauma exposure, using the Child Trauma Questionnaire (CTQ). DNA was extracted from their saliva samples and genotyped for MAOA variable-number of tandem repeat (VNTR) variants. Findings indicated that the highest number of substances were used by male students harboring low-activity MAOA alleles with a history of childhood emotional abuse. In contrast, female homozygous high-activity MAOA carriers with a history of emotional and physical abuse reported consumption of the greatest number of substances. Our results indicate that PSU among college students is influenced by the interaction of MAOA and child maltreatment in a sex-specific fashion. Further studies are warranted to understand the mechanisms of sex differences in the biosocial interplays underlying PSU in this at-risk group.

Monoamine oxidase A genotype and methylation moderate the association of maltreatment and aggressive behaviour

BackgroundThe association between childhood maltreatment and subsequent aggressive behaviour is modified by monoamine oxidase A (MAOA) functional polymorphism (MAOA-uVNTR) genotype, MAOA-Long (MAOA-L) in females, MAOA-Short (MAOA-S) in males. Childhood maltreatment is associated with differential DNA methylation in several genes. Consistent with recent proposals, we hypothesized that the association of the interaction of MAOA genotype and maltreatment with aggressive behaviour is further moderated by methylation of a region of interest (ROI) spanning the first exon and partial first intron of MAOA. MethodThe sample included 117 women and 77 men who completed interviews and questionnaires to report maltreatment and aggressive behaviour towards others and provided saliva samples for DNA extraction. The MAOA-uVNTR polymorphism was genotyped, and methylation of the MAOA ROI was assessed. ResultsFollowing adjustment for substance misuse, psychoactive medication use, and in males tobacco use, the highest levels of aggressive behaviour were found among maltreated male carriers of MAOA-S with high levels of exonic methylation. ConclusionMethylation levels within the MAOA ROI further contributed to the interaction of MAOA risk genotypes and maltreatment on aggressive behaviours among men.

A systematic review and meta-analysis examining the interrelationships between chemical and non-chemical stressors and inherent characteristics in children with ADHD

Children may be more vulnerable to the combined interactions of chemical and non-chemical stressors from their built, natural, and social environments when compared to adults. Attention deficit/hyperactivity disorder (ADHD) is the most commonly diagnosed childhood neurodevelopmental disorder and is considered a major public health issue, as 75% of childhood cases persist into adulthood. ADHD is characterized by developmentally inappropriate levels of hyperactivity, impulsivity, and inattention, with the neurotransmitter serotonin regulating these symptoms. Monoamine oxidase A (MAOA) aids in serotonin uptake and is often implicated in behavioral and emotional disorders, including ADHD. When children are exposed to cigarette smoke, bisphenol A (BPA), or organophosphate pesticides, MAOA activity is inhibited. Non-chemical stressors, such as traumatic childhood experiences, and lifestyle factors, complicate the relationship between genotype and exposures to chemical stressors. But the co-occurrence among outcomes between exposures to chemical stressors, non-chemical stressors, and the low activity MAOA genotype suggest that mental illness in children may be influenced by multiple interacting factors.In this systematic review, we examine the existing literature that combines exposures to chemical and non-chemical stressors (specifically childhood trauma), MAOA characteristics, and ADHD diagnosis to investigate the interrelationships present. We observe that chemical (lead [Pb], phthalates/plasticizers, persistent organic pollutants, and cigarette smoke) exposure is significantly related to ADHD in children. We also observed that existing literature examining the interaction between MAOA, exposures to chemical stressors, and traumatic experiences and their effect on ADHD outcomes is sparse. We recommend that future studies investigating childhood ADHD include chemical and non-chemical stressors and inherent characteristics to gain a holistic understanding of childhood mental health outcomes.

Role of monoamine-oxidase-A-gene variation in the development of glioblastoma in males: a case control study

BackgroundThe Mono-amine oxidase-A (MAO-A) enzyme is involved in the degradation and regulation of catecholamines such as serotonin, dopamine, epinephrine and nor-epinephrine. Preclinical studies suggest that this enzyme may contribute to an environment favorable for growth of malignant glioma. The MAO-A gene is located on the X-chromosome and has at least one functional genetic polymorphism. The aim of the present study was to explore possible effects of MAO-A genotype on development of glioblastoma in males.MethodsGenotypes for 437 glioma cases and 876 population-based controls from the Swedish Glioma International Case–Control study (GICC) were compared. We analyzed the germline DNA using the Illumina Oncoarray. We selected seven single nucleotide polymorphisms (SNPs) located in the MAO-A gene, and imputed genotypes based on data from the 1000 genomes project. We used 1579 male glioblastoma cases and 1875 controls comprising the whole GICC cohort for subsequent validation of findings.ResultsThe rs144551722 SNP was a significant predictor of development of glioblastoma in males (p-value = 0.0056) but not in females even after correction for multiple testing. We conducted haplotype analysis to confirm an association between MAO-A gene and risk of glioblastoma (p-value = 0.016). We found similar results in the validation sample.ConclusionsThese results suggest the possibility of a role for the MAO-A enzyme and the MAO-A gene in the development of glioblastoma in males.

Behavioral effects of postnatal ketamine exposure in rhesus macaque infants are dependent on MAOA-LPR genotype.

Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist widely used in pediatric anesthetic and therapeutic practices and veterinary medicine. Previous evidence suggests that exposure to ketamine during sensitive periods of development results in neural apoptosis and atypical behavior. Since monoamine neurotransmitters play important roles in prenatal and early postnatal neural development, and since previous work suggests ketamine can inhibit monoamine transporters, we hypothesized that there would be behavioral consequences of prenatal and early postnatal exposure to ketamine moderated by genotype of the promoter in the monoamine oxidase-A (MAOA) gene. From a large sample of animals (N=408), we compared groups of rhesus monkeys that had experienced a single exposure to ketamine during prenatal development, an exposure during prenatal development and one postnatal exposure, a postnatal exposure with no prenatal exposure, and no exposures. Animals were classified by putative activity levels for the MAOA genotype and were tested between 3 and 4 months of age on a battery of behavioral tests. Results suggested that animals exposed to ketamine postnatally, at a dose typically used for sedative effects that also had the low-activity variant of MAOA performed poorly on a visual memory test compared to animals with the high-activity variant of the MAOA gene.

MAOA variants differ in oscillatory EEG & ECG activities in response to aggression-inducing stimuli

Among the genetic variations in the monoamine oxidase A (MAOA) gene, upstream variable number tandem repeats (uVNTRs) of the promoter have been associated with individual differences in human physiology and aggressive behaviour. However, the evidence for a molecular or neural link between MAOA uVNTRs and aggression remains ambiguous. Additionally, the use of inconsistent promoter constructs in previous studies has added to the confusion. Therefore, it is necessary to demonstrate the genetic function of MAOA uVNTR and its effects on multiple aspects of aggression. Here, we identified three MAOA alleles in Koreans: the predominant 3.5R and 4.5R alleles, as well as the rare 2.5R allele. There was a minor difference in transcriptional efficiency between the 3.5R and 4.5R alleles, with the greatest value for the 2.5R allele, in contrast to existing research. Psychological indices of aggression did not differ among MAOA genotypes. However, our electroencephalogram and electrocardiogram results obtained under aggression-related stimulation revealed oscillatory changes as novel phenotypes that vary with the MAOA genotype. In particular, we observed prominent changes in frontal γ power and heart rate in 4.5R carriers of men. Our findings provide genetic insights into MAOA function and offer a neurobiological basis for various socio-emotional mechanisms in healthy individuals.

MAOA-VNTR Genotype Effects on Ventral Striatum-Hippocampus Network in Alzheimer's Disease: Analysis Using Structural Covariance Network and Correlation with Neurobehavior Performance.

Functional polymorphisms in the promoter region of the monoamine oxidase A (MAOA) gene are associated with brain MAOA activity and transcriptional efficiency in patients with Alzheimer's disease (AD). This study investigated structural covariance networks mediated by MAOA-variable number tandem repeat (VNTR) genotypes in patients with AD, and assessed whether this effect was associated with sex. A total of 193 patients with AD were classified into four genotype groups based on MAOA transcriptional efficiency (female low [L], low-high + high activity groups [LH + H]; male L, male H groups). Structural covariance networks were constructed focusing on triple-network and striatal networks. Covariance strength was analyzed in the four groups, and the genotype and sex main effects and their interactions were analyzed. Significant peak cluster volumes were correlated with neurobehavioral scores to establish the clinical significance. MAOA genotypes mediated the structural covariance strength on the dorsolateral prefrontal cortex (dLPFC)-caudate axis in both sexes, but a higher covariance strength was shown in the female L group and male H group. The independent effect of male sex was related to higher covariance strength in the frontal medial superior region in the dLPFC, dorsal caudate (DC), and ventral superior striatum (VSs) seeds. In contrast, female sex had higher covariance strength in the frontal opercular areas anchored by the dLPFC, DC, and VSs seeds. Topographies showing higher covariance strength with sex interactions were found in the male H group and female L group in the dLPFC supplementary motor axis, DC-SMA, and DC-precentral axis. In our patients with AD, MAOA-VNTR polymorphisms and sex had independent and interactive effects on structural covariance networks, of which the dLPFC-, VSs-, and DC-anchored networks represented major endophenotypes that determined cognitive outcomes. The sex-genotype interaction model suggested that male high activity and female low activity may modulate brain morphometric connectivity and determine cognitive scores.

MAOA genotype modulates default mode network deactivation during inhibitory control

It has been demonstrated, in a long line of research, that the low-activity genotype of the monoamine oxidase A (MAOA) gene is associated with aggression. Previous work has linked impaired response inhibition to aggression, but little is known about how this relates to the purported MAOA-aggression relationship in adolescents. Here, we examined how MAOA genotype influences neural correlates of inhibitory control in 74 healthy male adolescents using a GoStop and a Go/Nogo task while differentiating between action cancelation and action restraint. Carriers of the low-expressing MAOA alleles (MAOA-L) did not show altered brain activation in the prefrontal-subcortical inhibition network relative to carriers of the high-expressing alleles across inhibition conditions. However, they exhibited a more pronounced deactivation during response inhibition in the posterior cingulate cortex (PCC) and precuneus, areas belonging to the default mode network (DMN). Larger DMN suppression in MAOA-L carriers might represent a compensation mechanism for impaired cognitive control.

MAOA genotype influences neural response during an inhibitory task in adolescents with conduct disorder.

Conduct disorder (CD), a common psychiatric disorder in children and adolescents, is characterized by encroaching upon other rights and violations of age-appropriate social expectations repeatedly and persistently. Individuals with CD often have high aggressiveness and low inhibitory capacity. The monoamine oxidase A (MAOA) gene has long been associated with aggression. Effects of MAOA genotype on inhibitory control have been examined in general population. Several studies had revealed reduced activation in prefrontal areas, especially theanterior cingulate cortex (ACC), in low-expression MAOA (MAOA-L) allele carriers compared to high-expression MAOA (MAOA-H) allele carriers. However, little is known about its genetic risk influences on inhibitory processes in clinical samples. In this study, functional magnetic resonance imaging (fMRI) was administered to a sample of adolescent boys with CD during the performance of a GoStop task, 29 of whom carrying MAOA-L allele and 24 carrying MAOA-H allele. Relative to MAOA-H carriers, MAOA-L carriers in CD showed more pronounced deactivation in the precuneus, supplementary motor area (SMA) and dorsal anterior cingulate cortex (dACC). Deactivation within the default mode network (DMN) and inhibitory-related areas in MAOA-L carriers may be related to compensation for low sensitivity to inhibition and/or an atypical allocation of cognitive resources. The results suggested a possible neural mechanism through which MAOA affects inhibitory processes in a clinical sample.

Main and interaction effects of childhood trauma and the MAOA uVNTR polymorphism on psychopathy

Psychopathy is characterized by callous affect, interpersonal manipulation, a deviant lifestyle, and antisocial behavior. Previous research has linked psychopathic traits to childhood trauma, but also to the upstream variable number tandem repeat (uVNTR) polymorphism of the monoamine oxidase A (MAOA) gene. An interaction between childhood trauma and MAOA genotype has been associated with antisocial behavior, but so far little is known about interaction effects of childhood trauma and the MAOA uVNTR on psychopathy. In order to bridge this gap, we used data of 1531 male and 1265 female twins and their siblings from a Finnish community sample to estimate structural equation models. The psychopathy and childhood trauma constructs were conceptualized as bifactor models with one general and two orthogonal group factors. Data comprised self-reports on childhood trauma and psychopathic traits as well as MAOA uVNTR genotype. In both genders, childhood trauma was associated with the general factor that represents the overarching psychopathy construct, and with the group factor that captures social deviance, but not with the group factor capturing psychopathic core personality traits. Women with a low activity variant of the MAOA uVNTR reported slightly higher levels of psychopathy than those with a high activity allele, but only with respect to the general psychopathy factor. There was no evidence for an interaction effect between MAOA uVNTR genotype and childhood trauma on psychopathy in either gender. Our results suggest that psychopathy in general and social deviance in particular are associated with childhood trauma in men and women, and that psychopathic traits are subject to variation in the MAOA uVNTR genotype in women.

The interaction between monoamine oxidase A (MAOA) and childhood maltreatment as a predictor of personality pathology in females: Emotional reactivity as a potential mediating mechanism - ERRATUM.

Research consistently demonstrates that common polymorphic variation in monoamine oxidase A (MAOA) moderates the influence of childhood maltreatment on later antisocial behavior, with growing evidence that the allele (high vs. low activity) differs for females. However, little is known about how this Gene × Environment interaction functions to increase risk, or if this risk pathway is specific to antisocial behavior. Using a prospectively assessed, longitudinal sample of females (n = 2,004), we examined whether changes in emotional reactivity (ER) during adolescence mediated associations between this Gene × Environment and antisocial personality disorder in early adulthood. In addition, we assessed whether this putative risk pathway also conferred risk for borderline personality disorder, a related disorder characterized by high ER. While direct associations between early maltreatment and later personality pathology did not vary by genotype, there was a significant difference in the indirect path via ER during adolescence. Consistent with hypotheses, females with high-activity MAOA genotype who experienced early maltreatment had greater increases in ER during adolescence, and higher levels of ER predicted both antisocial personality disorder and borderline personality disorder symptom severity. Taken together, findings suggest that the interaction between MAOA and early maltreatment places women at risk for a broader range of personality pathology via effects on ER.

Associations of monoamine oxidase A gene first exon methylation with sexual abuse and current depression in women

Childhood physical abuse (PA) and sexual abuse (SA) interact with monoamine oxidase A (MAOA) gene polymorphism to modify risk for mental disorders. In addition, PA and SA may alter gene activity through epigenetic mechanisms such as DNA methylation, thereby further modifying risk for disorders. We investigated whether methylation in a region spanning the MAOA first exon and part of the first intron was associated with PA and/or SA, MAOA genotype, alcohol dependence, drug dependence, depression disorders, anxiety disorders, and conduct disorder. 114 Swedish women completed standardized diagnostic interviews and questionnaires to report PA and SA, and provided saliva samples for DNA extraction. DNA was genotyped for MAOA-uVNTR polymorphisms, and methylation of a MAOA region of interest (chrX: 43,515,544–43,515,991) was measured. SA, not PA, was associated with hypermethylation of the MAOA first exon relative to no-abuse, and the association was robust to adjustment for psychoactive medication, alcohol and drug dependence, and current substance use. SA and MAOA-uVNTR genotype, but not their interaction, was associated with MAOA methylation. SA associated with all measured mental disorders. Hypermethylation of MAOA first exon mediated the association of SA with current depression, and both methylation levels and SA independently predicted lifetime depression. Much remains to be learned about the independent effects of SA and MAOA-uVNTR genotypes on methylation of the MAOA first exon.

The interaction between monoamine oxidase A (MAOA) and childhood maltreatment as a predictor of personality pathology in females: Emotional reactivity as a potential mediating mechanism.

Research consistently demonstrates that common polymorphic variation in monoamine oxidase A (MAOA) moderates the influence of childhood maltreatment on later antisocial behavior, with growing evidence that the "risk" allele (high vs. low activity) differs for females. However, little is known about how this Gene × Environment interaction functions to increase risk, or if this risk pathway is specific to antisocial behavior. Using a prospectively assessed, longitudinal sample of females (n = 2,004), we examined whether changes in emotional reactivity (ER) during adolescence mediated associations between this Gene × Environment and antisocial personality disorder in early adulthood. In addition, we assessed whether this putative risk pathway also conferred risk for borderline personality disorder, a related disorder characterized by high ER. While direct associations between early maltreatment and later personality pathology did not vary by genotype, there was a significant difference in the indirect path via ER during adolescence. Consistent with hypotheses, females with high-activity MAOA genotype who experienced early maltreatment had greater increases in ER during adolescence, and higher levels of ER predicted both antisocial personality disorder and borderline personality disorder symptom severity. Taken together, findings suggest that the interaction between MAOA and early maltreatment places women at risk for a broader range of personality pathology via effects on ER.

Does prior traumatization affect the treatment outcome of CBT for panic disorder? The potential role of the MAOA gene and depression symptoms.

Although cognitive behavioral therapy (CBT) is highly effective in the treatment of anxiety disorders, many patients still do not benefit. This study investigates whether a history of traumatic event experience is negatively associated with outcomes of CBT for panic disorder. The moderating role of the monoamine oxidase A (MAOA) gene and depression symptoms as well as the association between trauma history and fear reactivity as a potential mechanism are further analyzed. We conducted a post-hoc analysis of 172 male and 60 female patients with panic disorder treated with CBT in a multi-center study. Treatment outcome was assessed at post-treatment using self-report and clinician rating scales. Fear reactivity before treatment was assessed via heart rate and self-reported anxiety during a behavioral avoidance test. Among females, we did not find any differences in treatment response between traumatized and non-traumatized individuals or any two-way interaction trauma history×MAOA genotype. There was a significant three-way interaction trauma history×MAOA genotype×depression symptoms on all treatment outcomes indicating that in traumatized female patients carrying the low-activity allele, treatment effect sizes decreased with increasing depression symptoms at baseline. No such effects were observed for males. In conclusion, we found no evidence for a differential treatment response in traumatized and non-traumatized individuals. There is preliminary evidence for poorer treatment outcomes in a subgroup of female traumatized individuals carrying the low-active variant of the MAOA gene. These patients also report more symptoms of depression symptomatology and exhibit a dampened fear response before treatment which warrants further investigation.

MAOA, Drug Selling, and Violent Victimization

Involvement in drug markets is a significant risk factor for criminal victimization. Separately, the monoamine oxidase A (MAOA) gene has been identified as correlating with risky and antisocial behaviors and moderating the effects of environmental risk factors on antisocial behaviors. Using a sample drawn from the National Longitudinal Study of Adolescent to Adult Health ( N = 8,860), we explore whether MAOA genotype moderates the effect of drug selling on violent victimization. Results show that drug selling increases violent victimization among males, but not females. Additionally, the effect of drug selling on violent victimization among males is greater among the carriers of the 2R/3R alleles of MAOA, providing evidence of Gene × Environment interaction. These results appear despite a number of controls that potentially make the drug selling–violent victimization relationship spurious. Implications of the findings are discussed.

Interactions between MAOA gene polymorphism and maternal parenting in predicting externalizing and internalizing problems and social competence among Chinese children: Testing the genetic vulnerability and differential susceptibility models

AbstractThe present study aimed to test whether monoamine oxidase A (MAOA) gene polymorphism was a marker of the genetic vulnerability model or the differential susceptibility model by investigating the interaction of MAOA gene polymorphism with maternal parenting on externalizing and internalizing problems and social competence among Chinese children. Participants were 290 children and their parents in China. MAOA genotypes were ascertained by polymerase chain reaction amplification. Mothers reported their parenting stress and engagement in parent–child activities when the child was 6 months old. Children's behavioral problems and social competence were rated by mothers and fathers at 48 months old. The results showed that MAOA genotypes interacted with maternal parenting stress in predicting boys' internalizing problems. Also, MAOA genotypes interacted with maternal engagement in parent–child activities in predicting boys' social competence. The analyses of regions of significance and the proportion of interaction index indicated that boys with the low‐activity genotype were at risk for (a) high internalizing problems under high maternal parenting stress and (b) low social competence if mothers displayed a low level of maternal engagement. No significant interaction effects were found among girls. The results suggested that the MAOA gene might be a marker of the genetic vulnerability model among Chinese boys.Highlights We evaluated whether MAOA gene was a marker of the genetic vulnerability model or the differential susceptibility model by investigating the interaction of MAOA gene polymorphism with maternal parenting on behavioral problems and social competence among 4‐year‐old Chinese children. The results of regions of significance and the proportion of interaction index indicated that boys with the low‐activity genotype were at risk of high internalizing problems or low social competence with high maternal parenting stress or low engagement. No significant interaction effects were found among girls. The results indicated that MAOA gene might be a marker of the genetic vulnerability model rather than the differential susceptibility model.

Cortico-limbic connectivity in MAOA-L carriers is vulnerable to acute tryptophan depletion.

A gene-environment interaction between expression genotypes of the monoamine oxidase A (MAOA) and adverse childhood experience increases the risk of antisocial behavior. However, the neural underpinnings of this interaction remain uninvestigated. A cortico-limbic circuit involving the prefrontal cortex (PFC) and the amygdala is central to the suppression of aggressive impulses and is modulated by serotonin (5-HT). MAOA genotypes may modulate the vulnerability of this circuit and increase the risk for emotion regulation deficits after specific life events. Acute tryptophan depletion (ATD) challenges 5-HT regulation and may identify vulnerable neuronal circuits, contributing to the gene-environment interaction. Functional magnetic resonance imaging measured the resting-state state activity in 64 healthy males in a double-blind, placebo-controlled study. Cortical maps of amygdala correlation identified the impact of ATD and its interaction with low- (MAOA-L) and high-expression variants (MAOA-H) of MAOA on cortico-limbic connectivity. Across all Regions of Interest (ROIs) exhibiting an ATD effect on cortico-limbic connectivity, MAOA-L carriers were more susceptible to ATD than MAOA-H carriers. In particular, the MAOA-L group exhibited a larger reduction of amygdala connectivity with the right prefrontal cortex and a larger increase of amygdala connectivity with the insula and dorsal PCC. MAOA-L carriers were more susceptable to a central 5-HT challenge in cortico-limbic networks. Such vulnerability of the cortical serotonergic system may contribute to the emergence of antisocial behavior after systemic challenges, observed as gene-environment interaction. Hum Brain Mapp 38:1622-1635, 2017. © 2016 Wiley Periodicals, Inc.

Interacting effect of MAOA genotype and maternal prenatal smoking on aggressive behavior in young adulthood.

Findings on the etiology of aggressive behavior have provided evidence for an effect both of genetic factors, such as variation in the monoamine oxidase A (MAOA) gene, and adverse environmental factors. Recent studies have supported the existence of gene×environment interactions, with early experiences playing a key role. In the present study, the effects of prenatal nicotine exposure, MAOA genotype and their interaction on aggressive behavior during young adulthood were examined. In a sample of 272 young adults (129 males, 143 females) from an epidemiological cohort study, smoking during pregnancy was measured with a standardized parent interview at the offspring's age of 3months. Aggressive behavior was assessed between the ages of 19 and 25years using the Young Adult Self-Report. DNA was genotyped for the MAOA 5' untranslated region variable number of tandem repeats polymorphism (VNTR). Results revealed a significant interaction between MAOA and smoking during pregnancy, indicating higher levels of aggressive behavior in young adults carrying the MAOA low-expressing genotype who had experienced prenatal nicotine exposure (n=8, p=.025). In contrast, in carriers of the MAOA high-expressing genotype, maternal smoking during pregnancy had no effect on aggressive behavior during young adulthood (n=20, p=.145). This study extends earlier findings demonstrating an interaction between MAOA genotype and prenatal nicotine exposure on aggressive behavior into young adulthood. The results point to the long-term adverse effects of smoking during pregnancy on the offspring's mental health, possibly underlining the importance of smoking cessation during pregnancy. According to the nature of the study (particularly sample size and power), analyses are exploratory and results need to be interpreted cautiously.