Monoamine oxidase A gene promoter variation and rearing experience influences aggressive behavior in rhesus monkeys

Newman, Timothy K.; Syagailo, Yana V.; Barr, Christina S.; Wendland, Jens R.; Champoux, Maribeth; Graessle, Markus; Suomi, Stephen J.; Higley, J. Dee; Lesch, Klaus‐Peter

doi:10.1016/j.biopsych.2004.10.012

Cited by 236 publications

(195 citation statements)

References 22 publications

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“…Similar to findings in human populations, aggressive behavior in non-human primates is increased in the presence of both low MAOA enzymatic activity as well as early exposure to a range of social behaviors that includes aggression. We have recently confirmed the relevance of genotype Â environment interaction in the sensitization process to aggression in rhesus monkeys, suggesting that the behavioral expression of allelic variation of MAOA activity is sensitive to social experiences early in development and that its functional outcome may depend upon the social context (Newman et al, 2004). The relevance of such environmental stressors acting on an extended neural circuitry in facilitating the influences of allelic variation of MAOA activity on behavior is underscored by the absence of consistent genotype effects on traits of impulsivity and aggression.…”

Section: Discussionsupporting

confidence: 54%

“…Finally, recent work focusing on both genetic and early environmental factors has begun to untangle expected complex relationships by demonstrating an interaction of MAOA-LPR genotype and adverse childhood environment modulating the risk for both conduct disorder and impulsive traits, antisocial behavior, aggressiveness, and violence in adulthood (Caspi et al, 2002;Foley et al, 2004;Huang et al, 2004). A corresponding MAOA genotype Â environment interaction effect on aggression was recently demonstrated in rhesus macaques, in which gene transcription is also modulated by an analogous polymorphic repeat in the upstream regulatory region of MAOA (rhMAOA-LPR) (Newman et al, 2004). Detailed species comparisons revealed that the MAOA-LPR is differentially configured among non-human primates but absent in other mammalians (Wendland et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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Cluster B Personality Disorders are Associated with Allelic Variation of Monoamine Oxidase A Activity

Jacob

Müller

Schmidt

et al. 2005

Neuropsychopharmacol

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Genetic variants of the monoamine oxidase A (MAOA) have been associated with aggression-, anxiety-, and addiction-related behavior in several nonclinical and clinical populations. Here, we investigated the influence of allelic variation of MAOA activity on aggressionrelated personality traits and disease risk in patients with personality disorders. Personality disorders were diagnosed with the Structured Clinical Interview of DSM-IV and were allocated to cluster A, B, and C. Personality features were assessed by the revised NEO Personality Inventory and the Tridimensional Personality Questionnaire. The genotype of the MAOA gene-linked polymorphic region (MAOA-LPR) was determined in 566 patients with personality disorders and in 281 healthy controls. MAOA genotype was significantly associated with cluster B personality disorders (w 2 ¼ 7.77, p ¼ 0.005, df ¼ 1) but not with cluster C personality disorders. In total, 26.0% of cluster B patients were hemi-or homozygous for the low-activity variant of the MAOA genotype, compared to 16.4% in the control group. Associations between MAOA variants and personality domains related to impulsivity and aggressiveness were inconsistent. Our findings further support the notion that allelic variation of MAOA activity contributes modestly to the balance of hyper-(impulsiveaggressive) and hyporeactive (anxious-depressive) traits.

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Section: Discussionsupporting

confidence: 54%

Section: Introductionmentioning

confidence: 99%

Cluster B Personality Disorders are Associated with Allelic Variation of Monoamine Oxidase A Activity

Jacob

Müller

Schmidt

et al. 2005

Neuropsychopharmacol

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“…18,19 In rhesus monkeys, a functional polymorphism orthologous to the human MAOA VNTR was found to influence both elicited and naturally occurring aggression in males. 20 The effect was mediated by whether the monkeys had been raised with their mothers, or in peer only nursery groups, with the highest measures of aggression occurring in mother reared monkeys with the low MAOA activity associated allele. 20 Cerebrospinal fluid (CSF) concentrations of the major metabolites of 5-HT (5-hydroxyindoleacetic acid, 5-HIAA), DA (homovanillic acid, HVA), and NE (3-methoxy-4-hydroxyphenylglycol, MHPG) are indirect measures of monoamine function in the human central nervous system (CNS).…”

Section: Introductionmentioning

confidence: 98%

“…20 The effect was mediated by whether the monkeys had been raised with their mothers, or in peer only nursery groups, with the highest measures of aggression occurring in mother reared monkeys with the low MAOA activity associated allele. 20 Cerebrospinal fluid (CSF) concentrations of the major metabolites of 5-HT (5-hydroxyindoleacetic acid, 5-HIAA), DA (homovanillic acid, HVA), and NE (3-methoxy-4-hydroxyphenylglycol, MHPG) are indirect measures of monoamine function in the human central nervous system (CNS). Several studies have demonstrated that levels of monoamine metabolites, especially 5-HIAA, are associated with aggressiveness and impulsivity, 21 thus suggesting that these measures might be appropriate intermediate phenotypes for more complex phenotypes such as externalizing disorders.…”

Section: Introductionmentioning

confidence: 98%

“…17 The role of MAOA in the development of antisocial behaviors has been partially clarified by studies evaluating gene -environment interaction. Studies in humans 6,18,19 and other primates 20 have demonstrated that MAOA genotypes influence the risk for antisocial behavior contingent on exposure to certain environmental factors. Adverse experiences early in life, such as childhood maltreatment, play a crucial role in the development of antisocial behavior.…”

Section: Introductionmentioning

confidence: 99%

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A functional polymorphism in the MAOA gene promoter (MAOA-LPR) predicts central dopamine function and body mass index

Ducci¹,

Newman²,

Funt³

et al. 2006

Mol Psychiatry

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Variation in brain monoaminergic activity is heritable and modulates risk of alcoholism and other addictions, as well as food intake and energy expenditure. Monoamine oxidase A deaminates the monoamine neurotransmitters serotonin, dopamine (DA), and noradrenalin. The monoamine oxidase A (MAOA) gene (Xp11.5) contains a length polymorphism in its promoter region (MAOA-LPR) that putatively affects transcriptional efficiency. Our goals were to test (1) whether MAOA-LPR contributes to interindividual variation in monoamine activity, assessed using levels of cerebrospinal fluid (CSF) monoamine metabolites; and (2) whether MAOA-LPR genotype influences alcoholism and/or body mass index (BMI). Male, unrelated criminal alcoholics (N = 278) and controls (N = 227) were collected from a homogeneous Finnish source population. CSF concentration of 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) were available from 208 participants. Single allele, hemizygous genotypes were grouped according to inferred effect of the MAOA alleles on transcriptional activity. MAOA-LPR genotypes had a significant effect on CSF HVA concentration (P = 0.01) but explained only 3% of the total variance. There was a detectable but nonsignificant genotype effect on 5-HIAA and no effects on MHPG. Specifically, the genotype conferring high MAOA activity was associated with lower HVA levels in both alcoholics and controls, a finding that persisted after accounting for the potential confounds of alcoholism, BMI, height, and smoking. MAOA-LPR genotype predicted BMI (P < 0.005), with the high-activity genotype being associated with lower BMI. MAOA-LPR genotypes were not associated with alcoholism or related psychiatric phenotypes in this data set. Our results suggest that MAOA-LPR allelic variation modulates DA turnover in the CNS, but does so in a manner contrary to our prior expectation that alleles conferring high activity would predict higher HVA levels in CSF. Our results are consistent with an emerging literature that suggests greater complexity in how variation in MAOA expression alters monoaminergic function. Finally, our work suggests that MAOA may be involved in the regulation of BMI. Independent samples are necessary to confirm this preliminary finding.

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FunctionalNPYVariation as a Factor in Stress Resilience and Alcohol Consumption in Rhesus Macaques

Lindell¹,

Schwandt²,

Sun³

et al. 2010

Arch Gen Psychiatry

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Context Neuropeptide Y (NPY) is important to countering stress and is involved in neuroadaptations that drive escalated alcohol drinking following repeated alcohol exposure in rodents. In humans, haplotype-driven diminution in NPY expression is predictive of amygdala response and emotional reactivity to stress. Genetic variation that affects the NPY system could impact resilience to stress and to developing addiction with continued alcohol use. Objective To determine whether functional NPY variation influences CSF NPY, behavioral adaptation to stress, and alcohol consumption in a nonhuman primate model of early adversity (peer rearing). Design We sequenced the rhesus macaque NPY locus (rhNPY) and performed in silico analysis to identify functional variants. We performed gel shift assays for a −1002 T>G using nuclear extract from testes, brain and hypothalamus. Levels of NPY in CSF were measured by RIA, and mRNA levels were assessed in amygdala using RT-PCR. During infancy, animals were exposed to repeated social separation stress, and tested for individual differences in alcohol consumption as young adults. Animals were genotyped for −1002 T>G, and the effects of this variant on mRNA expression, CSF NPY, behavior arousal during stress, and ethanol consumption were assessed by ANOVA. Results The G allele altered binding of regulatory proteins in all nuclear extracts tested, and −1002 T>G resulted in lower levels of NPY expression in amygdala. Macaques exposed to adversity had lower CSF NPY and exhibited higher levels of arousal during stress, but only as a function of the G allele. We also found that stress-exposed G allele carriers consumed more alcohol and exhibited an escalation in intake over cycles of alcohol availability and deprivation. Conclusions Our results suggest a role for NPY promoter variation in the susceptibility to alcohol use disorders and point to NPY as a candidate for examining GxE interactions in humans.

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Monoamine oxidase A gene promoter variation and rearing experience influences aggressive behavior in rhesus monkeys

Cited by 236 publications

References 22 publications

Cluster B Personality Disorders are Associated with Allelic Variation of Monoamine Oxidase A Activity

Cluster B Personality Disorders are Associated with Allelic Variation of Monoamine Oxidase A Activity

A functional polymorphism in the MAOA gene promoter (MAOA-LPR) predicts central dopamine function and body mass index

FunctionalNPYVariation as a Factor in Stress Resilience and Alcohol Consumption in Rhesus Macaques

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