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MAOA–Environment Interactions: Results May Vary

      In a seminal article, Brunner and colleagues (
      • Brunner H.G.
      • Nelen M.
      • Breakefield X.O.
      • Ropers H.H.
      • van Oost B.A.
      Abnormal behavior associated with a point mutation in the structural gene for monoamine oxidase A.
      ) discovered a stop codon unique to one Dutch family leading to altered metabolism of monoamine neurotransmitters and antisocial behavior in hemizygous males (Figure 1). Discovery of this rare functional variant was followed by the detection of a common functional variable number of tandem repeat locus that was associated to behavioral dyscontrol, especially in the context of stress exposure (Figure 1). In 2002, Caspi et al. (
      • Caspi A.
      • McClay J.
      • Moffitt T.E.
      • Mill J.
      • Martin J.
      • Craig I.W.
      • Taylor A.
      • Poulton R.
      Role of genotype in the cycle of violence in maltreated children.
      ) reported the first powerful demonstration of gene–environment interaction in behavior by showing that childhood maltreatment predicted antisocial behavior in men as a function of monoamine oxidase A (MAOA) genotype. This finding has proven to be a veritable cornucopia or prototype, spawning myriad studies that have sought to address the issue of whether the combined effects of low expression MAOA genotypes and stress are additive or interactive along with studies of the environment’s interaction with many other genes. Under the additive model, 2 + 2 = 4, but as is well understood, interactions can be subadditive (e.g., 2 + 2 = 3) or superadditive (e.g., 2 + 2 = 10).
      Figure thumbnail gr1
      Figure 1The monoamine oxidase (MAOA and MAOB) genes are located 20 kb from each other on the p arm of the X chromosome in tail-to-tail orientation. The variable number tandem repeats (VNTRs) and androgen responsive elements (AREs), responsible for differential behavior of MAOA, are located within the gene’s promoter region. The Brunner stop codon, which resides in the MAOA gene’s eighth exon, results in complete dysfunction of the gene. In the Venn diagram: amine groups (NH2) of molecular substrates are highlighted. MAOA preferentially degrades norepinephrine (top left) and serotonin (bottom left), whereas MAOB preferentially degrades benzylamine (top right) and phenylethylamine (bottom right). Both enzymes degrade dopamine (middle).
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      1. Byrd AL, Manuck SB (2014): MAOA, childhood maltreatment, and antisocial behavior: Meta-analysis of a gene–environment interaction. Biol Psychiatry 75:9–17.

      2. Haberstick BC, Lessem JM, Hewitt JK, Smolen A, Hopfer CJ, Halpern CT, et al. (2014): MAOA genotype, childhood maltreatment, and their interaction in the etiology of adult antisocial behaviors. Biol Psychiatry 75:25–30.

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      Linked Article

      • MAOA, Childhood Maltreatment, and Antisocial Behavior: Meta-analysis of a Gene-Environment Interaction
        Biological PsychiatryVol. 75Issue 1
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          In a seminal study of gene-environment interaction, childhood maltreatment predicted antisocial behavior more strongly in male subjects carrying an MAOA promoter variant of lesser, compared with higher, transcriptional efficiency. Many further investigations have been reported, including studies of other early environmental exposures and female subjects. Here, we report a meta-analysis of studies testing the interaction of MAOA genotype and childhood adversities on antisocial outcomes in predominantly nonclinical samples.
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      • MAOA Genotype, Childhood Maltreatment, and Their Interaction in the Etiology of Adult Antisocial Behaviors
        Biological PsychiatryVol. 75Issue 1
        • Preview
          Maltreatment by an adult or caregiver during childhood is a prevalent and important predictor of antisocial behaviors in adulthood. A functional promoter polymorphism in the monoamine oxidase A (MAOA) gene has been implicated as a moderating factor in the relationship between childhood maltreatment and antisocial behaviors. Although there have been numerous attempts at replicating this observation, results remain inconclusive.
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