MAO and Aggression

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MAO and Aggression
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Background

• Monoamine oxidase (MAO) enzyme involved in the
  metabolism of biogenic amines in the brain and
  peripheral tissue
• MAO-A breaks down serotonin, norepinephrine and
  dopamine
• MAO-B breaks down phenylethylamine, benzlamine
  and to a lesser extent serotonin, dopamine and
  the other neurotransmitters
• Both map to Xp, but are expressed differently
  across development

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MAO and Aggression

• Serotonin levels are hypothesized to be related
  to aggressive behavior
• Animals with no MAO-A have high levels of brain
  serotonin and are aggressive
• Brunner et al. (1993)

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Brunner et al. (1993)(Science, 262 578-580)

• Dutch family in which several males had
  borderline mental retardation and a pattern of
  impulsive aggression
• Suspected X-linked transmission
• Hypothesized MAO might be involved

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MAO-A Mutation

• Affected males have low levels of MAO A (but
  not B) activity
• In position 936 a C to T mutation changes a
  glutamine (CAG) codon to a termination (TAG)
  codon

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Caspi et al. (2002)(Science, 297 851-853)

• Rationale Not all maltreated children have bad
  outcomes. Could there be differential
  vulnerability owing in part to genetic factors?
• Sample Dunedin longitudinal study of a birth
  cohort males only
• Outcome
• Conduct disorder
• Conviction for violent offense
• Self-reported aggression scale
• Antisocial personality disorder

Composite
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How did they assess maltreatment?

• Composite of
• Observed harsh, indifferent mothering at age 3
  (16)
• Harsh corporal punishment at age 7 9 (10)
• 2 or more changes in primary caregiver (6)
• Severe physical punishment before age 11 (3)
• Unwanted sexual contact prior to age 11 (5)
• 64 experienced no maltreatment, 28 experienced
  1 (probable), and 8 experienced 2 or more
  (severe)

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What was the genetic polymorphism?

• In promoter region, 30 bp sequence repeated 2, 3,
  3.5, 4 or 5 times
• 3.5 4 are transcribed 2-10 more efficiently
  than others
• Frequencies vary markedly with ethnicity

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What did they find?
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What have we learned from this study?

• Does this study seek to explain why aggression
  comes about?
• Are they arguing this is the sole or even a major
  pathway to aggression?
• Is it problematic that there is no MAO-A effect
  in the None Maltreated Group?

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Candidate Gene

• What about risk for depression?

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Why did they only study males?

• Can predictions be made for females?
• Note 30 it is not possible to determine which
  of the two alleles is inactivated for each female
  participant
• Does MAOA account for sex differences in
  aggression?
• What can we say about the mothers? How about the
  fathers?

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Does this study have clinical utility?

• Pharmacologic versus behavioral interventions
• Ethics of labeling or pharmacological
  interventions with at-risk individuals
• Does the study need to have direct clinical
  utility to be useful?