Genetic Variation Within Serotonin Genes, Hormones, and Aggression

摘要

Inter-individual differences in aggressive behavior and related mental illnesses have important genetic as well as environmental underpinnings. Twin and adoption studies have shown that genetic factors contribute to approximately 50 % of vulnerability to aggression. Across-species aggressive behavior is more common in males than females, reflecting the different evolutionary roles of the two genders and pointing to the different effects on brain and behavior of the neuro-endocrinological process involved in sex differentiation. Indeed, a correlation between testosterone levels and aggression has been reported in studies on humans and other species. Multiple pieces of evidence support the role of genetic variation within genes belonging to the serotonin system, such as monoamine oxidase A (MAOA), HTR1B, HTR3B, SLC6A4, and HTR2B, in determining vulnerability to aggression. Recent studies also indicate the existence of a complex interaction between genes, hormones, and stress. MAOA is an X-linked gene encoding the monoamine oxidase A, a mitochondrial enzyme that metabolizes monoamine neurotransmitters including norepinephrine, dopamine, and serotonin. MAOA knockout mice have higher levels of these neurotransmitters and manifest increased aggressive behavior and stress reactivity. In humans, a rare stop codon variant leading to a complete MAOA deficiency has been reported in a single Dutch family in which eight males were affected by a syndrome characterized by borderline mental retardation and severe aggressive behavior. More recently, a common polymorphism influencing MAOA transcription (MAOA-LPR) has been found in the human MAOA promoter. At this locus, the allele associated with low MAOA activity (e.g., increased monoamines level) has been associated with increased risk of developing Conduct Disorder and Antisocial Personality Disorder among subjects exposed to severe childhood trauma. In addition, a powerful MAOA-LPR x endocrine interaction has been described in a sample of Finnish male violent offenders. In this study, a strong correlation between testosterone and aggressive behavior was found only among carriers of the low MAOA activity allele. More recently, a rare stop codon variant (Q20*) within the HTR2B serotonin receptor gene has been associated with psychiatric diseases marked by severe impulsivity and aggression. Similar to what has been observed for MAOA, the impact of Q20* was not in itself sufficient in determining aggressive behavior, but male sex, testosterone level, and exposure to alcohol had important roles.