Title: The Association of Polymorphisms in Genes affecting Monoamine Neurotransmission with Aggressive Behavior in Schizophrenic Violent Individuals
Name: Rael Strous
Year: 2000, 2001
Type: Research Grant

Violence remains an important sociobiological problem, and is reported to affect approximately 3.7% of the population each year. In the mentally ill, the prevalence of violent behavior is higher that in the general population. The etiology of violence in the general population, as well as in the mentally ill, is poorly understood, but there are very likely common biological and genetic factors that play a role. This international collaborative study intended to focus on the genetic aspects of violence, investigating polymorphic differences in genes that influence catecholaminergic neurotransmitter systems in the brain. Considering the wealth of research demonstrating an association between these monoamine neurotransmitter systems and aggression, polymorphic differences in the genes that affect monoamine transmission may play a role in human aggression. Our team has identified a common functional polymorphism at COMT codon 158. The COMT enzyme inactivates catecholamines by catalyzing S-adenosyl-L-methionine dependent methyl conjugation. This polymorphism results in substantial differences in enzyme activity. One allele encodes a methionine at codon 158 (158Met) and the other allele a valine (158Val). 158Val homozygotes have 3 to 4-fold higher levels of activity than 158Met homozygotes. The COMT polymorphism has since been investigated as a possible contributing factor in several psychiatric and behavioral conditions. This investigation confirmed previous evidence by our group showing a relationship between a polymorphism in the gene encoding the enzyme catechol-O-methyltransferase (COMT) and aggression in schizophrenia. Patients with schizophrenia (SZ) were assessed for violent behavior using the Lifetime History of Aggression (LHA) scale, an 11-item questionnaire that includes Aggression, Self-Directed Aggression, and Consequences/Antisocial Behavior subscales. DNA was genotyped for the COMT 158 polymorphism, as well as a functional polymorphism in the monoamine oxidase A (MAOA) gene promoter. Similar to our previously reported findings, a statistically significant association was found between aggressive behavior in SZ and the COMT 158 polymorphism; mean LHA scores were higher in subjects homozygous for 158Met, the low enzyme activity COMT variant (F(2,105) = 5.616, P = 0.005). Analysis of the major LHA subscales revealed that the association with 158Met was due to high scores on the Aggression, and Self-Directed Aggression subscales, but not the Consequences/Antisocial Behavior subscale. No significant association was detected for the MAOA gene alone. Our findings provide further support that COMT is a modifying gene that plays a role in determining interindividual variability in the proclivity for outward and self-directed aggressive behavior found in some schizophrenic patients. Considering the role of dopamine in schizophrenia and the finding that dopamine agonists provoke aggressive behavior, an increase in dopaminergic transmission caused by COMT 158Met is a possible mechanism through which this allele can act. In the context of preexisting prefrontal abnormalities in schizophrenia caused by genetic, developmental and/or environmental factors, 158Met homozygosity may lead to an increase in prefrontal dopamine with an increased propensity for impulsive, violent behavior in schizophrenia.

Bibliography: Rael, Strous. Aggressive behavior in schizophrenia is associated with the low enzyme activity COMT polymorphism: A replication study. Am J Med Genet. 2003;120B:29-34). (July 2003) American Journal of Medical Genetics (Strous RD, Nolan KA, Lapidus R, Diaz L, Saito T, Lachman HM.