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Brief Report   |    
Association Between Catechol O-Methyltransferase Genotype and Violence in Schizophrenia and Schizoaffective Disorder
Herbert M. Lachman, M.D.; Karen A. Nolan, Ph.D.; Pavel Mohr, M.D.; Takuya Saito, M.D.; Jan Volavka, M.D., Ph.D.
Am J Psychiatry 1998;155:835-837.

Abstract

OBJECTIVE: The authors previously reported a relationship between an allele encoding the low activity variant of catechol O-methyltransferase (COMT) and aggressive behavior in schizophrenic patients. This study replicates and extends these findings by using more direct measures of violent behavior. METHOD: Fifty-five white patients (34 men, 21 women) with DSM-IV diagnoses of schizophrenia or schizoaffective disorder were selected to form two groups (violent and nonviolent) on the basis of history of aggressive behavior. COMT genotypes were determined by restriction fragment length polymorphism analysis. RESULTS: A significant association was found between COMT genotype and history of violent behavior. Sixty-four percent of patients homozygous for the low-activity COMT allele were violent; 80% of patients homozygous for the high-activity allele were nonviolent. CONCLUSIONS: The gene determining the activity of an important regulatory enzyme in catecholamine inactivation is associated with violent behavior in patients with schizophrenia and schizoaffective disorder.

Abstract Teaser
Figures in this Article

Alterations in catecholamines have been implicated in aggressive behavior (13). Catechol O-methyltransferase (COMT) inactivates catecholamines (4) and therefore could be a factor in regulating aggressive behavior. A common polymorphism in the COMT gene, at codon 158, results in a valine to methionine substitution and is associated with threefold to fourfold differences in COMT activity between homozygous subjects; heterozygous subjects have intermediate levels of activity (59).

The methionine encoding, low-activity allele may be involved in obsessive-compulsive disorder (10) and rapid cycling bipolar disorder in velo-cardio-facial syndrome, a congenital anomaly associated with chromosome 22q11.2 deletions (11). Although we did not find an association between COMT genotype and schizophrenia, an association between the low-activity allele and greater violent behavior in schizophrenic patients was detected (12, 13).

This study was intended to replicate and extend the finding relating COMT genotype and aggression through use of more direct measures of violent behavior.

Fifty-five white patients (34 men and 21 women, including two nonblack Hispanics) with DSM-IV diagnoses of schizophrenia (N=39) or schizoaffective disorder (N=16) were recruited from Rockland Psychiatric Center (N=48) and Bronx Psychiatric Center (N=7). Written informed consent was obtained from all subjects. Most were inpatients (N=42) or residents in community care facilities (N=8). All had at least one prior inpatient psychiatric hospitalization. Violence classification was based on review of all available material (admission and discharge summaries, progress notes, treatment plans of current and prior hospitalizations, and, for inpatients, chart notes transcribed from official records of arrests and convictions provided by the New York State Bureau of Criminal Justice Services). Violent subjects had a documented history of multiple assaults. Assault was defined as an attack on another person, including hitting, kicking, slapping, biting, choking, throwing objects, and using weapons. Comparison subjects had no known history of violent or threatening behavior. Subjects showing intermediate levels of violence, such as single assault, verbal threats, or gestures, were not included in the study.

The COMT codon 158 polymorphism was determined by restriction fragment length polymorphism analysis through use of polymerase chain reaction amplified gene fragments and Nla III restriction digestion, as previously described in detail (9). Genotyping was performed by individuals who were blind to violence histories.

Chi-square analyses were applied to 3 by 2 (genotype by subject group) tables. Kruskal-Wallis analyses were applied to allele frequency distributions.

The nonviolent and violent groups were not significantly different in age (F=3.9, df=1,53, p=0.05) or diagnosis (χ2=1.2, df=1, p=0.27) (T1). The association between COMT genotype and violence was significant (p=0.03), as were between-group differences in allele frequencies (p=0.02). Sixty-four percent of patients homo~zygous for the low-activity COMT allele (LL genotype) were violent; 80% of patients homozygous for the high-activity allele (HH genotype) were nonviolent.

The significant between-group differences were due primarily to the male patients (genotype: χ2=9.7, df=2, p=0.008; allele frequency: Kruskal-Wallis statistic=5.4, df=1, p=0.02). The results were not significant in female patients (genotype: χ2=1.42, df=2, p=0.49; allele frequency: Kruskal-Wallis statistic=1.2, df=1, p=0.27). However, the group size was relatively small, and the proportion of schizoaffective subjects was greater among women.

This study replicates our previous report of an association between COMT genotype and aggression in schizophrenic subjects (13). The low-activity COMT allele appears to increase the propensity for violent behavior, whereas the high-activity allele may have a protective effect. The findings support other studies showing that alterations in catecholamine transmission play a role in violence (13, 1416). Since this is a replication study, this is likely a true association rather than a false positive result due to population stratification. The possibility of stratification is further diminished by the finding that the frequency of the COMT polymorphism appears to be fairly stable in different Caucasian populations (7, 17, 18).

These data strongly suggest that the COMT polymorphism, or a gene in linkage disequilibrium with the COMT locus, plays a role in violence in schizophrenia. However, considering that the number of patients in this and our previously published study is relatively small, and that the levels of significance achieved are modest, the findings still have to be replicated by other investigators. In addition, other studies will be needed to determine whether the COMT polymorphism plays a role in violence in the general population.

 

Received July 22, 1997; revision received Dec. 3, 1997; accepted Dec. 16, 1997. From the Department of Psychiatry and Medicine, Albert Einstein College of Medicine; and Nathan S. Kline Institute for Psychiatric Research, Orangeburg, N.Y. Address reprint requests to Dr. Lachman, Department of Psychiatry and Medicine, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461; lachman@aecom.yu.edu (e-mail). Supported by a Scottish Rite Schizophrenia Research grant (Dr. Lachman).

Pucilowski O, Kozak W, Valzelli L: Effect of 6-OHDA injected into the locus ceruleus on apomorphine-induced aggression. Pharmacol Biochem Behav  1986; 24:773–775
[PubMed]
[CrossRef]
 
Coccaro EF, Lawrence T, Trestman R, Gabriel S, Klar HM, Siever LJ: Growth hormone responses to intravenous clonidine challenge correlate with behavioral irritability in psychiatric patients and healthy volunteers. Psychiatry Res  1991; 39:129–139
[PubMed]
[CrossRef]
 
Ratey JJ, Gordon A: The psychopharmacology of aggression: toward a new day. Psychopharmacol Bull  1993; 29:65–73
[PubMed]
 
Axelrod J, Tomchick R: Enzymatic O-methylation of epinephrine and other catechols. J Biol Chem  1958; 233:702–705
[PubMed]
 
Weinshilboum RM, Raymond FA: Inheritance of low erythrocyte catechol-O-methyltransferase activity in man. Am J Hum Genet  1977; 29:125–135
[PubMed]
 
Boudikova B, Szumlanski C, Maidak B, Weinshilboum R: Human liver catechol-O-methyltransferase pharmacogenetics. Clin Pharmacol Ther  1990; 48:381–389
[PubMed]
[CrossRef]
 
Spielman RS, Weinshilboum RM: Genetics of red cell COMT activity: analysis of thermal stability and family data. Am J Med Genet  1981; 10:279–290
[PubMed]
[CrossRef]
 
Lotta T, Vidgren J, Tilgmann C, Ulmanen I, Melen K, Julkunen I, Taskinen J: Kinetics of human soluble and membrane-bound catechol O-methyltransferase: a revised mechanism and description of the thermolabile variant of the enzyme. Biochemistry  1995; 34:4202–4210
[PubMed]
[CrossRef]
 
Lachman H, Papolos DF, Saito T, Yu YM, Szumlanski CL, Wein~shilboum RM: Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmaco~genetics  1996; 6:243–250
[CrossRef]
 
Karayiorgou M, Altemus M, Galke BL, Goldman D, Murphy DL, Ott J, Gogos JA: Genotype determining low catechol-O-methyltransferase activity as a risk factor for obsessive-compulsive disorder. Proc Natl Acad Sci USA  1997; 94:4572–4575
[PubMed]
[CrossRef]
 
Lachman HM, Morrow B, Shprintzen R, Veit S, Parsia SS, Faed~da G, Goldberg R, Kucherlapati R, Papolos DF: Association of codon 108/158 catechol O-methyltransferase gene polymorphism with the psychiatric manifestations of velo-cardio-facial syndrome. Am J Med Genet Neuropsychiatr Genet  1996; 67:468–472
[CrossRef]
 
Strous RD, Bark N, Woerner M, Lachman HM: Lack of association of a functional catechol-O-methyltransferase gene polymorphism in schizophrenia. Biol Psychiatry  1997; 41:493–495
[PubMed]
[CrossRef]
 
Strous RD, Bark N, Parsia SS, Volavka J, Lachman HM: Analysis of a functional catechol O-methyltransferase gene polymorphism in schizophrenia: evidence for association with aggressive and antisocial behavior. Psychiatry Res  1997; 69:71–77
[PubMed]
[CrossRef]
 
Sorgi PJ, Ratey JJ, Polakoff S: β-Adrenergic blockers for the control of aggressive behaviors in patients with chronic schizophrenia. Am J Psychiatry  1986; 143:775–776
[PubMed]
 
Volavka J: Can aggressive behavior in humans be modified by beta blockers? Postgraduate Med Special Issue, Feb 29, 1988, pp 163–168
 
Brunner HG, Nelen M, Breakfield XO, Ropers HH, van Oost BA: Abnormal behavior associated with a point mutation in the structural gene for monoamine oxidase A. Science  1995; 262:578–580
 
Syvanen AC, Tilgmann C, Rinne J, Ulmanen I: Genetic polymorphism of catecholamine O-methyltransferase (COMT): correlation of genotype with individual variation of S-COMT activity and comparison of the allele frequencies in the normal population and parkinsonian patients in Finland. Pharmacogenetics  1997; 7:65–71
[PubMed]
[CrossRef]
 
McLeod HL, Fang L, Luo X, Scott EP, Evans WE: Ethnic differences in erythrocyte catechol O-methyltransferase activity in black and white Americans. J Pharmacol Exp Ther  1994; 270:26–29
[PubMed]
 
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References

Pucilowski O, Kozak W, Valzelli L: Effect of 6-OHDA injected into the locus ceruleus on apomorphine-induced aggression. Pharmacol Biochem Behav  1986; 24:773–775
[PubMed]
[CrossRef]
 
Coccaro EF, Lawrence T, Trestman R, Gabriel S, Klar HM, Siever LJ: Growth hormone responses to intravenous clonidine challenge correlate with behavioral irritability in psychiatric patients and healthy volunteers. Psychiatry Res  1991; 39:129–139
[PubMed]
[CrossRef]
 
Ratey JJ, Gordon A: The psychopharmacology of aggression: toward a new day. Psychopharmacol Bull  1993; 29:65–73
[PubMed]
 
Axelrod J, Tomchick R: Enzymatic O-methylation of epinephrine and other catechols. J Biol Chem  1958; 233:702–705
[PubMed]
 
Weinshilboum RM, Raymond FA: Inheritance of low erythrocyte catechol-O-methyltransferase activity in man. Am J Hum Genet  1977; 29:125–135
[PubMed]
 
Boudikova B, Szumlanski C, Maidak B, Weinshilboum R: Human liver catechol-O-methyltransferase pharmacogenetics. Clin Pharmacol Ther  1990; 48:381–389
[PubMed]
[CrossRef]
 
Spielman RS, Weinshilboum RM: Genetics of red cell COMT activity: analysis of thermal stability and family data. Am J Med Genet  1981; 10:279–290
[PubMed]
[CrossRef]
 
Lotta T, Vidgren J, Tilgmann C, Ulmanen I, Melen K, Julkunen I, Taskinen J: Kinetics of human soluble and membrane-bound catechol O-methyltransferase: a revised mechanism and description of the thermolabile variant of the enzyme. Biochemistry  1995; 34:4202–4210
[PubMed]
[CrossRef]
 
Lachman H, Papolos DF, Saito T, Yu YM, Szumlanski CL, Wein~shilboum RM: Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmaco~genetics  1996; 6:243–250
[CrossRef]
 
Karayiorgou M, Altemus M, Galke BL, Goldman D, Murphy DL, Ott J, Gogos JA: Genotype determining low catechol-O-methyltransferase activity as a risk factor for obsessive-compulsive disorder. Proc Natl Acad Sci USA  1997; 94:4572–4575
[PubMed]
[CrossRef]
 
Lachman HM, Morrow B, Shprintzen R, Veit S, Parsia SS, Faed~da G, Goldberg R, Kucherlapati R, Papolos DF: Association of codon 108/158 catechol O-methyltransferase gene polymorphism with the psychiatric manifestations of velo-cardio-facial syndrome. Am J Med Genet Neuropsychiatr Genet  1996; 67:468–472
[CrossRef]
 
Strous RD, Bark N, Woerner M, Lachman HM: Lack of association of a functional catechol-O-methyltransferase gene polymorphism in schizophrenia. Biol Psychiatry  1997; 41:493–495
[PubMed]
[CrossRef]
 
Strous RD, Bark N, Parsia SS, Volavka J, Lachman HM: Analysis of a functional catechol O-methyltransferase gene polymorphism in schizophrenia: evidence for association with aggressive and antisocial behavior. Psychiatry Res  1997; 69:71–77
[PubMed]
[CrossRef]
 
Sorgi PJ, Ratey JJ, Polakoff S: β-Adrenergic blockers for the control of aggressive behaviors in patients with chronic schizophrenia. Am J Psychiatry  1986; 143:775–776
[PubMed]
 
Volavka J: Can aggressive behavior in humans be modified by beta blockers? Postgraduate Med Special Issue, Feb 29, 1988, pp 163–168
 
Brunner HG, Nelen M, Breakfield XO, Ropers HH, van Oost BA: Abnormal behavior associated with a point mutation in the structural gene for monoamine oxidase A. Science  1995; 262:578–580
 
Syvanen AC, Tilgmann C, Rinne J, Ulmanen I: Genetic polymorphism of catecholamine O-methyltransferase (COMT): correlation of genotype with individual variation of S-COMT activity and comparison of the allele frequencies in the normal population and parkinsonian patients in Finland. Pharmacogenetics  1997; 7:65–71
[PubMed]
[CrossRef]
 
McLeod HL, Fang L, Luo X, Scott EP, Evans WE: Ethnic differences in erythrocyte catechol O-methyltransferase activity in black and white Americans. J Pharmacol Exp Ther  1994; 270:26–29
[PubMed]
 
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