Association study of a functional catechol-O-methyltransferase (COMT) Val108/158Met polymorphism and suicide attempts in patients with alcohol dependence.

Alcohol dependence is frequently associated with aggressive and suicidal behaviour. Genetic factors contribute to both behaviours. Candidate genes, related to suicide and aggression, include genes involved in serotonin, norepinephrine and dopamine pathways. The enzyme catechol-O-methyl transferase (COMT) degrades dopamine, epinephrine and norepinephrine. The functional polymorphism (COMT Val108/158Met) affects COMT activity, with the valine (Val) variant associated with higher and the methionine (Met) variant with lower COMT activity. This polymorphism is associated with aggressive and suicidal behaviour, but the literature data on this relationship is contradictory and inconsistent. The hypothesis of this study was that Met allele carriers with alcohol dependence will have a higher frequency of suicide attempts compared to other genotypes. Participants were 312 male and 81 female medication-free patients with alcohol dependence and 487 male and 122 female unrelated, non-suicidal medication-free Caucasian healthy subjects. Our results showed significant (χ2 test with standardized residuals) differences in the frequencies of COMT variants in all alcoholics, alcoholics with different comorbid diagnoses, and in male but not in female alcoholics, with or without suicide attempts. Male alcoholic suicide attempters, compared to male non-attempters, had the higher frequency of Met/Met genotype or Met allele, and significantly (Kruskal-Wallis ANOVA on ranks and Mann-Whitney test) higher aggression and depression scores. These results confirmed the associations between Met allele and aggressive behaviour or violent suicide attempts in various psychiatric diagnoses, and suggested that Met allele of the COMT Val108/158 Met might be used as an independent biomarker of suicidal behaviour across different psychopathologies.

[1]  Janet B W Williams,et al.  Diagnostic and Statistical Manual of Mental Disorders , 2013 .

[2]  E. Walker,et al.  Diagnostic and Statistical Manual of Mental Disorders , 2013 .

[3]  N. Pivac,et al.  Association study of a functional catechol-o-methyltransferase polymorphism and smoking in healthy Caucasian subjects , 2010, Neuroscience Letters.

[4]  James Davis,et al.  Key neurochemical markers for the prevention of suicide , 2009 .

[5]  A. Wenzel,et al.  Candidate Endophenotypes for Genetic Studies of Suicidal Behavior , 2009, Biological Psychiatry.

[6]  J. Mann,et al.  No Association of COMT Val158Met Polymorphism with Suicidal Behavior or CSF Monoamine Metabolites in Mood Disorders , 2008, Archives of suicide research : official journal of the International Academy for Suicide Research.

[7]  A. McGirr,et al.  The relationship of impulsive aggressiveness to suicidality and other depression-linked behaviors , 2007, Current psychiatry reports.

[8]  P. Baud,et al.  Catechol‐O‐methyltransferase polymorphism (COMT) in suicide attempters: A possible gender effect on anger traits , 2007, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[9]  M. Tsuang,et al.  Meta‐analyses suggest association between COMT, but not HTR1B, alleles, and suicidal behavior , 2007, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[10]  G. Turecki,et al.  Panic disorder and suicidality: is comorbidity with depression the key? , 2007, Journal of affective disorders.

[11]  N. Kato,et al.  Association study of monoamine oxidase and catechol-O-methyltransferase genes with smoking behavior , 2007, Pharmacogenetics and genomics.

[12]  Ladislav Hosák,et al.  Role of the COMT gene Val158Met polymorphism in mental disorders: A review , 2007, European Psychiatry.

[13]  D. Goldman,et al.  Increased anxiety and other similarities in temperament of alcoholics with and without antisocial personality disorder across three diverse populations. , 2007, Alcohol.

[14]  B. Bondy,et al.  Genetics of suicide , 2006, Molecular Psychiatry.

[15]  G. Klerman,et al.  Hostility and depression associated with suicide attempts. , 2006, The American journal of psychiatry.

[16]  L. Sher.  Alcoholism and suicidal behavior: a clinical overview , 2006, Acta psychiatrica Scandinavica.

[17]  M. Alda,et al.  Risk factors for suicide completion in major depression: a case-control study of impulsive and aggressive behaviors in men. , 2005, The American journal of psychiatry.

[18]  J. Kennedy,et al.  Gene–gene interaction between MAOA and COMT in suicidal behavior , 2005, Neuroscience Letters.

[19]  H. Ono,et al.  Association between Catechol-O-Methyltransferase Functional Polymorphism and Male Suicide Completers , 2004, Neuropsychopharmacology.

[20]  Hans-Jürgen Möller,et al.  A functional single nucleotide polymorphism (V158M) in the COMT gene is associated with aggressive personality traits , 2003, Biological Psychiatry.

[21]  S. Tsai,et al.  Association Analysis of a Functional Catechol-O-Methyltransferase Gene Polymorphism in Schizophrenic Patients in Taiwan , 2001, Neuropsychobiology.

[22]  M. Karvonen,et al.  Suicidal behavior in patients with schizophrenia is related to COMT polymorphism , 2000, Psychiatric genetics.

[23]  A. Farmer,et al.  What can psychiatric genetics offer suicidology? , 2000, Crisis.

[24]  T. Kashdan,et al.  Analysis of catechol-O-methyltransferase and 5-hydroxytryptamine transporter polymorphisms in patients at risk for suicide , 2000, Psychiatry Research.

[25]  R. Ebstein,et al.  Homicidal behavior in schizophrenia associated with a genetic polymorphism determining low catechol O-methyltransferase (COMT) activity. , 1999, American journal of medical genetics.

[26]  K. Blennow,et al.  Reduced cerebrospinal HVA concentrations and HVA/5-HIAA ratios in suicide attempters Monoamine metabolites in 120 suicide attempters and 47 controls , 1999, European Neuropsychopharmacology.

[27]  G. Engström,et al.  Temperament traits in seasonal affective disorder, suicide attempters with non-seasonal major depression and healthy controls. , 1999, Journal of affective disorders.

[28]  J. Guelfi,et al.  Impulsivity: a relevant dimension in depression regarding suicide attempts? , 1999, Journal of affective disorders.

[29]  M. Koulu,et al.  Association between the functional variant of the catechol-O-methyltransferase (COMT) gene and type 1 alcoholism , 1999, Molecular Psychiatry.

[30]  C Waternaux,et al.  Toward a clinical model of suicidal behavior in psychiatric patients. , 1999, The American journal of psychiatry.

[31]  T. Gregg,et al.  Neuropharmacology of brain-stimulation-evoked aggression , 1999, Neuroscience & Biobehavioral Reviews.

[32]  D. Pfaff,et al.  Catechol-O-methyltransferase-deficient mice exhibit sexually dimorphic changes in catecholamine levels and behavior. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[33]  L. Bierut,et al.  Suicidal behaviour: an epidemiological and genetic study , 1998, Psychological Medicine.

[34]  K. Ohara,et al.  Low activity allele of catechol‐o‐methyltransferase gene and Japanese unipolar depression , 1998, Neuroreport.

[35]  J. Haller,et al.  Catecholaminergic involvement in the control of aggression: hormones, the peripheral sympathetic, and central noradrenergic systems , 1997, Neuroscience & Biobehavioral Reviews.

[36]  J. Volavka,et al.  Analysis of a functional catechol-O-methyltransferase gene polymorphism in schizophrenia: evidence for association with aggressive and antisocial behavior , 1997, Psychiatry Research.

[37]  R. Weinshilboum,et al.  Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. , 1996, Pharmacogenetics.

[38]  N. Harada,et al.  Effects of testosterone and its metabolites on aromatase-immunoreactive cells in the quail brain: Relationship with the activation of male reproductive behavior , 1996, The Journal of Steroid Biochemistry and Molecular Biology.

[39]  A. Roy,et al.  Attempted suicide among living co-twins of twin suicide victims. , 1995, The American journal of psychiatry.

[40]  A. Amundsen,et al.  Alcohol abuse and suicide: a 40-year prospective study of Norwegian conscripts. , 1995, Addiction.

[41]  I. Ulmanen,et al.  Kinetics of human soluble and membrane-bound catechol O-methyltransferase: a revised mechanism and description of the thermolabile variant of the enzyme. , 1995, Biochemistry.

[42]  D. Brent,et al.  Personality disorder, personality traits, impulsive violence, and completed suicide in adolescents. , 1994, Journal of the American Academy of Child and Adolescent Psychiatry.

[43]  R. Ulrich,et al.  Risk factors for suicidal behavior in borderline personality disorder. , 1994, The American journal of psychiatry.

[44]  V. Arango,et al.  Quantitative autoradiography of α 1- and α 2-adrenergic receptors in the cerebral cortex of controls and suicide victims , 1993, Brain Research.

[45]  J. Mann,et al.  CSF 5-HIAA and HVA concentrations in elderly depressed patients who attempted suicide. , 1990, The American journal of psychiatry.

[46]  P. Vitaliano,et al.  Anger, hostility, and depression in assaultive vs. suicide-attempting males. , 1989, Journal of clinical psychology.

[47]  M. Branchey,et al.  Age of alcoholism onset. I. Relationship to psychopathology. , 1989, Archives of general psychiatry.

[48]  Shirley A. Miller,et al.  A simple salting out procedure for extracting DNA from human nucleated cells. , 1988, Nucleic acids research.

[49]  Cloninger Cr.  A systematic method for clinical description and classification of personality variants: A proposal. , 1987 .

[50]  S. Paul,et al.  Reduced CSF concentrations of homovanillic acid and homovanillic acid to 5-hydroxyindoleacetic acid ratios in depressed patients: relationship to suicidal behavior and dexamethasone nonsuppression. , 1986, The American journal of psychiatry.

[51]  A. Roy.  Suicide in Twins , 1986, Archives of general psychiatry.

[52]  K. Tardiff.  The risk of assaultive behavior in suicidal patients , 1981, Acta psychiatrica Scandinavica.

[53]  Frederick K. Goodwin,et al.  Aggression in humans correlates with cerebrospinal fluid amine metabolites , 1979, Psychiatry Research.

[54]  M. Hamilton.  A RATING SCALE FOR DEPRESSION , 1960, Journal of neurology, neurosurgery, and psychiatry.

[55]  A. Roy,et al.  Childhood trauma as a correlative factor of suicidal behavior – via aggression traits. Similar results in an Italian and in a French sample , 2009, European Psychiatry.

[56]  Thomas J. H. Chen,et al.  Manipulation of catechol-O-methyl-transferase (COMT) activity to influence the attenuation of substance seeking behavior, a subtype of Reward Deficiency Syndrome (RDS), is dependent upon gene polymorphisms: a hypothesis. , 2007, Medical hypotheses.

[57]  J. Opitz,et al.  American journal of medical genetics. Part B, Neuropsychiatric genetics , 2003 .

[58]  M Knapp,et al.  Association study of the low-activity allele of catechol-O-methyltransferase and alcoholism using a family-based approach , 2001, Molecular Psychiatry.

[59]  A. Drewnowski,et al.  Journals of Gerontology , 2001 .

[60]  P. Duberstein,et al.  Personality traits and suicidal behavior and ideation in depressed inpatients 50 years of age and older. , 2000, The journals of gerontology. Series B, Psychological sciences and social sciences.

[61]  R. Weinshilboum,et al.  Methylation pharmacogenetics: catechol O-methyltransferase, thiopurine methyltransferase, and histamine N-methyltransferase. , 1999, Annual review of pharmacology and toxicology.

[62]  M. First,et al.  Structured Clinical Interview for DSM-IV Axis I Disorders , 1997 .

[63]  R. Kessler,et al.  Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey. , 1994, Archives of general psychiatry.

[64]  V. Arango,et al.  Quantitative autoradiography of alpha 1- and alpha 2-adrenergic receptors in the cerebral cortex of controls and suicide victims. , 1993, Brain research.

[65]  C. Robert Cloninger.  A systematic method for clinical description and classification of personality variants. A proposal. , 1987, Archives of general psychiatry.

[66]  J Volavka,et al.  Association between catechol O-methyltransferase genotype and violence in schizophrenia and schizoaffective disorder. , 1998, The American journal of psychiatry.