COMT and DRD3 polymorphisms, environmental exposures, and personality traits related to common mental disorders.

In a community sample of 2,327 Caucasians, we tested the hypotheses that polymorphisms in the COMT and DRD3 genes are associated with personality traits conferring vulnerability to anxiety, depression, or alcohol misuse, or with current symptoms of these; and that the association is stronger in persons who also have been exposed to stressor experiences. To conserve resources and to allow replication, the genetic analysis was undertaken in two stages. For the COMT polymorphism, no statistically significant associations were found in the first sample of 862 persons. The remainder of the sample was therefore not analysed for that gene. For the DRD3 polymorphism, those in the first sample with at least one of the Ser(9) alleles had significantly higher scores in neuroticism (p=0.006) and behavioral inhibition (p=0.003). There was a trend, failing to meet the 1% significance criterion, for those with this genotype also to have higher depression and anxiety. The groups did not differ in alcohol use. In persons with the Ser(9) allele who were also exposed to stressors, there was a higher level of depression at the 5% level; and the depression level was higher in homozygotes. But when the remainder of the sample (1,465) was analysed, none of the associations reached statistical significance. We conclude that neither the COMT nor DRD3 polymorphisms are associated with anxiety, depression, or alcohol abuse. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:102-107, 2000

[1]  J. Macher,et al.  Dopamine D3 receptor gene: organization, transcript variants, and polymorphism associated with schizophrenia. , 1996, American journal of medical genetics.

[2]  J. Fernández-Piqueras,et al.  No association between particular DRD3 and DAT gene polymorphisms and manic‐depressive illness in a Spanish sample , 1996, Psychiatric genetics.

[3]  D. Collier,et al.  Linkage, association and mutational analysis of the dopamine D3 receptor gene in schizophrenia. , 1996, Molecular psychiatry.

[4]  M. Asai,et al.  Dopamine D3 receptor gene polymorphism and the psychiatric symptoms seen in first‐break schizophrenic patients , 1995, Psychiatric genetics.

[5]  Michael W. Bridges,et al.  Distinguishing optimism from neuroticism (and trait anxiety, self-mastery, and self-esteem): a reevaluation of the Life Orientation Test. , 1994, Journal of personality and social psychology.

[6]  A. Korten,et al.  An association study of a functional polymorphism of the serotonin transporter gene with personality and psychiatric symptoms , 1998, Molecular Psychiatry.

[7]  T. Brugha,et al.  The List of Threatening Experiences: a subset of 12 life event categories with considerable long-term contextual threat , 1985, Psychological Medicine.

[8]  D. Shields,et al.  Preliminary evidence of an association between bipolar disorder in females and the catechol‐O‐methyltransferase gene , 1998, Psychiatric genetics.

[9]  M. Martres,et al.  Amino acid substitution in the dopamine D3 receptor as a useful polymorphism for investigating psychiatric disorders , 1992 .

[10]  C. Carver,et al.  Behavioral inhibition, behavioral activation, and affective responses to impending reward and punishment: The BIS/BAS Scales , 1994 .

[11]  Robin M. Murray,et al.  No evidence for an association of affective disorders with high- or low-activity allele of catechol-o-methyltransferase gene , 1997, Biological Psychiatry.

[12]  L. Saugstad,et al.  In defence of international classification , 1985, Psychological Medicine.

[13]  M. Leboyer,et al.  Failure to find evidence for linkage or association between the dopamine D3 receptor gene and schizophrenia. , 1994, The American journal of psychiatry.

[14]  B. Gutiérrez,et al.  Association analysis of the catechol O-methyltransferase gene and bipolar affective disorder. , 1997, The American journal of psychiatry.

[15]  T. Harris,et al.  Life events and illness , 1990 .

[16]  J. Lieberman,et al.  Association study of dopamine D3 receptor gene and schizophrenia. , 1995, American journal of medical genetics.

[17]  P. Sham,et al.  Catch me if you can: are catechol- and indoleamine genes pleiotropic QTLs for common mental disorders? , 1997, Molecular Psychiatry.

[18]  M. Owen,et al.  Association studies in psychiatric genetics , 1997, Molecular Psychiatry.

[19]  O. Aasland,et al.  Development of the Alcohol Use Disorders Identification Test (AUDIT): WHO Collaborative Project on Early Detection of Persons with Harmful Alcohol Consumption--II. , 1993, Addiction.

[20]  R. Fukuda,et al.  Further evidence of no linkage between schizophrenia and the dopamine D3 receptor gene locus. , 1994, American journal of medical genetics.

[21]  P. Duncan-Jones,et al.  Detecting anxiety and depression in general medical settings. , 1988, BMJ.

[22]  H. Lachman,et al.  Ultra-ultra rapid cycling bipolar disorder is associated with the low activity catecholamine-O-methyltransferase allele , 1998, Molecular Psychiatry.

[23]  K. Ohara,et al.  No association between anxiety disorders and catechol-O-methyltransferase polymorphism , 1998, Psychiatry Research.

[24]  H. Christensen,et al.  A short form of the Positive and Negative Affect Schedule: evaluation of factorial validity and invariance across demographic variables in a community sample , 1999 .

[25]  H. Möller,et al.  Dopamine D3 receptor Gly9/Ser9 polymorphism and schizophrenia: no increased frequency of homozygosity in German familial cases , 1996, Schizophrenia Research.

[26]  A. Bedford,et al.  A new personal disturbance scale (DSSI/sAD). , 1976, The British journal of social and clinical psychology.

[27]  J. Shine,et al.  Exclusion of close linkage of bipolar disorder to the dopamine D3 receptor gene in nine Australian pedigrees. , 1993, Journal of Affective Disorders.

[28]  M. Martres,et al.  Lack of association between alcohol-dependence and D3 dopamine receptor gene in three independent samples. , 1995, American journal of medical genetics.

[29]  S. Tsuji,et al.  Association study between schizophrenia and dopamine D3 receptor gene polymorphism. , 1996, American journal of medical genetics.

[30]  J. Ott,et al.  Genotype determining low catechol-O-methyltransferase activity as a risk factor for obsessive-compulsive disorder. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[31]  Scott Henderson,et al.  Neurosis and the Social Environment , 1982 .

[32]  M. Nobile,et al.  Lack of association between obsessive-compulsive disorder and the dopamine D3 receptor gene: some preliminary considerations. , 1994, American journal of medical genetics.

[33]  J. Beeghly Child and Adolescent Psychiatry: Modern Approaches, 2nd ed , 1986 .

[34]  D. Collier,et al.  Catechol-O-methyltransferase Val158Met polymorphism: frequency analysis in Han Chinese subjects and allelic association of the low activity allele with bipolar affective disorder. , 1997, Pharmacogenetics.

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

[36]  A. Rolfs,et al.  Dopamine D1, D2 and D3 receptor genes in alcohol dependence , 1995, Psychiatric genetics.

[37]  E. Smeraldi,et al.  An association study between schizophrenia and the dopamine receptor genes DRD3 and DRD4 using haplotype relative risk. , 1994, Human heredity.

[38]  E. Gershon,et al.  No association detected between a D3 receptor gene-expressed variant and schizophrenia. , 1996, American journal of medical genetics.

[39]  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.

[40]  N Risch,et al.  The Future of Genetic Studies of Complex Human Diseases , 1996, Science.

[41]  P. Sokoloff,et al.  No evidence of linkage between schizophrenia and D3 dopamine receptor gene locus in Icelandic pedigrees , 1993, Psychiatry Research.

[42]  I. T. Miller,et al.  High-activity catechol-O-methyltransferase allele is more prevalent in polysubstance abusers. , 1997, American journal of medical genetics.

[43]  C. Broeckhoven,et al.  Association study of bipolar disorder with candidate genes involved in catecholamine neurotransmission: DRD2, DRD3, DAT1, and TH genes. , 1996, American journal of medical genetics.

[44]  V. Vieland,et al.  Statistical Evidence: A Likelihood Paradigm , 1998 .

[45]  G. Kirov,et al.  No association between bipolar disorder and alleles at a functional polymorphism in the COMT gene , 1997, British Journal of Psychiatry.

[46]  R. Murray,et al.  Low activity allele of catechol-O-methyltransferase gene associated with rapid cycling bipolar disorder , 1998, Molecular Psychiatry.

[47]  V. Nimgaonkar In defense of genetic association studies , 1997, Molecular Psychiatry.

[48]  G. Parker Parental 'affectionless control' as an antecedent to adult depression. A risk factor delineated. , 1983, Archives of general psychiatry.

[49]  J. Kelsoe,et al.  Lack of association of catechol-O-methyltransferase (COMT) functional polymorphism in bipolar affective disorder , 1997, Psychiatric genetics.

[50]  D. Blackwood,et al.  Molecular genetics in psychiatric epidemiology: the promise and challenge , 1999, Psychological Medicine.