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Tyrosine hydroxylase (TH) is the rate-limiting enzyme in the synthesis of dopamine and norepinephrine. It may be involved in the pathophysiology of psychiatric disorders and positive associations have been reported for TH gene markers in mood disorders. While most replications failed to confirm the initial findings, other papers suggested a potential role of this gene in the etiology of mood disorders. Among the many different reasons for a lack of consistent replications, a critical role is played by the "correct" phenotype identification. Actually, up to now the only classification criteria has been the psychiatric diagnosis, but within the same psychiatric diagnoses the symptomatologic presentation may vary dramatically depending upon severity, presence of psychotic features or other psychopathologic traits. Thus, the aim of our study is to evaluate a possible association for TH gene with symptomatology in a sample of subjects affected by mood disorders. We have developed a phenotype definition based on the observed symptomatology divided into the four factors "Excitement," "Depression," "Delusion," and "Disorganization." Our sample includes 46 mood disorder subjects, investigated by the OPCRIT (operational criteria checklist for psychotic illness) checklist for their symptomatological pattern and typed for TH variants by polymerase chain reaction (PCR) amplification. Depressive factor was associated with TH variants (F = 4.79, df = 4, 87, P = 0.006), with TH*2 subjects presenting lower depressive scores. Subjects with genotype TH*2/2 were the only ones in the sample to report mild depressive episodes. TH variants may be related with depressive symptomatology in subjects affected by mood disorders.

A major role of the serotonergic system has been hypothesized in the pathogenesis of schizophrenia, mostly based on the evidence of action of new and atypical neuroleptics such as Risperidone or Clozapine. We evaluated the genotypes and alleles of the 5HT2a receptor gene in 67 nuclear families following the Haplotype Relative Risk (HRR) strategy and in a second sample of 100 schizophrenics and 103 controls. The 5HT2a receptor gene polymorphism, following PCR amplification and subsequent Hpa II digestion, reveals a two-alleles system in the coding region of the gene. We did not find statistically significant differences between patients and controls for genotypes, nor for alleles, both in the HRR and in the case-control groups. These results do not confirm the positive association obtained by Inayama et al.: [Neuropsychopharmacology 1(35): 145-219, 1994] and by Williams et al. [Lancet, 397:1294-1296, 1996] in our population.

We investigated a variant of the dopamine D2 receptor gene (Ser311/Cys311 substitution) in Caucasian patients with schizophrenia (n = 273), delusional disorder (n = 62), bipolar I affective disorder (n = 63), and controls (n = 255). No evidence for association between the receptor variant and any of the diseases was found, even when patients with younger age-of-onset (< 25 years) were compared with controls. Furthermore, in a subgroup of schizophrenia patients whom we assessed for negative symptoms, those with the Cys allele did not differ from the remainder of the group. Also, the bipolar affective disorder patients with psychotic features did not show evidence for association with the receptor variant. Thus, our results do not provide evidence for an association between this D2 receptor variant and schizophrenia, or delusional disorder, or bipolar affective disorder.

Several groups have reported an association between schizophrenia and the MscI polymorphism in the first exon of the dopamine D3 receptor gene (DRD3). We studied this polymorphism using a North American sample (117 patients plus 188 controls) and an Italian sample (97 patients plus 64 controls). In the first part of the study, we compared allele frequencies of schizophrenia patients and unmatched controls and observed a significant difference in the total sample (P = 0.01). The second part of the study involved a case control approach in which each schizophrenia patient was matched to a control of the same sex, and of similar age and ethnic background. The DRD3 allele frequencies of patients and controls revealed no significant difference between the two groups in the Italian (N = 53) or the North American (N = 54) matched populations; however, when these two matched samples were combined, a significant difference was observed (P = 0.026). Our results suggest that the MscI polymorphism may be associated with schizophrenia in the populations studied.

The dopamine D4 receptor is of major interest in schizophrenia research due to its high affinity for the atypical neuroleptic clozapine and a high degree of variability in the receptor gene (DRD4). Although several genetic linkage analyses performed on schizophrenia multiplex families from different regions of the world have either excluded or failed to prove that DRD4 is a major genetic factor for the development of schizophrenia, analyses for moderate predisposing effects are still of significant interest. We performed a study examining differences in allele frequencies of 4 different DRD4 polymorphisms in schizophrenia patients and age, sex, and ethnic origin matched controls. None of these 4 polymorphisms showed evidence for genetic association with schizophrenia, although a trend towards excess of the allele with 7 repeats in the (48)n bp exon III polymorphism was observed. Complexities in the DRD4 genetic investigation and further analytic approaches are discussed.

Eight recent studies have focused on the putative association of the dopamine D2 receptor (DRD2) gene and alcoholism. In this report, these studies are reviewed and the data and findings are examined in a meta-analysis. Four reports find a statistically significant increased risk for alcoholism in subjects carrying the A1 allele and 4 failed to observe a significant increase in risk. Overall, our meta-analysis of the results from all 8 studies supported a statistically significant association between the A1 allele of DRD2 and alcoholism, with an apparent increase in relative risk associated with increased severity of alcoholism. These results must be interpreted cautiously because the A1 allele of DRD2 varies significantly in frequency from one population to another. This variability in the population frequency of the A1 allele could result in an apparent association resulting from unrelated population differences. These findings support the need for carefully designed studies that minimize the ethnic heterogeneity of the subject and control populations.