Association of DISC1 gene with schizophrenia in families from two distinct French and Algerian populations.

OBJECTIVE: The Disrupted-in-Schizophrenia-1 (DISC1) gene is a promising genetic risk factor for major mental illnesses, especially schizophrenia. Several variants encompassing the DISC1 gene have been associated with schizophrenia and specific clinical features. Negative results were nevertheless observed, stratification biases, heterogeneity of the analyzed samples and low statistical power being potentially involved. METHODS: We analyzed four single nucleotide polymorphisms (SNPs), including three non-synonymous SNPs, of DISC1 in two independent samples of trios, from France and Algeria, using family-based association tests to elude statistical limits. RESULTS: In 114 French schizophrenia trios, the C allele of non-synonymous rs6675281/Leu607Phe/C1872T was significantly over-transmitted [odds ratio (OR)=2.3, 95% confidence interval (CI)=1.1-4.4]. This same SNP was also more frequently transmitted in the 100 Algerian schizophrenia trios (OR=2.6, 95% CI=0.9-7.3). In the combined 214 trios, a significant over-transmission of the C allele of rs6675281 to the affected probands was observed (P=0.002), even after correction for multiple testing (P corrected=0.01 OR=2.4 and 95% CI=1.3-4.2). Assessing if a dimension of schizophrenia could be more specifically involved, we found that patients with the C allele had a significantly higher Scale for the Assessment of Negative Symptoms total score (P=0.0002). CONCLUSION: The analysis adds convergent evidence in favor of a significant role of the DISC1 gene as a risk factor for schizophrenia, as present in two different samples, in family trios rather than with a case--control approach, and even when multiple tests are controlled for. We could further potentially attribute this effect to the negative dimension of schizophrenia.

Excess of transmission of the G allele of the -1438A/G polymorphism of the 5-HT2A receptor gene in patients with schizophrenia responsive to antipsychotics.

BACKGROUND: The -1438A/G polymorphism of the 5-HT2A gene has been found to be associated with clinical response to clozapine and other second generation antipsychotics. Testing the impact of this marker on response to first generation antipsychotics (which have a lower affinity for the 5-HT2A receptor) provides the opportunity to help disentangling the two different roles that this polymorphism might have. A psychopharmacogenetic role should be detected only for antipsychotics with high affinity to the 5-HT2A receptor (therefore to second generation antipsychotics). An alternative role would imply tagging a subgroup of patients responsive to any antipsychotic, whatever their affinity, meaning that the association is more depending on non pharmacological charaterictics, such as clinical specificities. METHODS: A family-based sample of 100 Algerian patients with schizophrenia (according to DSM-IV criteria) and their 200 biological parents was recruited, in order to avoid stratification biases. Patients were all treated, or have been treated, by conventional antipsychotics (mainly haloperidol) for at least four weeks, at appropriate dosage. May and Dencker scale was used to distinguish responders and non responders. RESULTS: No allele of the -1438A/G polymorphism of the 5-HT2A gene was transmitted in excess (50 transmitted for 38 untransmitted) in the whole sample of patients with schizophrenia (p = .90). In contrast, a significant excess of transmission of the G allele was observed (p = .02) in the subgroup of patients with good treatment response (17 transmitted for 6 untransmitted). CONCLUSION: Using a TDT approach, we showed that the G allele of the -1438A/G polymorphism of the gene coding for the 5-HT2A receptor was associated to schizophrenia with good response to conventional antipsychotics, although this conclusion is based on 88 informative patients only. Because previous data showed the same result with atypical antipsychotics, it can be concluded that the G allele tags a subgroup of schizophrenic patients with greater chance of improvement with antipsychotics of either type.