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 (Pcorrected=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.