Analysis of treatment-resistant schizophrenia and 384 markers from candidate genes

The treatment of patients with schizophrenia who fail to respond to antipsychotics is a major challenge and the proportion of treatment-resistant patients is estimated to be 20 to 40%. There are few genetic association studies that have compared resistant versus non-resistant schizophrenic patients; however, many genetic association studies focusing on antipsychotic response have been published. This contribution investigates the genetics of treatment-resistant schizophrenia, testing 384 candidate gene loci related to the neurobiology of the disease. First, we identified a subgroup of treatment-resistant patients in a sample of 240 schizophrenia patients using the American Psychiatric Association criteria and then we genotyped all patients using a custom Illumina Bead Chip comprising of 384 single nucleotide polymorphisms. We screened all markers for nominal significance and for statistical significance after multiple-testing correction. The most significant single nucleotide polymorphism was the rs2152324 marker in the NALCN gene (P=0.004); however, after the FDR correction, the P-value was not significant. Our analysis of 384 markers across candidate genes did not indicate any robust association with treatment-resistant schizophrenia. However, this phenotype can be assessed retrospectively in cross-sectional studies and these preliminary results point out the importance of choosing alternative phenotypes in psychiatric pharmacogenetics.