title: Analysis of treatment-resistant schizophrenia and 384 markers from candidate genes.
abstract: 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.
authors.affiliation: Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, Ontario, Toronto, Canada.
authors.forename: Celine
authors.initials: C
authors.lastname: Teo
authors.forename: Clement
authors.initials: C
authors.lastname: Zai
authors.forename: Carol
authors.initials: C
authors.lastname: Borlido
authors.forename: Carmine
authors.initials: C
authors.lastname: Tomasetti
authors.forename: John
authors.initials: J
authors.lastname: Strauss
authors.forename: Takahiro
authors.initials: T
authors.lastname: Shinkai
authors.forename: Bernard
authors.initials: B
authors.lastname: Le Foll
authors.forename: Albert
authors.initials: A
authors.lastname: Wong
authors.forename: James L
authors.initials: JL
authors.lastname: Kennedy
authors.forename: Vincenzo
authors.initials: V
authors.lastname: De Luca
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D004351:Drug Resistance / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D012559:Schizophrenia / Q000188:drug therapy* / Q000235:genetics*
chemical_list: D014150:Antipsychotic Agents; D005819:Genetic Markers