title: Genome-wide association study of patient-rated and clinician-rated global impression of severity during antipsychotic treatment.
abstract: OBJECTIVE
  To examine the unique and congruent findings between multiple raters in a genome-wide association study (GWAS) in the context of understanding individual differences in treatment response during antipsychotic therapy for schizophrenia.
  
  
  METHODS
  We performed GWAS to search for genetic variation affecting treatment response. The analysis sample included 738 patients with schizophrenia, successfully genotyped for ∼492k single nucleotide polymorphisms (SNPs) from the Clinical Antipsychotic Trial of Intervention Effectiveness. Outcomes included both clinician and patient report of illness severity on global impression scales, the clinical global impression severity scale and patient global impression, respectively. Our criterion for genome-wide significance was a prespecified threshold ensuring that, on average, only 10% of the significant findings are false discoveries.
  
  
  RESULTS
  Thirteen SNPs reached genome-wide significance. The top findings indicated three SNPs in PDE4D, 5q12.1 (P=4.2×10, 1.6×10, 1.8×10), mediating the effects of quetiapine on patient-reported severity and an additional three SNPs in TJP1, 15q13.1 (P=2.25×10, 4.86×10, 4.91×10), mediating the effects of risperidone on patient-reported severity. For clinician-reported severity, two SNPs in PPA2, 4q24 (P=3.68×10, 5.05×10), were found to reach genome-wide significance.
  
  
  CONCLUSIONS
  We found evidence of both a novel and a consistent association when examining the results from the patient and clinician ratings, suggesting that different raters may capture unique facets of schizophrenia. Although our findings require replication and functional validation, this study shows the potential of GWAS to discover genes that potentially mediate treatment response of antipsychotic medication.
authors.affiliation: Center for Biomarker Research and Personalized Medicine, School of Pharmacy, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia 23298-0581, USA. slclark2@vcu.edu
authors.forename: Shaunna L
authors.initials: SL
authors.lastname: Clark
authors.forename: Renan P
authors.initials: RP
authors.lastname: Souza
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Adkins
authors.forename: Karolina
authors.initials: K
authors.lastname: Aberg
authors.forename: József
authors.initials: J
authors.lastname: Bukszár
authors.forename: Joseph L
authors.initials: JL
authors.lastname: McClay
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Sullivan
authors.forename: Edwin J C G
authors.initials: EJ
authors.lastname: van den Oord
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D015415:Biomarkers / Q000378:metabolism*; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D012559:Schizophrenia / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology
chemical_list: D014150:Antipsychotic Agents; D015415:Biomarkers