Genome-wide association study of patient-rated and clinician-rated global impression of severity during antipsychotic treatment

aCenter for Biomarker Research and Personalized Medicine, School of Pharmacy, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia bDepartments of Genetics, Psychiatry & Epidemiology, University of North Carolina at Chapel Hill, North Carolina, USA cDepartment of General Biology, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil dDepartment of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Pharmacogenetics and Genomics (Impact Factor: 3.48). 12/2012; 23(2). DOI: 10.1097/FPC.0b013e32835ca260
Source: PubMed


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.

Materials and 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.

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.

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.

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Available from: Joseph L. McClay, Jan 30, 2015
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