Genome-wide association study of paliperidone efficacy

OBJECTIVE: Clinical response to the atypical antipsychotic paliperidone is known to vary among schizophrenic patients. We carried out a genome-wide association study to identify common genetic variants predictive of paliperidone efficacy. METHODS: We leveraged a collection of 1390 samples from individuals of European ancestry enrolled in 12 clinical studies investigating the efficacy of the extended-release tablet paliperidone ER (n(1)=490) and the once-monthly injection paliperidone palmitate (n(2)=550 and n(3)=350). We carried out a genome-wide association study using a general linear model (GLM) analysis on three separate cohorts, followed by meta-analysis and using a mixed linear model analysis on all samples. The variations in response explained by each single nucleotide polymorphism (h(2)(SNP)) were estimated. RESULTS: No SNP passed genome-wide significance in the GLM-based analyses with suggestive signals from rs56240334 [P=7.97×10(−8) for change in the Clinical Global Impression Scale-Severity (CGI-S); P=8.72×10(−7) for change in the total Positive and Negative Syndrome Scale (PANSS)] in the intron of ADCK1. The mixed linear model-based association P-values for rs56240334 were consistent with the results from GLM-based analyses and the association with change in CGI-S (P=4.26×10(−8)) reached genome-wide significance (i.e. P<5×10(−8)). We also found suggestive evidence for a polygenic contribution toward paliperidone treatment response with estimates of heritability, h(2)(SNP), ranging from 0.31 to 0.43 for change in the total PANSS score, the PANSS positive Marder factor score, and CGI-S. CONCLUSION: Genetic variations in the ADCK1 gene may differentially predict paliperidone efficacy in schizophrenic patients. However, this finding should be replicated in additional samples.