title: Genome-wide association study of paliperidone efficacy.
abstract: 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.
  
  
  
  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 (n1=490) and the once-monthly injection paliperidone palmitate (n2=550 and n3=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 (hSNP) were estimated.
  
  
  
  No SNP passed genome-wide significance in the GLM-based analyses with suggestive signals from rs56240334 [P=7.97×10 for change in the Clinical Global Impression Scale-Severity (CGI-S); P=8.72×10 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) reached genome-wide significance (i.e. P<5×10). We also found suggestive evidence for a polygenic contribution toward paliperidone treatment response with estimates of heritability, hSNP, ranging from 0.31 to 0.43 for change in the total PANSS score, the PANSS positive Marder factor score, and CGI-S.
  
  
  
  Genetic variations in the ADCK1 gene may differentially predict paliperidone efficacy in schizophrenic patients. However, this finding should be replicated in additional samples.
authors.affiliation: aNeuroscience, Janssen Research & Development, LLC bJanssen Scientific Affairs, LLC, Titusville cJanssen Research & Development, LLC, Raritan dBlue Note Biosciences, LLC, Princeton, New Jersey eBiostatistics and Bioinformatics, The Scripps Translational Science Institute fDepartment of Molecular and Experimental Medicine, The Scripps Research Institute gScripps Health hHuman Biology, J. Craig Venter Institute, La Jolla iMD Revolution, San Diego, California, USA.
authors.forename: Qingqin
authors.initials: Q
authors.lastname: Li
authors.forename: Nathan E
authors.initials: NE
authors.lastname: Wineinger
authors.forename: Dong-Jing
authors.initials: DJ
authors.lastname: Fu
authors.forename: Ondrej
authors.initials: O
authors.lastname: Libiger
authors.forename: Larry
authors.initials: L
authors.lastname: Alphs
authors.forename: Adam
authors.initials: A
authors.lastname: Savitz
authors.forename: Srihari
authors.initials: S
authors.lastname: Gopal
authors.forename: Nadine
authors.initials: N
authors.lastname: Cohen
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Schork
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D014150:Antipsychotic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D002648:Child; D002986:Clinical Trials as Topic; D005260:Female; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D008297:Male; D008875:Middle Aged; D000068882:Paliperidone Palmitate / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000071184:Pharmacogenomic Variants; D020641:Polymorphism, Single Nucleotide; D011494:Protein Kinases / Q000235:genetics* / Q000378:metabolism; D011569:Psychiatric Status Rating Scales; D012559:Schizophrenia / Q000188:drug therapy*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; C000623307:ADCK1 protein, human; D011494:Protein Kinases; D000068882:Paliperidone Palmitate