title: Large-scale candidate gene study to identify genetic risk factors predictive of paliperidone treatment response in patients with schizophrenia.
abstract: OBJECTIVE
  Clinical response to antipsychotic medications can vary markedly in patients with schizophrenia. Identifying genetic variants associated with treatment response could help optimize patient care and outcome. To this end, we carried out a large-scale candidate gene study to identify genetic risk factors predictive of paliperidone efficacy.
  
  
  METHODS
  A central nervous system custom chip containing single nucleotide polymorphisms from 1204 candidate genes was utilized to genotype a discovery cohort of 684 schizophrenia patients from four clinical studies of paliperidone extended-release and paliperidone palmitate. Variants predictive of paliperidone efficacy were identified and further tested in four independent replication cohorts of schizophrenic patients (N=2856).
  
  
  RESULTS
  We identified an SNP in ERBB4 that may contribute toward differential treatment response to paliperidone. The association trended in the same direction as the discovery cohort in two of the four replication cohorts, but ultimately did not survive multiple testing corrections. The association was not replicated in the other two independent cohorts. We also report several SNPs in well-known schizophrenia candidate genes that show suggestive associations with paliperidone efficacy.
  
  
  CONCLUSIONS
  These preliminary findings suggest that genetic variation in the ERBB4 gene may differentially affect treatment response to paliperidone in individuals with schizophrenia. They implicate the neuregulin 1 (NRG1)-ErbB4 pathway for modulating antipsychotic response. However, these findings were not robustly reproduced in replication cohorts.
authors.affiliation: aJanssen Research & Development, LLC, Raritan bJanssen Scientific Affairs, LLC, Titusville, New Jersey cJanssen Research & Development, LLC, Titusville, New Jersey, USA.
authors.forename: Dai
authors.initials: D
authors.lastname: Wang
authors.forename: Dong-Jing
authors.initials: DJ
authors.lastname: Fu
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Wu
authors.forename: Alice
authors.initials: A
authors.lastname: Shapiro
authors.forename: Reyna
authors.initials: R
authors.lastname: Favis
authors.forename: Adam
authors.initials: A
authors.lastname: Savitz
authors.forename: Hedy
authors.initials: H
authors.lastname: Chung
authors.forename: Larry
authors.initials: L
authors.lastname: Alphs
authors.forename: Srihari
authors.initials: S
authors.lastname: Gopal
authors.forename: Magali
authors.initials: M
authors.lastname: Haas
authors.forename: Nadine
authors.initials: N
authors.lastname: Cohen
authors.forename: Qingqin
authors.initials: Q
authors.lastname: Li
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D014150:Antipsychotic Agents / Q000008:administration & dosage*; D002648:Child; D002675:Child, Preschool; D056726:Genetic Association Studies / Q000379:methods*; D006801:Humans; D007555:Isoxazoles / Q000008:administration & dosage*; D008875:Middle Aged; D020890:Neuregulin-1 / Q000235:genetics; D000068882:Paliperidone Palmitate; D020641:Polymorphism, Single Nucleotide; D011743:Pyrimidines / Q000008:administration & dosage*; D066247:Receptor, ErbB-4 / Q000235:genetics*; D012559:Schizophrenia / Q000188:drug therapy* / Q000235:genetics; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; D007555:Isoxazoles; C094131:NRG1 protein, human; D020890:Neuregulin-1; D011743:Pyrimidines; C587689:ERBB4 protein, human; D066247:Receptor, ErbB-4; D000068882:Paliperidone Palmitate