Association of the NPAS3 gene and five other loci with response to the antipsychotic iloperidone identified in a whole genome association study

Mol Psychiatry. 2009 Aug;14(8):804-19. doi: 10.1038/mp.2008.56. Epub 2008 Jun 3.

Abstract

A whole genome association study was performed in a phase 3 clinical trial conducted to evaluate a novel antipsychotic, iloperidone, administered to treat patients with schizophrenia. Genotypes of 407 patients were analyzed for 334,563 single nucleotide polymorphisms (SNPs). SNPs associated with iloperidone efficacy were identified within the neuronal PAS domain protein 3 gene (NPAS3), close to a translocation breakpoint site previously observed in a family with schizophrenia. Five other loci were identified that include the XK, Kell blood group complex subunit-related family, member 4 gene (XKR4), the tenascin-R gene (TNR), the glutamate receptor, inotropic, AMPA 4 gene (GRIA4), the glial cell line-derived neurotrophic factor receptor-alpha2 gene (GFRA2), and the NUDT9P1 pseudogene located in the chromosomal region of the serotonin receptor 7 gene (HTR7). The study of these polymorphisms and genes may lead to a better understanding of the etiology of schizophrenia and of its treatment. These results provide new insight into response to iloperidone, developed with the ultimate goal of directing therapy to patients with the highest benefit-to-risk ratio.

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Antipsychotic Agents / therapeutic use*
  • Double-Blind Method
  • Female
  • Genome-Wide Association Study / methods
  • Glial Cell Line-Derived Neurotrophic Factor Receptors / drug effects
  • Glial Cell Line-Derived Neurotrophic Factor Receptors / genetics
  • Humans
  • Isoxazoles / therapeutic use*
  • Male
  • Middle Aged
  • Nerve Tissue Proteins / drug effects
  • Nerve Tissue Proteins / genetics*
  • Pharmacogenetics
  • Piperazines / therapeutic use
  • Piperidines / therapeutic use*
  • Polymorphism, Single Nucleotide
  • Pseudogenes / genetics
  • Receptors, AMPA / drug effects
  • Receptors, AMPA / genetics
  • Schizophrenia / drug therapy*
  • Schizophrenia / genetics*
  • Tenascin / drug effects
  • Tenascin / genetics
  • Thiazoles / therapeutic use
  • Transcription Factors / drug effects
  • Transcription Factors / genetics*
  • Young Adult

Substances

  • Antipsychotic Agents
  • GFRA2 protein, human
  • Glial Cell Line-Derived Neurotrophic Factor Receptors
  • Isoxazoles
  • NPAS3 protein, human
  • Nerve Tissue Proteins
  • Piperazines
  • Piperidines
  • Receptors, AMPA
  • Tenascin
  • Thiazoles
  • Transcription Factors
  • glutamate receptor ionotropic, AMPA 4
  • tenascin R
  • ziprasidone
  • iloperidone