1Mol. Psychiatry 2009 Aug 14: 804-19
TitleAssociation of the NPAS3 gene and five other loci with response to the antipsychotic iloperidone identified in a whole genome association study.
AbstractA 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.
SCZ Keywordsschizophrenia
2J Clin Psychiatry 2012 Mar 73: 367-71
TitleAnalysis of gene variants previously associated with iloperidone response in patients with schizophrenia who are treated with risperidone.
AbstractWe examined 6 single nucleotide polymorphisms (SNPs) previously reported to be associated with response to iloperidone therapy for association with response to risperidone therapy.
Patients with schizophrenia (DSM-IV) were assessed during 2006 and 2007 for response/nonresponse (defined as ? 20%/<20% improvement in Positive and Negative Syndrome Scale [PANSS] total score) after 2 weeks of risperidone treatment (2 to 6 mg/d). Responders continued risperidone treatment; nonresponders were randomly assigned to either risperidone or olanzapine treatment (10 to 20 mg/d) for an additional 10 weeks. Associations between change in PANSS total (primary outcome measure), positive, and negative scores and the 6 SNPs were examined in risperidone-treated patients (N = 145). Genotype frequencies and improvement in PANSS total scores were analyzed for those SNPs significantly associated with change in PANSS total score.
The SNPs XKR4 rs9643483 and GRIA4 rs2513265 were significantly associated with change in PANSS total response (adjusted P < .05 for both), with the same direction of effect as reported for iloperidone. For patients with nonresponsive genotypes for these SNPs, mean improvement in PANSS total score for African Americans was two-thirds that seen for whites (XKR4: -13.9 versus -21.4; GRIA4: -12.5 versus -20.9).
In this retrospective pharmacogenomic analysis, we found that 2 SNPs previously linked to iloperidone response were also associated with response to risperidone.
clinicaltrials.gov Identifier: NCT00337662.
SCZ Keywordsschizophrenia
3Anim. Genet. 2014 Jun 45: 439-41
TitleA polymorphism in XKR4 is significantly associated with serum prolactin concentrations in beef cows grazing tall fescue.
AbstractFescue toxicosis is a common syndrome of poor growth and reproductive performance of beef cattle grazing endophyte-infected tall fescue infected with Lolium arundinaceum Schreb. Together with decreased feed intake, decreased growth rates and tissue necrosis due to vasoconstriction, depressed circulating serum prolactin concentrations are typically observed in cattle afflicted with fescue toxicosis. Polymorphisms within the XK, Kell blood group complex subunit-related family, member 4 (XKR4) gene located on BTA14 have been previously reported to be associated with rump fat thickness, residual feed intake, average daily feed intake and average daily gain in cattle. Associations also have been reported between XKR4 genotype and effectiveness of the dopamine antagonist iloperidone as a treatment of schizophrenia in humans. Domperidone, a related dopamine antagonist, mediates effects of fescue toxicosis on livestock, including restoring depressed concentrations of prolactin. A mixed-breed population of 592 beef cattle grazing endophyte-infected tall fescue was used to examine the association between XKR4 genotype and circulating prolactin concentrations. The SNP rs42646708 was significantly (P = 0.0002) associated with serum prolactin concentrations and explained 2.45% of the phenotypic variation. Effect of genotype at the SNP was tested across five breeds, with significant associations within both Angus (P = 0.0275) and Simmental (P = 0.0224) breeds. These results suggest XKR4 may play a role in mediating the negative effects of fescue toxicosis, and polymorphisms within this gene may be useful markers for selection for genetic resistance to the debilitating effects of endophyte-infected tall fescue.
SCZ Keywordsschizophrenia