| 1 | Mol. Psychiatry 2009 Aug 14: 804-19 |
|---|---|
| PMID | 18521090 |
| Title | Association of the NPAS3 gene and five other loci with response to the antipsychotic iloperidone identified in a whole genome association study. |
| 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. |
| SCZ Keywords | schizophrenia |
| 2 | Psychopharmacology (Berl.) 2010 Jun 210: 347-54 |
| PMID | 20369355 |
| Title | Glial cell line-derived neurotrophic factor receptor alpha 2 (GFRA2) gene is associated with tardive dyskinesia. |
| Abstract | Tardive dyskinesia (TD) has a pharmacogenetic component in which the interaction of antipsychotic exposure with individual genetic variation mediates risk. The glial cell line-derived neurotrophic factor (GDNF) signalling pathway has been associated with neuroprotective effects in central dopaminergic neurons and spinal motor neurons. Clinical trials have also investigated whether GDNF may ameliorate Parkinson's disease symptoms. We tested whether variants in the GDNF receptor alpha 2 (GFRA2) gene could play a role in TD susceptibility evaluating 16 variants in 172 Caucasian schizophrenia subjects. We observed one significant allelic association (rs4739285, permuted p = 0.042) and two genotypic associations: rs4739285 under additive inheritance model and rs4739217 under dominant inheritance model (permuted p = 0.044). Moreover, carriers of the major alleles for both rs6587002 and rs4739217 presented significantly higher risk for TD (OR = 2.04, permuted p = 0.014), while subjects with the minor allele for rs4739217 and the major allele for rs6988470 were less likely to have TD (OR = 0.21, permuted p = 0.0007). Haplotype results indicate that the minor allele of the rs4739217 is a risk factor for TD (permuted allelic p = 0.074). Age was also a risk factor for TD in our sample (p = 0.0001). Taken together, our findings suggest that GFRA2 genetic variants and age may play a role in TD susceptibility, but further work is required to confirm these findings. |
| SCZ Keywords | schizophrenia |
| 3 | J Psychiatr Res 2010 Aug 44: 700-6 |
| PMID | 20116071 |
| Title | Genetic association of the GDNF alpha-receptor genes with schizophrenia and clozapine response. |
| Abstract | GDNF (glial-cell-line derived neurotrophic factor) is a potent neurotrophic factor for dopaminergic neurons. Neuropsychiatric diseases and their treatments are associated with alterations in the levels of both GDNF and its receptor family (GDNF family receptor alpha or GFRA). GFRA1, GFRA2 and GFRA3 are located in chromosomal regions with suggestive linkage to schizophrenia. In this study we analyzed polymorphisms located in all four known GFRA genes and examined association with schizophrenia and clozapine response. We examined SNPs across the genes GFRA1-4 in 219 matched case-control subjects, 85 small nuclear families and 140 schizophrenia patients taking clozapine for 6months. We observed that GFRA3 rs11242417 and GFRA1 rs11197557 variants were significantly associated with schizophrenia after combining results from both schizophrenia samples. Furthermore, we found an overtransmission of the G-C GFRA1 rs7920934-rs730357 haplotype to subjects with schizophrenia and association of A-T-G-G GFRA3 rs10036665-rs10952-rs11242417-rs7726580 with schizophrenia in the case-control sample. On the other hand, GFRA2 variants were not associated with schizophrenia diagnosis but subjects carrying T-G-G rs1128397-rs13250096-rs4567028 haplotype were more likely to respond to clozapine treatment. The statistical significance of results survived permutation testing but not Bonferroni correction. We also found nominally-significant evidence for interactions between GFRA1, 2 and 3 associated with schizophrenia and clozapine response, consistent with the locations of these three genes within linkage regions for schizophrenia. |
| SCZ Keywords | schizophrenia |