Genetic variation in CYP3A43 is associated with response to antipsychotic medication.

Genetic variation in cytochrome enzymes is known to affect drug metabolism and influence treatment response. Recently, the rs472660 variant in CYP3A43 has been associated with olanzapine response and clearance. In this study, we investigated the impact of rs472660 and the putatively functional marker rs680055 on antipsychotic response. We genotyped the rs472660 and rs680055 single nucleotide polymorphisms (SNPs) in N = 152 schizophrenia patients of European descent collected at two sample sites who were predominately treated with second generation antipsychotics for up to 6 months. Treatment response was assessed prospectively using Brief Psychiatric Rating Scale (BPRS) scores. Statistical analysis was performed using Chi square and analysis of covariance. The rs680055 SNP was significantly associated with treatment response. Carriers of the minor allele had significantly lower BPRS scores at study end (p = 5.9 × 10(-4)) with 8 % of the variance being explained by rs680055 genotype. Post hoc analyses revealed that this effect was present in both samples and in both genders. The rs472660 SNP was also associated with response (p = 0.027); however, this finding was not significant after multiple test correction. This is the first evidence that the rs680055 missense mutation influences antipsychotic response. Although our finding for rs472660 was only a non-significant trend after correction, our results still support the notion that this SNP may play a role in antipsychotic response. Despite the fact that the functional role of CYP3A43 in antipsychotic metabolism is not fully understood yet, our study provides an important contribution to understanding genetic factors of antipsychotic response.

The putative functional rs1045881 marker of neurexin-1 in schizophrenia and clozapine response.

Neurexin-1 (NRXN1) modulates recruitment of NMDA receptors. Furthermore, clozapine reduces hyperactivity of NMDA receptors. Thus, regulation of the NRXN1 gene may mediate the efficacy of clozapine at reducing cortical hyperactivity. We examined the putative functional SNP, rs1045881, for association with schizophrenia, and the potential role of this SNP in clozapine response. The rs1045881 variant was not significantly associated with schizophrenia (N=302 case-control pairs), but with clozapine response (N=163; p=0.030). Baseline and BPRS scores after six months revealed a trend for rs1045881 genotype by treatment interaction (p=0.079). In the post hoc analysis, a significant association between BPRS negative symptoms score and genotype was observed (p=0.033). These results suggest that the rs1045881 NRXN1 polymorphism may influence clozapine response.

ANK3, CACNA1C and ZNF804A gene variants in bipolar disorders and psychosis subphenotype.

OBJECTIVES. The ANK3, CACNA1C and ZNF804A genes have been implicated in both bipolar disorders (BPD) and schizophrenia (SCZ). It has been suggested that BPD with psychosis may be a clinical manifestation of genes overlapping between BPD and SCZ. We therefore tested the association of these genes with BPD in a large family-based sample, and then dissected the phenotype into psychosis present or absent subgroups. METHODS. We genotyped four high interest single nucleotide polymorphisms from ANK3 (rs10994336, rs9804190), CACNA1C (rs1006737), and ZNF804A (rs1344706). Family based association testing (FBAT) was performed on 312 families, and within psychotic (N = 158) and non-psychotic BPD (N = 119) subgroups. RESULTS. In the whole sample, we found a nominal association in ZNF804A (rs1344706, P = 0.046), and a trend in CACNA1C (rs1006737, P = 0.077). In the psychotic BPD subgroup, as hypothesized, stronger signals were observed in ZNF804A (P = 0.019) and CACNA1C (P = 0.017). We found no association in the ANK3 markers, but the rs10994336 variant was nominally associated with non-psychotic BPD (P = 0.046). Exploratory analysis revealed the rs1344706 variant was also implicated in suicide-attempt behaviour (P = 0.038). CONCLUSIONS. These tentative results are consistent with the hypothesis that the subphenotype of BPD with psychosis may represent a clinical manifestation of shared genetic liability between BPD and SCZ.

Neurexin-1 and frontal lobe white matter: an overlapping intermediate phenotype for schizophrenia and autism spectrum disorders.

BACKGROUND: Structural variation in the neurexin-1 (NRXN1) gene increases risk for both autism spectrum disorders (ASD) and schizophrenia. However, the manner in which NRXN1 gene variation may be related to brain morphology to confer risk for ASD or schizophrenia is unknown. METHOD/PRINCIPAL FINDINGS: 53 healthy individuals between 18-59 years of age were genotyped at 11 single nucleotide polymorphisms of the NRXN1 gene. All subjects received structural MRI scans, which were processed to determine cortical gray and white matter lobar volumes, and volumes of striatal and thalamic structures. Each subject's sensorimotor function was also assessed. The general linear model was used to calculate the influence of genetic variation on neural and cognitive phenotypes. Finally, in silico analysis was conducted to assess potential functional relevance of any polymorphisms associated with brain measures. A polymorphism located in the 3' untranslated region of NRXN1 significantly influenced white matter volumes in whole brain and frontal lobes after correcting for total brain volume, age and multiple comparisons. Follow-up in silico analysis revealed that this SNP is a putative microRNA binding site that may be of functional significance in regulating NRXN1 expression. This variant also influenced sensorimotor performance, a neurocognitive function impaired in both ASD and schizophrenia. CONCLUSIONS: Our findings demonstrate that the NRXN1 gene, a vulnerability gene for SCZ and ASD, influences brain structure and cognitive function susceptible in both disorders. In conjunction with our in silico results, our findings provide evidence for a neural and cognitive susceptibility mechanism by which the NRXN1 gene confers risk for both schizophrenia and ASD.