Genetic predictors of antipsychotic response to lurasidone identified in a genome wide association study and by schizophrenia risk genes.

Biomarkers which predict response to atypical antipsychotic drugs (AAPDs) increases their benefit/risk ratio. We sought to identify common variants in genes which predict response to lurasidone, an AAPD, by associating genome-wide association study (GWAS) data and changes (Δ) in Positive And Negative Syndrome Scale (PANSS) scores from two 6-week randomized, placebo-controlled trials of lurasidone in schizophrenia (SCZ) patients. We also included SCZ risk SNPs identified by the Psychiatric Genomics Consortium using a polygenic risk analysis. The top genomic loci, with uncorrected p<10-4, include: 1) synaptic adhesion (PTPRD, LRRC4C, NRXN1, ILIRAPL1, SLITRK1) and scaffolding (MAGI1, MAGI2, NBEA) genes, both essential for synaptic function; 2) other synaptic plasticity-related genes (NRG1/3 and KALRN); 3) the neuron-specific RNA splicing regulator, RBFOX1; and 4) ion channel genes, e.g. KCNA10, KCNAB1, KCNK9 and CACNA2D3). Some genes predicted response for patients with both European and African Ancestries. We replicated some SNPs reported to predict response to other atypical APDs in other GWAS. Although none of the biomarkers reached genome-wide significance, many of the genes and associated pathways have previously been linked to SCZ. Two polygenic modeling approaches, GCTA-GREML and PLINK-Polygenic Risk Score, demonstrated that some risk genes related to neurodevelopment, synaptic biology, immune response, and histones, also contributed to prediction of response. The top hits predicting response to lurasidone did not predict improvement with placebo. This is the first evidence from clinical trials that SCZ risk SNPs are related to clinical response to an AAPD. These results need to be replicated in an independent sample.

Glucagon-like peptide 1 receptor (GLP1R) haplotypes correlate with altered response to multiple antipsychotics in the CATIE trial.

Glucagon-like peptide 1 receptor (GLP1R) signaling has been shown to have antipsychotic properties in animal models and to impact glucose-dependent insulin release, satiety, memory, and learning in man. Previous work has shown that two coding mutations (rs6923761 and rs1042044) are associated with altered insulin release and cortisol levels. We identified four frequently occurring haplotypes in Caucasians, haplotype 1 through haplotype 4, spanning exons 4-7 and containing the two coding variants. We analyzed response to antipsychotics, defined as predicted change in PANSS-Total (dPANSS) at 18 months, in Caucasian subjects from the Clinical Antipsychotic Trial of Intervention Effectiveness treated with olanzapine (n=139), perphenazine (n=78), quetiapine (n=14), risperidone (n=143), and ziprasidone (n=90). Haplotype trend regression analysis revealed significant associations with dPANSS for olanzapine (best p=0.002), perphenazine (best p=0.01), quetiapine (best p=0.008), risperidone (best p=0.02), and ziprasidone (best p=0.007). We also evaluated genetic models for the two most common haplotypes. Haplotype 1 (uniquely including the rs1042044 [Leu(260)] allele) was associated with better response to olanzapine (p=0.002), and risperidone (p=0.006), and worse response to perphenazine (p=.03), and ziprasidone (p=0.003), with a recessive genetic model providing the best fit. Haplotype 2 (uniquely including the rs6923761 [Ser(168)] allele) was associated with better response to perphenazine (p=0.001) and worse response to olanzapine (p=.02), with a dominant genetic model providing the best fit. However, GLP1R haplotypes were not associated with antipsychotic-induced weight gain. These results link functional genetic variants in GLP1R to antipsychotic response.

Pharmacogenetics of second-generation antipsychotics.

This review considers pharmacogenetics of the so called 'second-generation' antipsychotics. Findings for polymorphisms replicating in more than one study are emphasized and compared and contrasted with larger-scale candidate gene studies and genome-wide association study analyses. Variants in three types of genes are discussed: pharmacokinetic genes associated with drug metabolism and disposition, pharmacodynamic genes encoding drug targets, and pharmacotypic genes impacting disease presentation and subtype. Among pharmacokinetic markers, CYP2D6 metabolizer phenotype has clear clinical significance, as it impacts dosing considerations for aripiprazole, iloperidone and risperidone, and variants of the ABCB1 gene hold promise as biomarkers for dosing for olanzapine and clozapine. Among pharmacodynamic variants, the TaqIA1 allele of the DRD2 gene, the DRD3 (Ser9Gly) polymorphism, and the HTR2C -759C/T polymorphism have emerged as potential biomarkers for response and/or side effects. However, large-scale candidate gene studies and genome-wide association studies indicate that pharmacotypic genes may ultimately prove to be the richest source of biomarkers for response and side effect profiles for second-generation antipsychotics.

Replication of SULT4A1-1 as a pharmacogenetic marker of olanzapine response and evidence of lower weight gain in the high response group.

AIM: Antipsychotic efficacy biomarkers have the potential to improve outcomes in psychotic patients. This study examined the effect of SULT4A1-1 haplotype status (rs2285162 [A]-rs2285167 [G]) on olanzapine response. PATIENTS & METHODS: We evaluated 87 olanzapine treated subjects from Phases 1, 1B and 2 of the CATIE trial for the impact of SULT4A1-1 status on change in Positive and Negative Syndrome Scale (PANSS) total score using two models of response. We also examined weight change. RESULTS: SULT4A1-1-positive status correlated with superior olanzapine response in Phase 1 (p = 0.004 for model 1 and p = 0.001 for model 2) and Phases 1B/2 (p = 0.05 for model 1 and p = 0.007 for model 2). SULT4A1-1-positive subjects gained significantly less weight per month on olanzapine, 0.15 lbs, than did SULT4A1-1-negative subjects, 2.27 lbs (p = 0.04). CONCLUSION: This study provides a second replication of superior olanzapine response in SULT4A1-1-positive subjects compared with SULT4A1-1-negative subjects. SULT4A1-1-positive subjects treated with olanzapine also gained less weight than SULT4A1-1-negative subjects.

Genotypic variation in the SV2C gene impacts response to atypical antipsychotics the CATIE study.

Pharmacogenetic (PGx) predictors of response would improve outcomes in antipsychotic treatment. Based on both biological rationale and prior evidence of an impact on Parkinson's disease, we conducted an association study for 106 SNPs in the synaptic vesicle protein 2C (SV2C) gene using genetic and treatment response data from the Clinical Trial of Antipsychotic Intervention Effectiveness (CATIE). We examined response to the atypical antipsychotics for Caucasian subjects in the blinded phases, Phases 1A, 1B, and 2, of CATIE with sample sizes as follows: olanzapine (N=134), quetiapine (N=124), risperidone (N=134), and ziprasidone (N=74). Response was defined as change in the Positive and Negative Syndrome Scale (PANSS) score using a mixed model repeat measures approach. Subjects homozygous for the T allele of rs11960832 displayed significantly worse response to olanzapine treatment, the only finding with study-wide significance (p=2.94×10(-5); false discovery rate=2.18×10(-2)). These subjects also displayed worse response to quetiapine with nominal significance (p=4.56×10(-2)). While no other SNP achieved study-wide significance, one SNP (rs10214163) influencing Parkinson's disease displayed nominally significant association with olanzapine and quetiapine response, while the second such SNP (rs30196) showed a statistical trend toward correlating with olanzapine and quetiapine response. Furthermore, both coding SNPs examined (rs31244 and rs2270927) displayed nominally significant correlations with treatment response: one for olanzapine (rs227092), and one for quetiapine (rs31244). The fact that multiple SNPs in SV2C may impact response to atypical antipsychotics suggests that further evaluation of SNPs in this gene as PGx predictors of antipsychotic response is warranted.

Sulfotransferase 4A1 Haplotype 1 (SULT4A1-1) Is Associated With Decreased Hospitalization Events in Antipsychotic-Treated Patients With Schizophrenia.

OBJECTIVE: To evaluate a common genetic variant, sulfotransferase 4A1 haplotype 1 (SULT4A1-1), as a predictor of hospitalization events due to the exacerbation of schizophrenia for patients treated with antipsychotic medications. Haplotypes were determined using single nucleotide polymorphism data. METHOD: The study included 417 white subjects from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study with a DSM-IV diagnosis of schizophrenia. Patients were assigned to 1 of 4 atypical antipsychotics (olanzapine, quetiapine, risperidone, or ziprasidone) or to the first-generation antipsychotic perphenazine. Kaplan-Meier survival analysis and Cox proportional hazards regression models were used to measure if haplotype status impacted hospitalization events for these 5 treatments. Haplotype status was evaluated for its relationship to hospitalization events regardless of treatment and for the individual treatments, with or without previous exacerbation. Data for the CATIE study were collected from January 2001 to December 2004. The current post hoc analysis was performed between May 2011 and August 2011. RESULTS: In phase 1 of the trial, considering only the first hospitalization events, the haplotype had a significant impact on hospitalization events, with a hazard ratio for SULT4A1-1(-) versus SULT4A1-1(+) of 2.54 (P = .048). When prior exacerbation was included in the model for phase 1, the hazard ratio was 2.34 (P = .072) considering only the first hospitalization event and 2.71 (P = .039) considering all hospitalization events in the phase. When data for all phases were evaluated, SULT4A1-1(-) status was associated with increased hospitalization risk for subjects treated with olanzapine, with a hazard ratio of 8.26 (P = .041), and possibly for subjects treated with quetiapine, with a hazard ratio of 6.80 (P = .070). CONCLUSIONS: The SULT4A1-1 haplotype may be an important predictor of risk of hospitalization. SULT4A1-1(+) status was significantly associated with decreased risk of hospitalization when the subjects were treated with olanzapine.

Targeted pharmacogenetic analysis of antipsychotic response in the CATIE study.

AIM: This study evaluated the impact of 6789 SNPs on treatment response to antipsychotics in Caucasian patients from the CATIE study. MATERIALS & METHODS: An Illumina (CA, USA) BeadChip was designed that targeted genes potentially impacting disease risk, disease presentation or antipsychotic response. SNPs tagged regions of linkage disequilibrium or functional variants not detectable using previous genotypes for CATIE. Change in Positive and Negative Syndrome scale total score was modeled using a mixed model repeated measures method that assumed a 30-day lag period. Genetic association analysis was performed using linear regression. RESULTS: Association analysis identified 20 SNPs with p-values of ≤5 × 10(-4). Many of these are in genes previously implicated in schizophrenia and other neuropsychiatric diseases. CONCLUSION: The targeted approach identified SNPs possibly influencing response to antipsychotic drugs in Caucasian patients suffering from schizophrenia. The findings support a biological link between disease risk and presentation and antipsychotic response.

Evidence for a SULT4A1 haplotype correlating with baseline psychopathology and atypical antipsychotic response.

AIM: This study evaluated the impact of SULT4A1 gene variation on psychopathology and antipsychotic drug response in Caucasian subjects from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study and a replication sample. PATIENTS & METHODS: SULT4A1 haplotypes were determined using SNP data. The relationship to baseline psychopathology was evaluated using linear regression of Positive and Negative Syndrome Scale (PANSS) total score. Drug response was evaluated using Mixed Model Repeat Measures (MMRM) for change in PANSS. RESULTS: For the CATIE sample, patients carrying a haplotype designated SULT4A1-1(+) displayed higher baseline PANSS (p = 0.03) and, when treated with olanzapine, demonstrated a significant interaction with time (p = 0.009) in the MMRM. SULT4A1-1(+) patients treated with olanzapine displayed improved response compared with SULT4A1-1(-) patients treated with olanzapine (p = 0.008) or to SULT4A1-1(+) patients treated with risperidone (p = 0.006). In the replication sample, SULT4A1-1(+) patients treated with olanzapine demonstrated greater improvement than SULT4A1-1(-) patients treated with olanzapine (p = 0.05) or than SULT4A1-1(+) patients treated with risperidone (p = 0.05). CONCLUSION: If validated, determination of SULT4A1-1 haplotype status might be useful for identifying patients who show an enhanced response to long-term olanzapine treatment. Original submitted 6 October 2010; Revision submitted 9 December 2010.

A MicroRNA gene is hosted in an intron of a schizophrenia-susceptibility gene.

Schizophrenia (SZ) is a neuropsychiatric disorder that affects about 1% of the adult population. Numerous genes have been implicated in SZ susceptibility. MicroRNAs (miRNA) are small RNA molecules that regulate the translation of mRNAs via interactions with their 3' untranslated regions. Identification of known miRNA targets on all human genes indicated that miRNA-346 targets SZ susceptibility genes listed in the SchizophreniaGene database twice as frequently as expected relative to other genes in the genome. The gene encoding this miRNA, miR-346, is located in intron 2 of the glutamate receptor ionotropic delta 1 (GRID1) gene, which has been previously implicated in SZ susceptibility. We used quantitative real-time PCR to determine the expression levels of miR-346 and GRID1 using brain RNA samples from the Stanley Array Collection, Stanley Medical Research Institute. Expression of both miR-346 and GRID1 is lower in SZ patients than that in normal controls (P=0.017 and 0.086, respectively). However, the expression of miR-346 and GRID1 is less correlated in SZ patients than in bipolar patients or in normal controls. This study implicates the importance of a miRNA in SZ.

MUC1 and estrogen receptor alpha gene polymorphisms in dry eye patients.

Dry eye syndrome is a collection of common disorders of multifactorial etiology. Although the epidemiology of dry eye has been well studied, reports of genetic patterns that might influence susceptibility to dry eye are few. We reported that the frequency of non-Sjögren's aqueous-deficient dry eye patients expressing only the MUC1/A splice variant of the mucin MUC1 may be lower than that of a normal control group [Imbert, Y., Darling, D.S., Jumblatt, M.M., Foulks, G.N., Couzin, E.G., Steele, P.S., Young, W.W., Jr., 2006. MUC1 splice variants in human ocular surface tissues: possible differences between dry eye patients and normal controls. Exp. Eye Res. 83, 493-501]. Also, He et al. [He, Y., Li, X., Bao, Y., Sun, J., Liu, J., 2006. The correlation of polymorphism of estrogen receptor gene to dry eye syndrome in postmenopausal women. Yan. Ke. Xue. Bao. 22, 233-236] reported a difference between Chinese dry eye and control groups in the frequency of a polymorphism in estrogen receptor alpha (ERalpha). In the present study we determined the statistical significance and generality of these observations and tested if the MUC1 splice variant difference between subject groups reflected a difference in the MUC1 variable number of tandem repeat (VNTR) size class. There was a perfect correlation between the MUC1/A or MUC1/B splice variant pattern and the SNP genotype frequency of the SNP (rs4072037) controlling that splicing event. In contrast, western and Southern blotting indicated that MUC1 VNTR size class corresponded to the MUC1 SNP genotype in only 80% of cases. We determined the status of the MUC1 SNP in normal and dry eye populations all of whom were female Caucasians. The MUC1 SNP genotype frequency of the normal control group was statistically different from both the non-Sjögren's aqueous-deficient dry eye group with ocular surface staining (P=0.017) and the evaporative dry eye group (P=0.015). We also tested SNP rs2234693 to analyze the polymorphism in the ERalpha gene and found no significant difference in the SNP genotype frequency between the control group and either of the dry eye subtypes. Thus, among Caucasians there is no evidence for an association of the ERalpha gene polymorphism with dry eye syndrome as previously described in a Chinese population. In conclusion, the etiologies of evaporative dry eye and non-Sjögren's aqueous-deficient dry eye are known to be different. However, our results suggest that both of these subtypes of dry eye disease may share a common mechanism or factor related to MUC1 genotypic differences that affects susceptibility to ocular surface damage. This altered susceptibility may not be related to the MUC1 VNTR size class. Therefore, mechanisms influencing protection of the ocular surface against inflammation and damage in different types of dry eye disease warrant further investigation particularly in relation to MUC1 genotype.

Association of Sult4A1 SNPs with psychopathology and cognition in patients with schizophrenia or schizoaffective disorder.

A number of genes located on chromosome 22q11-13, including catechol-O-methyltransferase (COMT), are potential schizophrenia susceptibility genes. Recently, the sulfotransferase-4A1 (Sult4A1) locus within chromosome 22q13 was reported to be linked to schizophrenia in a family TDT study. Sult4A1 is related to metabolism of monoamines, particularly dopamine and norepinephrine, both of which have been implicated in the pathophysiology of the psychopathology and cognitive dysfunction components of schizophrenia. An available, prospectively collected data base was interrogated to determine how three Sult4A1 SNPs: rs138060, rs138097, and rs138110, previously shown to be associated with schizophrenia might be associated with psychopathology, cognition, and quality of life in a sample of 86 Caucasian patients with schizophrenia or schizoaffective disorder. The majority of patients met criteria for treatment resistant schizophrenia and had been drug-free for one week or longer at the time of evaluation. The major findings were: 1) patients heterozygous (T/G) for rs138060 had significantly worse Brief Psychiatric Rating Scale (BPRS) Total and anxiety/depression sub-scale scores, and higher Scale for the Assessment of Positive Symptoms (SAPS) Total scores than G/G homozygous patients; and 2) patients heterozygous (A/G) for rs138097 demonstrated significantly worse performance on neuropsychological testing, specifically on tests of executive function and working memory, compared to patients homozygous for the G and A alleles. RS138110 was unrelated to psychopathology and cognition. These results provide the first evidence of how genetic variation in Sult4A1 may be related to clinical symptoms and cognitive function in schizophrenia, and permit future studies to attempt to replicate these potentially important findings.

Evidence for two schizophrenia susceptibility genes on chromosome 22q13.

OBJECTIVE: Previous linkage scans and meta-analyses for schizophrenia susceptibility loci failed to include the most distal portion of chromosome 22q. Accordingly, 27 families having individuals affected with schizophrenia and schizophrenia-spectrum disorders were analyzed using a set of highly informative markers covering all of chromosome 22q. METHODS: Microsatellite and single nucleotide polymorphism markers were evaluated by nonparametric linkage, parametric linkage, and transmission disequilibrium testing of 22q. RESULTS: The maximum nonparametric logarithm of odd scores were 2.9 (P=0.0016) for schizophrenia and 2.7 (P=0.003) for a broader disease definition that included schizotypal personality disorder-both at 44.5 cM within the Sult4A1 locus. Parametric models assuming dominant modes of inheritance and genetic heterogeneity gave maximum multipoint logarithm of odd scores for the broader disease definition at the Sult4A1 locus of 3.3 (P=0.0006) and single point logarithm of odd scores of 3.1-4.8 for Sult4A1 markers (P=0.000015-0.0005). A distal locus, centered at 61 cM, shows a maximum nonparametric logarithm of odd scores of 1.5 (P=0.072) for the broader disease definition. Transmission disequilibrium testing for three adjacent microsatellite markers located near the distal linkage peak revealed significant values for marker D22s526 for schizophrenia (P=0.0016-0.14) and for broader disease definitions including schizotypal personality disorder (P=0.0002-0.0003), and both schizotypal personality disorder plus schizoaffective disorder (P=0.00001-0.000077). CONCLUSION: At least two separable, but closely linked, loci within 22q13 influencing susceptibility to schizophrenia-spectrum disorders, might be possible.

Transmission disequilibrium suggests a role for the sulfotransferase-4A1 gene in schizophrenia.

Previous studies suggest a role for chromosome 22q13 in schizophrenia. This segment of chromosome 22 contains the sulfotransferase-4A1 (Sult4A1) gene, which encodes an enzyme thought to be involved in neurotransmitter metabolism in the central nervous system. To evaluate this candidate, we developed a microsatellite marker targeting a polymorphism in its 5' nontranslated region (D22s1749E). Using samples obtained from the National Institutes of Mental Health Schizophrenia Genetics Initiative, we evaluated 27 families having multiple siblings with schizophrenia and schizophrenia-spectrum disorders for transmission disequilibrium (TDT) of this marker along with three single nucleotide polymorphisms (SNPs) spanning a 37 kb segment containing the Sult4A1 gene. TDT for D22s1749E was significant (P < 0.05), with a tendency for the 213 nt allele to be preferentially transferred to affected children (P = 0.0079). Global chi-square values for haplotypes involving the SNPs (ss146366, ss146407, and ss146420) and D22s1749E, also showed significant TDT values (P = 0.0006-0.0016). Consequently, we proposed that Sult4A merited more careful scrutiny as a candidate gene for schizophrenia susceptibility.