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Genome-wide pharmacogenomic analysis of response to treatment with antipsychotics.

ABSTRACT: Schizophrenia is an often devastating neuropsychiatric illness. Understanding the genetic variation affecting response to antipsychotics is important to develop novel diagnostic tests to match individual schizophrenia patients to the most effective and safe medication. In this study, we use a genome-wide approach to detect genetic variation underlying individual differences in response to treatment with the antipsychotics olanzapine, quetiapine, risperidone, ziprasidone and perphenazine. Our sample consisted of 738 subjects with DSM-IV schizophrenia who took part in the Clinical Antipsychotic Trials of Intervention Effectiveness. Subjects were genotyped using the Affymetrix 500 K genotyping platform plus a custom 164 K chip to improve genome-wide coverage. Treatment outcome was measured using the Positive and Negative Syndrome Scale. Our criterion for genome-wide significance was a prespecified threshold that ensures that, on an average, only 10% of the significant findings are false discoveries. The top statistical result reached significance at our prespecified threshold and involved a single-nucleotide polymorphism (SNP) in an intergenic region on chromosome 4p15. In addition, SNPs in Ankyrin Repeat and Sterile Alpha Motif Domain-Containing Protein 1B (ANKS1B) and in the Contactin-Associated Protein-Like 5 gene (CNTNAP5), which mediated the effects of olanzapine and risperidone on Negative symptoms, were very close to our threshold for declaring significance. The most significant SNP in CNTNAP5 is nonsynonymous, giving rise to an amino-acid substitution. In addition to highlighting our top results, we provide all P-values for download as a resource for investigators with the requisite samples to carry out replication. This study demonstrates the potential of genome-wide association studies to discover novel genes that mediate the effects of antipsychotics, which could eventually help to tailor drug treatment to schizophrenic patients.

SUBMITTER: McClay JL

PROVIDER: S-EPMC2888895 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Genome-wide pharmacogenomic analysis of response to treatment with antipsychotics.

McClay J L JL Adkins D E DE Aberg K K Stroup S S Perkins D O DO Vladimirov V I VI Lieberman J A JA Sullivan P F PF van den Oord E J C G EJ

Molecular psychiatry 20090901 1

Schizophrenia is an often devastating neuropsychiatric illness. Understanding the genetic variation affecting response to antipsychotics is important to develop novel diagnostic tests to match individual schizophrenia patients to the most effective and safe medication. In this study, we use a genome-wide approach to detect genetic variation underlying individual differences in response to treatment with the antipsychotics olanzapine, quetiapine, risperidone, ziprasidone and perphenazine. Our sam ...[more]

PMID: 19721433

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Project description:ObjectiveThe goal of pharmacogenomics is the translation of genomic discoveries into individualized patient care. Recent advances in the means to survey human genetic variation are fundamentally transforming our understanding of the genetic basis of interindividual variation in therapeutic response. The goal of this study was to systematically evaluate high-throughput genotyping technologies for their ability to assay variation in pharmacogenetically important genes (pharmacogenes). These platforms are either being proposed for or are already being widely used for clinical implementation; therefore, knowledge of coverage of pharmacogenes on these platforms would serve to better evaluate current or proposed pharmacogenetic association studies.MethodAmong the genes included in our study are drug-metabolizing enzymes, transporters, receptors, and drug targets, of interest to the entire pharmacogenetic community. We considered absolute and linkage disequilibrium (LD)-informed coverage, minor allele frequency spectrum, and functional annotation for a Caucasian population. We also examined the effect of LD, effect size, and cohort size on the power to detect single nucleotide polymorphism associations.ResultsIn our analysis of 253 pharmacogenes, we found that no platform showed more than 85% coverage of these genes (after accounting for LD). Furthermore, the lack of coverage showed a marked increase at minor allele frequencies of less than 20%. Even after accounting for LD, only 30% of the missense polymorphisms (which are enriched for low-frequency alleles) were covered by HapMap, with still lower coverage on the other platforms.ConclusionWe have conducted the first systematic evaluation of the Axiom Genomic Database, Omni 2.5 M, and the Drug Metabolizing Enzymes and Transporters chip. This study is the first to utilize the 1000 Genomes Project to present a comprehensive evaluative framework. Our results provide a much-needed assessment of microarray-based genotyping and next-generation sequencing technologies' ability to survey fully the variation in genes of particular interest to the pharmacogenetics community. Our findings demonstrate the limitations of genome-wide methods and the challenges of implementing pharmacogenomic tests into the clinical context.

Project description:The unique physico-chemical properties of gold nanoparticles (AuNPs) find manifold applications in diagnostics, medicine and catalysis. Chemical synthesis produces reactive AuNPs and generates hazardous by-products. Alternatively, plants can be utilized to produce AuNPs in an eco-friendly manner. To better control the biosynthesis of AuNPs, we need to first understand the detailed molecular response induced by AuCl(-) 4 In this study, we carried out global transcriptome analysis in root tissue of Arabidopsis grown for 12- h in presence of gold solution (HAuCl4) using the novel unbiased Affymetrix exon array. Transcriptomics analysis revealed differential regulation of a total of 704 genes and 4900 exons. Of these, 492 and 212 genes were up- and downregulated, respectively. The validation of the expressed key genes, such as glutathione-S-transferases, auxin responsive genes, cytochrome P450 82C2, methyl transferases, transducin (G protein beta subunit), ERF transcription factor, ABC, and MATE transporters, was carried out through quantitative RT-PCR. These key genes demonstrated specific induction under AuCl4(-) treatment relative to other heavy metals, suggesting a unique plant-gold interaction. GO enrichment analysis reveals the upregulation of processes like oxidative stress, glutathione binding, metal binding, transport, and plant hormonal responses. Changes predicted in biochemical pathways indicated major modulation in glutathione mediated detoxification, flavones and derivatives, and plant hormone biosynthesis. Motif search analysis identified a highly significant enriched motif, ACGT, which is an abscisic acid responsive core element (ABRE), suggesting the possibility of ABA- mediated signaling. Identification of abscisic acid response element (ABRE) points to the operation of a predominant signaling mechanism in response to AuCl(-) 4 exposure. Overall, this study presents a useful picture of plant-gold interaction with an identification of candidate genes involved in nanogold synthesis.

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Genome-wide pharmacogenomic analysis of response to treatment with antipsychotics.

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Genome-wide pharmacogenomic analysis of response to treatment with antipsychotics.

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