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Genomewide Pharmacogenomic Analysis of Response to Treatment with Antipsychotics
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 schizophrenic patients to the most effective and safe medication. Here we use a genomewide appro...
Autores principales: | , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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2009
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2888895/ https://www.ncbi.nlm.nih.gov/pubmed/19721433 http://dx.doi.org/10.1038/mp.2009.89 |
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author | McClay, Joseph L. Adkins, Daniel E. Åberg, Karolina Stroup, Scott Perkins, Diana O. Vladimirov, Vladimir I. Lieberman, Jeffrey A. Sullivan, Patrick F. van den Oord, Edwin J.C.G. |
author_facet | McClay, Joseph L. Adkins, Daniel E. Åberg, Karolina Stroup, Scott Perkins, Diana O. Vladimirov, Vladimir I. Lieberman, Jeffrey A. Sullivan, Patrick F. van den Oord, Edwin J.C.G. |
author_sort | McClay, Joseph L. |
collection | PubMed |
description | 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 schizophrenic patients to the most effective and safe medication. Here we use a genomewide 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 (CATIE). Subjects were genotyped using the Affymetrix 500K genotyping platform plus a custom 164K chip to improve genomewide coverage. Treatment outcome was measured using the Positive and Negative Syndrome Scale (PANSS). Our criterion for genomewide significance was a pre-specified threshold that ensures, on average, only 10% of the significant findings are false discoveries. The top statistical result reached significance at our pre-specified threshold and involved a SNP in an intergenic region on chromosome 4p15. In addition, SNPs in ANKS1B and CNTNAP5 that 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 GWAS to discover novel genes that mediate effects of antipsychotics, which eventually could help to tailor drug treatment to schizophrenic patients. |
format | Text |
id | pubmed-2888895 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2009 |
record_format | MEDLINE/PubMed |
spelling | pubmed-28888952011-07-01 Genomewide Pharmacogenomic Analysis of Response to Treatment with Antipsychotics McClay, Joseph L. Adkins, Daniel E. Åberg, Karolina Stroup, Scott Perkins, Diana O. Vladimirov, Vladimir I. Lieberman, Jeffrey A. Sullivan, Patrick F. van den Oord, Edwin J.C.G. Mol Psychiatry Article 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 schizophrenic patients to the most effective and safe medication. Here we use a genomewide 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 (CATIE). Subjects were genotyped using the Affymetrix 500K genotyping platform plus a custom 164K chip to improve genomewide coverage. Treatment outcome was measured using the Positive and Negative Syndrome Scale (PANSS). Our criterion for genomewide significance was a pre-specified threshold that ensures, on average, only 10% of the significant findings are false discoveries. The top statistical result reached significance at our pre-specified threshold and involved a SNP in an intergenic region on chromosome 4p15. In addition, SNPs in ANKS1B and CNTNAP5 that 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 GWAS to discover novel genes that mediate effects of antipsychotics, which eventually could help to tailor drug treatment to schizophrenic patients. 2009-09-01 2011-01 /pmc/articles/PMC2888895/ /pubmed/19721433 http://dx.doi.org/10.1038/mp.2009.89 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article McClay, Joseph L. Adkins, Daniel E. Åberg, Karolina Stroup, Scott Perkins, Diana O. Vladimirov, Vladimir I. Lieberman, Jeffrey A. Sullivan, Patrick F. van den Oord, Edwin J.C.G. Genomewide Pharmacogenomic Analysis of Response to Treatment with Antipsychotics |
title | Genomewide Pharmacogenomic Analysis of Response to Treatment with Antipsychotics |
title_full | Genomewide Pharmacogenomic Analysis of Response to Treatment with Antipsychotics |
title_fullStr | Genomewide Pharmacogenomic Analysis of Response to Treatment with Antipsychotics |
title_full_unstemmed | Genomewide Pharmacogenomic Analysis of Response to Treatment with Antipsychotics |
title_short | Genomewide Pharmacogenomic Analysis of Response to Treatment with Antipsychotics |
title_sort | genomewide pharmacogenomic analysis of response to treatment with antipsychotics |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2888895/ https://www.ncbi.nlm.nih.gov/pubmed/19721433 http://dx.doi.org/10.1038/mp.2009.89 |
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