Genome-wide pharmacogenomic study of neurocognition as an indicator of antipsychotic treatment response in schizophrenia

Joseph L. McClay, Daniel E. Adkins, Karolina Berg, Jozsef Bukszár, Amit N. Khachane, Richard S.E. Keefe, Diana O. Perkins, Joseph Patrick McEvoy, T. Scott Stroup, Robert E. Vann, Patrick M. Beardsley, Jeffrey A. Lieberman, Patrick F. Sullivan, Edwin J.C.G. Van Den Oord

Research output: Contribution to journalArticle

80 Citations (Scopus)

Abstract

Neurocognitive deficits are a core feature of schizophrenia and, therefore, represent potentially critical outcome variables for assessing antipsychotic treatment response. We performed genome-wide association studies (GWAS) with 492K single nucleotide polymorphisms (SNPs) in a sample of 738 patients with schizophrenia from the Clinical Antipsychotic Trials of Intervention Effectiveness study. Outcome variables consisted of a neurocognitive battery administered at multiple time points over an 18-month period, measuring processing speed, verbal memory, vigilance, reasoning, and working memory domains. Genetic mediation of improvements in each of these five domains plus a composite neurocognitive measure was assessed for each of five antipsychotics (olanzapine, perphenazine, quetiapine, risperidone, and ziprasidone). Six SNPs achieved genome-wide significance using a pre-specified threshold that ensures, on average, only 1 in 10 findings is a false discovery. These six SNPs were located within, or in close proximity to, genes EHF, SLC26A9, DRD2, GPR137B, CHST8, and IL1A. The more robust findings, that is those significant across multiple neurocognitive domains and having adjacent SNPs showing evidence for association, were rs286913 at the EHF gene (p-value 6.99 × 108, q-value 0.034, mediating the effects of ziprasidone on vigilance), rs11240594 at SLC26A9 (p-value 1.4 × 107, q-value 0.068, mediating the effects of olanzapine on processing speed), and rs11677416 at IL1A (p-value 6.67 × 107, q-value 0.081, mediating the effects of olanzapine on working memory). This study has generated several novel candidate genes for antipsychotic response. However, our findings will require replication and functional validation. To facilitate replication efforts, we provide all GWAS p-values for download.

Original languageEnglish (US)
Pages (from-to)616-626
Number of pages11
JournalNeuropsychopharmacology
Volume36
Issue number3
DOIs
StatePublished - Feb 1 2011

Fingerprint

olanzapine
Antipsychotic Agents
Single Nucleotide Polymorphism
Schizophrenia
Genome
Genome-Wide Association Study
Short-Term Memory
Perphenazine
Genes
Risperidone
Therapeutics
Clinical Trials
Pharmacogenomic Testing

Keywords

  • genome-wide association
  • personalized medicine
  • pharmacogenomics
  • schizophrenia
  • single nucleotide polymorphisms

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health

Cite this

McClay, J. L., Adkins, D. E., Berg, K., Bukszár, J., Khachane, A. N., Keefe, R. S. E., ... Van Den Oord, E. J. C. G. (2011). Genome-wide pharmacogenomic study of neurocognition as an indicator of antipsychotic treatment response in schizophrenia. Neuropsychopharmacology, 36(3), 616-626. https://doi.org/10.1038/npp.2010.193

Genome-wide pharmacogenomic study of neurocognition as an indicator of antipsychotic treatment response in schizophrenia. / McClay, Joseph L.; Adkins, Daniel E.; Berg, Karolina; Bukszár, Jozsef; Khachane, Amit N.; Keefe, Richard S.E.; Perkins, Diana O.; McEvoy, Joseph Patrick; Stroup, T. Scott; Vann, Robert E.; Beardsley, Patrick M.; Lieberman, Jeffrey A.; Sullivan, Patrick F.; Van Den Oord, Edwin J.C.G.

In: Neuropsychopharmacology, Vol. 36, No. 3, 01.02.2011, p. 616-626.

Research output: Contribution to journalArticle

McClay, JL, Adkins, DE, Berg, K, Bukszár, J, Khachane, AN, Keefe, RSE, Perkins, DO, McEvoy, JP, Stroup, TS, Vann, RE, Beardsley, PM, Lieberman, JA, Sullivan, PF & Van Den Oord, EJCG 2011, 'Genome-wide pharmacogenomic study of neurocognition as an indicator of antipsychotic treatment response in schizophrenia', Neuropsychopharmacology, vol. 36, no. 3, pp. 616-626. https://doi.org/10.1038/npp.2010.193
McClay, Joseph L. ; Adkins, Daniel E. ; Berg, Karolina ; Bukszár, Jozsef ; Khachane, Amit N. ; Keefe, Richard S.E. ; Perkins, Diana O. ; McEvoy, Joseph Patrick ; Stroup, T. Scott ; Vann, Robert E. ; Beardsley, Patrick M. ; Lieberman, Jeffrey A. ; Sullivan, Patrick F. ; Van Den Oord, Edwin J.C.G. / Genome-wide pharmacogenomic study of neurocognition as an indicator of antipsychotic treatment response in schizophrenia. In: Neuropsychopharmacology. 2011 ; Vol. 36, No. 3. pp. 616-626.
@article{269122ffb0274b4eaf3441c86fdf5b14,
title = "Genome-wide pharmacogenomic study of neurocognition as an indicator of antipsychotic treatment response in schizophrenia",
abstract = "Neurocognitive deficits are a core feature of schizophrenia and, therefore, represent potentially critical outcome variables for assessing antipsychotic treatment response. We performed genome-wide association studies (GWAS) with 492K single nucleotide polymorphisms (SNPs) in a sample of 738 patients with schizophrenia from the Clinical Antipsychotic Trials of Intervention Effectiveness study. Outcome variables consisted of a neurocognitive battery administered at multiple time points over an 18-month period, measuring processing speed, verbal memory, vigilance, reasoning, and working memory domains. Genetic mediation of improvements in each of these five domains plus a composite neurocognitive measure was assessed for each of five antipsychotics (olanzapine, perphenazine, quetiapine, risperidone, and ziprasidone). Six SNPs achieved genome-wide significance using a pre-specified threshold that ensures, on average, only 1 in 10 findings is a false discovery. These six SNPs were located within, or in close proximity to, genes EHF, SLC26A9, DRD2, GPR137B, CHST8, and IL1A. The more robust findings, that is those significant across multiple neurocognitive domains and having adjacent SNPs showing evidence for association, were rs286913 at the EHF gene (p-value 6.99 × 108, q-value 0.034, mediating the effects of ziprasidone on vigilance), rs11240594 at SLC26A9 (p-value 1.4 × 107, q-value 0.068, mediating the effects of olanzapine on processing speed), and rs11677416 at IL1A (p-value 6.67 × 107, q-value 0.081, mediating the effects of olanzapine on working memory). This study has generated several novel candidate genes for antipsychotic response. However, our findings will require replication and functional validation. To facilitate replication efforts, we provide all GWAS p-values for download.",
keywords = "genome-wide association, personalized medicine, pharmacogenomics, schizophrenia, single nucleotide polymorphisms",
author = "McClay, {Joseph L.} and Adkins, {Daniel E.} and Karolina Berg and Jozsef Buksz{\'a}r and Khachane, {Amit N.} and Keefe, {Richard S.E.} and Perkins, {Diana O.} and McEvoy, {Joseph Patrick} and Stroup, {T. Scott} and Vann, {Robert E.} and Beardsley, {Patrick M.} and Lieberman, {Jeffrey A.} and Sullivan, {Patrick F.} and {Van Den Oord}, {Edwin J.C.G.}",
year = "2011",
month = "2",
day = "1",
doi = "10.1038/npp.2010.193",
language = "English (US)",
volume = "36",
pages = "616--626",
journal = "Neuropsychopharmacology",
issn = "0893-133X",
publisher = "Nature Publishing Group",
number = "3",

}

TY - JOUR

T1 - Genome-wide pharmacogenomic study of neurocognition as an indicator of antipsychotic treatment response in schizophrenia

AU - McClay, Joseph L.

AU - Adkins, Daniel E.

AU - Berg, Karolina

AU - Bukszár, Jozsef

AU - Khachane, Amit N.

AU - Keefe, Richard S.E.

AU - Perkins, Diana O.

AU - McEvoy, Joseph Patrick

AU - Stroup, T. Scott

AU - Vann, Robert E.

AU - Beardsley, Patrick M.

AU - Lieberman, Jeffrey A.

AU - Sullivan, Patrick F.

AU - Van Den Oord, Edwin J.C.G.

PY - 2011/2/1

Y1 - 2011/2/1

N2 - Neurocognitive deficits are a core feature of schizophrenia and, therefore, represent potentially critical outcome variables for assessing antipsychotic treatment response. We performed genome-wide association studies (GWAS) with 492K single nucleotide polymorphisms (SNPs) in a sample of 738 patients with schizophrenia from the Clinical Antipsychotic Trials of Intervention Effectiveness study. Outcome variables consisted of a neurocognitive battery administered at multiple time points over an 18-month period, measuring processing speed, verbal memory, vigilance, reasoning, and working memory domains. Genetic mediation of improvements in each of these five domains plus a composite neurocognitive measure was assessed for each of five antipsychotics (olanzapine, perphenazine, quetiapine, risperidone, and ziprasidone). Six SNPs achieved genome-wide significance using a pre-specified threshold that ensures, on average, only 1 in 10 findings is a false discovery. These six SNPs were located within, or in close proximity to, genes EHF, SLC26A9, DRD2, GPR137B, CHST8, and IL1A. The more robust findings, that is those significant across multiple neurocognitive domains and having adjacent SNPs showing evidence for association, were rs286913 at the EHF gene (p-value 6.99 × 108, q-value 0.034, mediating the effects of ziprasidone on vigilance), rs11240594 at SLC26A9 (p-value 1.4 × 107, q-value 0.068, mediating the effects of olanzapine on processing speed), and rs11677416 at IL1A (p-value 6.67 × 107, q-value 0.081, mediating the effects of olanzapine on working memory). This study has generated several novel candidate genes for antipsychotic response. However, our findings will require replication and functional validation. To facilitate replication efforts, we provide all GWAS p-values for download.

AB - Neurocognitive deficits are a core feature of schizophrenia and, therefore, represent potentially critical outcome variables for assessing antipsychotic treatment response. We performed genome-wide association studies (GWAS) with 492K single nucleotide polymorphisms (SNPs) in a sample of 738 patients with schizophrenia from the Clinical Antipsychotic Trials of Intervention Effectiveness study. Outcome variables consisted of a neurocognitive battery administered at multiple time points over an 18-month period, measuring processing speed, verbal memory, vigilance, reasoning, and working memory domains. Genetic mediation of improvements in each of these five domains plus a composite neurocognitive measure was assessed for each of five antipsychotics (olanzapine, perphenazine, quetiapine, risperidone, and ziprasidone). Six SNPs achieved genome-wide significance using a pre-specified threshold that ensures, on average, only 1 in 10 findings is a false discovery. These six SNPs were located within, or in close proximity to, genes EHF, SLC26A9, DRD2, GPR137B, CHST8, and IL1A. The more robust findings, that is those significant across multiple neurocognitive domains and having adjacent SNPs showing evidence for association, were rs286913 at the EHF gene (p-value 6.99 × 108, q-value 0.034, mediating the effects of ziprasidone on vigilance), rs11240594 at SLC26A9 (p-value 1.4 × 107, q-value 0.068, mediating the effects of olanzapine on processing speed), and rs11677416 at IL1A (p-value 6.67 × 107, q-value 0.081, mediating the effects of olanzapine on working memory). This study has generated several novel candidate genes for antipsychotic response. However, our findings will require replication and functional validation. To facilitate replication efforts, we provide all GWAS p-values for download.

KW - genome-wide association

KW - personalized medicine

KW - pharmacogenomics

KW - schizophrenia

KW - single nucleotide polymorphisms

UR - http://www.scopus.com/inward/record.url?scp=78651383514&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78651383514&partnerID=8YFLogxK

U2 - 10.1038/npp.2010.193

DO - 10.1038/npp.2010.193

M3 - Article

C2 - 21107309

AN - SCOPUS:78651383514

VL - 36

SP - 616

EP - 626

JO - Neuropsychopharmacology

JF - Neuropsychopharmacology

SN - 0893-133X

IS - 3

ER -