Genome-wide pharmacogenomic study of neurocognition as an indicator of antipsychotic treatment response in schizophrenia.
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 × 10(-8), q-value 0.034, mediating the effects of ziprasidone on vigilance), rs11240594 at SLC26A9 (p-value 1.4 × 10(-7), q-value 0.068, mediating the effects of olanzapine on processing speed), and rs11677416 at IL1A (p-value 6.67 × 10(-7), 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.
Center for Biomarker Research and Personalized Medicine, School of Pharmacy, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298-0533, USA. jlmcclay@vcu.edu
Joseph L
JL
McClay
Daniel E
DE
Adkins
Karolina
K
Aberg
Jozsef
J
Bukszár
Amit N
AN
Khachane
Richard S E
RS
Keefe
Diana O
DO
Perkins
Joseph P
JP
McEvoy
T Scott
TS
Stroup
Robert E
RE
Vann
Patrick M
PM
Beardsley
Jeffrey A
JA
Lieberman
Patrick F
PF
Sullivan
Edwin J C G
EJ
van den Oord
D000328:Adult; D017920:Antiporters / Q000235:genetics; D014150:Antipsychotic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001288:Attention / Q000187:drug effects; D003072:Cognition Disorders / Q000188:drug therapy / Q000209:etiology / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D055106:Genome-Wide Association Study; D006801:Humans; D053582:Interleukin-1alpha / Q000235:genetics; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects / Q000502:physiology; D009483:Neuropsychological Tests; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012559:Schizophrenia / Q000150:complications / Q000188:drug therapy / Q000235:genetics; D000076988:Sulfate Transporters; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics
D017920:Antiporters; D014150:Antipsychotic Agents; C403306:EHF protein, human; C508584:IL1A protein, human; D053582:Interleukin-1alpha; C455628:SLC26A9 protein, human; D000076988:Sulfate Transporters; D014157:Transcription Factors