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 × 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.

Figure 1

(a and b) Regional plots of p-values for SNPs flanking the six genome-wide significant findings (solid black dots). The y axis is the –log₁₀ of the p-values for each SNP, while the x axis denotes genomic position according to genome build 36 (hg18). All genotyped SNPs within ∼±100 kb of the primary findings are plotted.

Figure 2

Box and whisker plots of treatment response, by genotype, for the six genome-wide significant SNP associations. The y axis units are SD. Vigil_zipras=vigilance with ziprasidone; Speed_olanza=processing speed with olanzapine; Memory_olanza=working memory with olanzapine. For rs4805924 and rs11214606, only two genotpype groups are plotted. Although rare allele homozygotes were present for both SNPs in CATIE, none of these had at least two observations in the relevant neurocognitive outcome/drug combination (working memory and olanzapine) to allow a treatment effect to be calculated.