Five novel loci associated with antipsychotic treatment response in patients with schizophrenia: a genome-wide association study

Abstract

Antipsychotic drugs improve schizophrenia symptoms and reduce the frequency of relapse, but treatment response is highly variable. Little is known about the genetic factors associated with treatment response. We did a genome-wide association study of antipsychotic treatment response in patients with schizophrenia. The discovery cohort comprised patients with schizophrenia from 32 psychiatric hospitals in China that are part of the Chinese Antipsychotics Pharmacogenomics Consortium. Patients who met inclusion criteria were randomly assigned (1:1:1:1:1:1) to six groups (olanzapine, risperidone, quetiapine, aripiprazole, ziprasidone, and haloperidol or perphenazine; those assigned to haloperidol or perphenazine were subsequently assigned [1:1] to one or the other) for 6 weeks. Antipsychotic response was quantified with percentage change on the Positive and Negative Syndrome Scale. Single-nucleotide polymorphisms (SNPs) were tested for their association with treatment response. Linkage-disequilibrium-independent SNPs that exhibited potential associations (ie, p<1 × 10-5) were tested in a validation cohort comprising patients from the Chinese Antipsychotics Pharmacogenetics Consortium from five collaborative hospitals, who were treated with olanzapine, risperidone, or aripiprazole for 8 weeks. The discovery cohort contained 2413 patients and the validation cohort 1379 patients. In the discovery cohort, we identified three novel SNPs (rs72790443 in MEGF10 [p=1·37 × 10-8], rs1471786 in SLC1A1 [p=1·77 × 10-8], and rs9291547 in PCDH7 [p=4·48 × 10-8]) that were associated with antipsychotic treatment response at a genome-wide significance level. These associations were confirmed in the validation cohort (p<0·05). In the combined sample of the discovery and validation cohorts, we identified five novel loci showing genome-wide significant associations with general antipsychotic treatment response (rs72790443 in MEGF10 [p=1·40 × 10-9], rs1471786 in SLC1A1 [p=2·33 × 10-9], rs9291547 in PCDH7 [p=3·24 × 10-9], rs12711680 in CNTNAP5 [p=2·12 × 10-8], and rs6444970 in TNIK [p=4·85 × 10-8]). In antipsychotic-specific groups, after the combination of results from both samples, the rs2239063 SNP in CACNA1C was associated with treatment response to olanzapine (p=1·10 × 10-8), rs16921385 in SLC1A1 was associated with treatment response to risperidone (p=4·40 × 10-8), and rs17022006 in CNTN4 was associated with treatment response to aripiprazole (p=2·58 × 10-8). We have identified genes related to synaptic function, neurotransmitter receptors, and schizophrenia risk that are associated with response to antipsychotics. These findings improve understanding of the mechanisms underlying treatment responses, and the identified biomarkers could eventually guide choice of antipsychotic in patients with schizophrenia. National Key Technology R&D Program of China, National Natural Science Foundation of China.