Background Antipsychotic drugs improve schizophrenia symptoms and reduce the frequency of relapse, but treatmentresponse is highly variable. Little is known about the genetic factors associated with treatment response. We did agenome-wide association study of antipsychotic treatment response in patients with schizophrenia.Methods The discovery cohort comprised patients with schizophrenia from 32 psychiatric hospitals in China thatare part of the Chinese Antipsychotics Pharmacogenomics Consortium. Patients who met inclusion criteria wererandomly assigned (1:1:1:1:1:1) to six groups (olanzapine, risperidone, quetiapine, aripiprazole, ziprasidone, andhaloperidol or perphenazine; those assigned to haloperidol or perphenazine were subsequently assigned [1:1] toone or the other) for 6 weeks. Antipsychotic response was quantified with percentage change on the Positive andNegative Syndrome Scale. Single-nucleotide polymorphisms (SNPs) were tested for their association with treatmentresponse. Linkage-disequilibrium-independent SNPs that exhibited potential associations (ie, p<1 × 10 – ⁵) weretested in a validation cohort comprising patients from the Chinese Antipsychotics Pharmacogenetics Consortiumfrom five collaborative hospitals, who were treated with olanzapine, risperidone, or aripiprazole for 8 weeks.

Findings 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 x 10 – ⁸], rs1471786 in SLC1A1 [p=1·77 x 10 – ⁸], andrs9291547 in PCDH7 [p=4·48 x 10 – ⁸]) that were associated with antipsychotic treatment response at a genome-widesignificance level. These associations were confirmed in the validation cohort (p<0·05). In the combined sample ofthe discovery and validation cohorts, we identified five novel loci showing genome-wide significant associations withgeneral 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 CACNA1Cwas associated with treatment response to olanzapine (p=1·10 × 10 – ⁸), rs16921385 in SLC1A1 was associated withtreatment response to risperidone (p=4·40 × 10 – ⁸), and rs17022006 in CNTN4 was associated with treatment responseto aripiprazole (p=2·58 × 10 – ⁸).

Interpretation We have identified genes related to synaptic function, neurotransmitter receptors, and schizophreniarisk that are associated with response to antipsychotics. These findings improve understanding of the mechanismsunderlying treatment responses, and the identified biomarkers could eventually guide choice of antipsychotic inpatients with schizophrenia.