Genome-wide association study identified six loci associated with adverse drug reactions to aripiprazole in schizophrenia patients

Aripiprazole is recommended for routine use in schizophrenia patients. However, the biological mechanism for the adverse drug reactions (ADRs) among schizophrenia patients with the antipsychotic drug aripiprazole is far from clear. To explore the potential genetic factors that may cause movement-related adverse antipsychotic effects in patients, we conducted an association analysis between movement-related ADRs and SNPs in schizophrenia patients receiving aripiprazole monotherapy. In this study, multiple ADRs of 384 patients were quantified within 6-week treatment, and the scores of movement-related ADRs at baseline and follow-up time points during treatment were obtained. The highest score record was used as the quantitative index in analysis, and genetic analysis at the genome-wide level was conducted. The SNP rs4149181 in SLC22A8 [P = 2.28 × 10−8] showed genome-wide significance, and rs2284223 in ADCYAP1R1 [P = 9.76 × 10−8], rs73258503 in KCNIP4 [P = 1.39 × 10−7], rs678428 in SMAD9 [P = 4.70 × 10−7], rs6421034 in NAP1L4 [P = 6.80 × 10−7], and rs1394796 in ERBB4 [P = 8.60 × 10−7] were found to be significantly associated with movement-related ADRs. The combined prediction model of these six loci showed acceptable performance in predicting adverse events [area under the curve (AUC): 0.84]. Combined with the function and network of the above genes and other candidate loci (KCNA1, CACNG1, etc.), we hypothesize that SLC22A8 and KCNIP4-Kv channel perform their respective functions as transporter or channel and participate in the in vivo metabolism or effects of aripiprazole. The above results imply the important function of ion transporters and channels in movement-related adverse antipsychotic effects in aripiprazole monotherapy schizophrenia patients.