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Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders involving structural and functional impairment of the brain. Inwardly rectifying potassium (Kir) channels may contribute to the etiology of ASD by altering brain function. This study investigated the associations between genetic variants of KCNJ2 and KCNJ10 genes (encoding Kir2.1 and Kir4.1, respectively) and ASD risk in patients, and Kir channel expression in ASD model rats. This case-control study involved a cohort of 269 Chinese children with ASD and 243 unrelated healthy controls. Twelve tag single nucleotide polymorphisms (SNPs) from the KCNJ2 and KCNJ10 genes were genotyped by Sequenom Mass Array, while a valproic acid (VPA)-induced rat model of ASD was used to evaluate Kir channel expression in the hippocampus. Among the 12 examined SNPs, only KCNJ10 rs1186689 was significantly associated with disease susceptibility; the variant T allele conferred a lower risk of developing ASD [odds ratio (OR) = 0.61, 95% confidence interval (CI) = 0.47–0.80, p false discovery rate (FDR) = 0.012, and OR = 0.63, 95% CI = 0.48–0.84, pFDR = 0.014 at the allelic and genotypic levels, respectively]. Additionally, hippocampal Kir2.1 and Kir4.1 levels were decreased in VPA as compared to control rats. These results demonstrated that KCNJ10 (rs1186689) polymorphisms was correlated with ASD susceptibility in Chinese Han children, and the abnormal expression of Kir2.1 and Kir4.1 in ASD model rats suggested a mechanism by which Kir channels may play a role in ASD.