Predicted microRNA target relationships. Red denotes genes and green denotes microRNAs.

Converging evidence suggests an association between schizophrenia and the impairment of posttranscriptional regulation of brain development through microRNA systems. Our study compared the overall frequency of 121 rare variants (RVs) in 59 genes associated with the microRNA system in genome-wide association studies (GWAS)-derived data including 768 SZ cases and 1348 healthy controls and validated in an independent GWAS data including 1802 SZ cases and 1447 controls. In genes associated with the control of microRNAs, there are approximately 50% more RVs in SZ cases than in controls. Then, we profiled genome-wide microRNA expression in blood collected from 15 early-onset SZ (EOS) cases and 15 healthy controls. The observed lower microRNA activity in EOS patients compared with the healthy controls suggests that microRNAs are abnormally down-regulated. Finally, we constructed a microRNA-messenger RNA (mRNA) regulatory network using our previous genome-wide mRNA expression data generated from a separate sample of 18 EOS cases and 12 healthy controls. Results: Our findings indicated there was a predicted regulatory network among some down-regulated microRNAs and some up-regulated mRNAs. Collectively, results from all 3 lines of evidence, suggest that the genetically based dysregulation of microRNA systems undermines microRNAs’ inhibitory effects, resulting in the abnormal up-regulation of genome transcription in the development of SZ.

Fuquan Zhang, Yong Xu, Yin Yao Shugart, Weihua Yue, Guoyang Qi, Guozhen Yuan, Zaohuo Cheng, Jianjun Yao, Jidong Wang, Guoqiang Wang, Hongbao Cao, Wei Guo, Zhenhe Zhou, Zhiqiang Wang, Lin Tian, Chunhui Jin, Jianmin Yuan, Chenxing Liu, and Dai Zhang. Converging evidence implicates the abnormal microRNA system in schizophrenia.  Schizophrenia Bulletin   . 2015; 41(3):728-735.