John Jibin, Bhatia Triptish, Kukshal Prachi, Chandna Puneet, Nimgaonkar Vishwajit L, Deshpande Smita N, Thelma B K
Department of Genetics, University of Delhi South Campus, Benito Juarez Road, New Delhi 110 021, India.
Department of Psychiatry, PGIMER-Dr. RML Hospital, New Delhi 110 001, India.
Schizophr Res. 2016 Jul;174(1-3):29-34. doi: 10.1016/j.schres.2016.03.031. Epub 2016 Apr 19.
MicroRNAs (miRNAs) bind to 3'UTRs of genes and negatively regulate their expression. With ~50% of miRNAs expressing in the brain, they play an important role in neuronal development, plasticity, cognition and neurological disorders. Conserved miRNA targets are present in >60% genes in humans and are under evolutionary pressure to maintain pairing with miRNA. However, such binding may be affected by genetic variant(s) in the target sites (MiRSNPs), thereby altering gene expression. Differential expression of a large number of genes in postmortem brains of schizophrenia (SZ) patients compared to controls has been documented. Thus studying the role of MiRSNPs which are underinvestigated in SZ becomes attractive. We systematically selected 35 MiRSNPs with predicted functional relevance in 3'UTRs of genes shown previously to be associated with SZ, genotyped and tested their association with disease, using independent discovery and replication samples (total n=1017 cases; n=1073 controls). We also explored genetic associations with two sets of quantitative traits, namely tardive dyskinesia (TD) and cognitive functions disrupted in SZ in subsets of the study cohort. In the primary analysis, a significant association of MiRSNP rs7430 at PPP3CC was observed with SZ in the discovery and the replication samples [discovery: P=0.01; OR (95% CI) 1.24 (1.04-1.48); replication: P=0.03; OR (95% CI) 1.20 (1.02-1.43)]. In the exploratory analyses, five SNPs were nominally associated with TD (P values 0.04-0.004). Separately, 12 SNPs were associated with one or more of the eight cognitive domains (P values 0.05-0.003). These associations, particularly the SNP at PPP3CC merit further investigations.
微小RNA（miRNA）与基因的3'非翻译区（3'UTR）结合并负向调节其表达。约50%的miRNA在大脑中表达，它们在神经元发育、可塑性、认知及神经疾病中发挥重要作用。保守的miRNA靶标存在于超过60%的人类基因中，并且处于进化压力之下以维持与miRNA的配对。然而，这种结合可能会受到靶位点的遗传变异（MiRSNP）影响，从而改变基因表达。与对照组相比，精神分裂症（SZ）患者死后大脑中大量基因的差异表达已有文献记载。因此，研究在SZ中研究较少的MiRSNP的作用变得很有吸引力。我们系统地选择了35个在先前显示与SZ相关的基因的3'UTR中具有预测功能相关性的MiRSNP，进行基因分型并使用独立的发现和重复样本（共n = 1017例；n = 1073例对照）测试它们与疾病的关联。我们还在研究队列的子集中探索了与两组定量性状的遗传关联，即迟发性运动障碍（TD）和SZ中受损的认知功能。在初步分析中，在发现和重复样本中均观察到PPP3CC处的MiRSNP rs7430与SZ存在显著关联[发现：P = 0.01；比值比（95%置信区间）1.24（1.04 - 1.48）；重复：P = 0.03；比值比（95%置信区间）1.20（1.02 - 1.43）]。在探索性分析中，五个单核苷酸多态性（SNP）与TD名义上相关（P值为0.04 - 0.004）。另外，12个SNP与八个认知领域中的一个或多个相关（P值为0.05 - 0.003）。这些关联，特别是PPP3CC处的SNP值得进一步研究。
