Genetic and functional insights into long noncoding RNAs in schizophrenia

Long noncoding RNAs (lncRNAs) are widely expressed regulatory RNAs that play critical roles in diverse biological processes, including brain development, neural stem cell maintenance, and synaptogenesis. Alterations in lncRNA expression have been implicated in schizophrenia (SCZ), however, the genetic drivers and biological consequences of these alterations remain largely unknown. Here, we systematically characterize SCZ associated lncRNAs. We first identify lncRNAs that are significantly dysregulated in the brains of SCZ cases (n = 153) compared with control subjects (n = 300) by using transcriptomic data from the Lieber Institute for Brain Development Phase 2 study (LIBD2). Expression quantitative trait loci (eQTL) analysis uncovers genetic variants that are associated with lncRNA expression in the prenatal and postnatal human brain. By integrating lncRNA eQTL data and genome-wide associations of SCZ, we identify multiple lncRNAs whose genetically regulated expression changes are associated with SCZ. Finally, we selected one candidate lncRNA, LINC01068, for in vitro functional validation, and showed that knockdown of LINC01068 in cultured human neural stem cells (hNSCs) impairs the proliferation, migration, and differentiation of hNSCs. Transcriptomic analysis reveals that LINC01068 regulates SCZ-associated genes and synaptic pathways, indicating the important roles of LINC01068 in SCZ. In summary, this study systematically characterizes SCZ-associated lncRNAs and suggests that LINC01068 confers SCZ risk by affecting neurodevelopment and synaptic-associated pathways. Although our results have not yet been validated in independent datasets, the findings of this study demonstrate the critical roles of lncRNAs and provide important genetic and functional insights into lncRNAs in SCZ.