Schizophrenia (SCZ) is a severe mental disorder with a lifetime prevalence of ~ 0.5–1% across all human populations. This disease is characterized by positive symptoms (i.e., delusions and hallucinations), negative symptoms (i.e., apathy, impaired motivation, and social withdrawal), and cognitive impairment (i.e., disorganized thoughts, impaired working memory, and executive function). As one of the most common mental diseases, SCZ has a high mortality and significant long-term morbidity, and the economic burden of SCZ is particularly great. Family, twin, and adoption studies have demonstrated that SCZ has a strong genetic factor, with an estimated heritability around 0.80. SCZ has the highest heritability among neuropsychiatric disorders. Recent genome-wide association studies (GWAS) have identified multiple risk loci that show strong associations with schizophrenia. However, pinpointing the potential causal genes at the reported loci remains a major challenge. Here we identify candidate causal genes for schizophrenia using an integrative genomic approach. Sherlock integrative analysis shows that ALMS1, GLT8D1, and CSNK2B are SCZ risk genes, which are validated using independent brain expression quantitative trait loci (eQTL) data and integrative analysis method (SMR). Consistently, gene expression analysis in schizophrenia cases and controls further supports the potential role of these genes in the pathogenesis of SCZ. Finally, we show that GLT8D1 and CSNK2B knockdown promote the proliferation and inhibit the differentiation abilities of neural stem cells, and alter morphology and synaptic transmission of neurons. Based on the functional roles of GLT8D1 and CSNK2B in neural stem cell, we are also characterizing the potential roles of these genes in human glioma stem/initiating cells.

This study links some of the risk variants from the largest GWAS of SCZ to specific genes, which not only provides a framework to investigate how genetic variants contribute to SCZ risk through modulating gene expression, but also provides a starting point to dissect the possible role of the identified genes in the pathophysiology of SCZ.

Yang, Cui-Ping, Li, Xiao-Yan, Wu, Yong, Shen Qiu-Shuo are the co-first authors of this paper. Chen, Yong-Bin, Luo, Xiong-Jian are the co-corresponding authors.

Link to the article：https://www.nature.com/articles/s41467-018-03247-3.