Abstract
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 schizophrenia 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 three genes in the pathogenesis of schizophrenia. 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. These convergent lines of evidence suggest that the ALMS1, CSNK2B, and GLT8D1 genes may be involved in pathophysiology of schizophrenia.
Highlights
Recent genome-wide association studies (GWAS) have identified multiple risk loci that show strong associations with schizophrenia
To explore whether the newly identified SCZassociated expression-associated SNPs (eSNPs) of AMLS1, GLT8D1, and CSNK2B are associated with hippocampal structure in normal individuals, we examined the association between eSNPs of AMLS1, GLT8D1, CSNK2B (Table 1), and hippocampal structure using the data from the Enhanced Neuro Imaging Genetics through Meta-Analysis (ENIGMA) consortium[46]
We further investigated the functional roles of GLT8D1 and CSNK2B in neural stem cells (NSCs) differentiation and found that the ratio of Tuj[1], microtubule-associated protein 2 (MAP2, a marker of mature neurons), glial fibrillary acidic protein (GFAP, a marker of glia cells), and O4positive cells, as well as the mRNA expression levels of the key NSCs differentiation regulators, such as Neurod[1], Gfap, oligo[1], and oligo[2] were significantly decreased in GLT8D1 and CSNK2B knockdown groups compared with controls (Figs. 4 and 5a, b, and Supplementary Fig. 9), indicating that the differentiation abilities of NSCs were impaired by GLT8D1 and CSNK2B knockdown
Summary
Recent genome-wide association studies (GWAS) have identified multiple risk loci that show strong associations with schizophrenia. Despite the fact that multiple promising candidate genes have been identified by genetic linkage and association studies[21,22], the vast majority of the heritability of SCZ remains unexplained. To identify genes whose expression levels are affected by SCZ risk variants and to explore the potential role of these genes in SCZ pathogenesis, we performed comprehensive integrative analyses by integrating data from different layers, including genetic associations from largescale GWAS (PGC2)[20], brain expression quantitative trait loci (eQTL), protein–protein interaction (PPI), co-expression, spatiotemporal expression pattern, differential gene expression in SCZ cases and controls, association with human brain structure, and in vitro functional studies. Our integrative analyses showed that ALMS1, CSNK2B, and GLT8D1 genes may represent promising risk genes for SCZ
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