Network-Based Analysis of Schizophrenia Genome-Wide Association Data to Detect the Joint Functional Association Signals

Abstract

Schizophrenia is a common psychiatric disorder with high heritability and complex genetic architecture. Genome-wide association studies (GWAS) have identified several significant loci associated with schizophrenia. However, the explained heritability is still low. Growing evidence has shown schizophrenia is attributable to multiple genes with moderate effects. In-depth mining and integration of GWAS data is urgently expected to uncover disease-related gene combination patterns. Network-based analysis is a promising strategy to better interpret GWAS to identify disease-related network modules. We performed a network-based analysis on three independent schizophrenia GWASs by using a refined analysis framework, which included a more accurate gene P-value calculation, dynamic network module searching algorithm and detailed functional analysis for the obtained modules genes. The result generated 79 modules including 238 genes, which form a highly connected subnetwork with more statistical significance than expected by chance. The result validated several reported disease genes, such as MAD1L1, MCC, SDCCAG8, VAT1L, MAPK14, MYH9 and FXYD6, and also obtained several novel candidate genes and gene-gene interactions. Pathway enrichment analysis of the module genes suggested they were enriched in several neural and immune system related pathways/GO terms, such as neurotrophin signaling pathway, synaptosome, regulation of protein ubiquitination, and antigen processing and presentation. Further crosstalk analysis revealed these pathways/GO terms were cooperated with each other, and identified several important genes, which might play vital roles to connect these functions. Our network-based analysis of schizophrenia GWASs will facilitate the understanding of genetic mechanisms of schizophrenia.

Sex-Specific Proteomics Changes Induced by Genetic Deletion of the Fibroblast Growth Factor 14 (FGF14) Regulator of Neuronal Ion Channels

“…Importantly, many of the proteins with significantly changed expression in the male fgf14-/-mice, including ALDH1A1, PRKAR2B, and VAT1L, have previously been linked to SZ and other neuropsychiatric disorders with a domain of cognitive symptoms (Figure 3) [63][64][65][66]. These results also further support the role of FGF14 in synaptic signaling [18,21].…”

Analysis of Gene Expression Variance in Schizophrenia Using Structural Equation Modeling

“…Pathway analysis of GWAS data, performed by The Network and Pathway Analysis Subgroup of the Psychiatric Genomics Consortium (2015) showed enrichment of several GO terms, associated with neuron structure and histone H3-K4 methylation. Analysis of GWAS data (Chang et al, 2015) resulted in a large list of enriched pathways (insulin signaling pathway, neurotrophin signaling pathway, focal adhesion, VEGF signaling pathway, GnRH signaling pathway, tight junction and regulation of actin cytoskeleton) and likely candidate pathways directly connected to those enriched (Wnt signaling pathway, adherens junction, apoptosis, calcium signaling pathway, PI3K-Akt signaling pathway, leukocyte transendothelial migration, long-term potentiation, cell cycle and MAPK signaling pathway). Analysis of GWAS together with mutation and CNV data (Kotlar et al, 2015) revealed potential involvement of the ARC signaling complex, NMDAR complex, VGCC and FMRP target pathways, which play an important role in long-term potentiation and long-term depression pathway.…”

Language deficits in schizophrenia and autism as related oscillatory connectomopathies: an evolutionary account

“…Similarly, analyses of GWA data related to SZ have revealed enrichment in several neural pathways and functions, like neurotrophin signaling pathway and synaptosome assembly (Chang et al 2015), corticogenesis and neurotransmitter homeostasis (Papaleo et al 2012), and aspects of postsynaptic density at glutamatergic synapses (Hall et al 2015).…”