Integrated Pathway-Based Approach Identifies Association between Genomic Regions at CTCF and CACNB2 and Schizophrenia

Abstract

In the present study, an integrated hierarchical approach was applied to: (1) identify pathways associated with susceptibility to schizophrenia; (2) detect genes that may be potentially affected in these pathways since they contain an associated polymorphism; and (3) annotate the functional consequences of such single-nucleotide polymorphisms (SNPs) in the affected genes or their regulatory regions. The Global Test was applied to detect schizophrenia-associated pathways using discovery and replication datasets comprising 5,040 and 5,082 individuals of European ancestry, respectively. Information concerning functional gene-sets was retrieved from the Kyoto Encyclopedia of Genes and Genomes, Gene Ontology, and the Molecular Signatures Database. Fourteen of the gene-sets or pathways identified in the discovery dataset were confirmed in the replication dataset. These include functional processes involved in transcriptional regulation and gene expression, synapse organization, cell adhesion, and apoptosis. For two genes, i.e. CTCF and CACNB2, evidence for association with schizophrenia was available (at the gene-level) in both the discovery study and published data from the Psychiatric Genomics Consortium schizophrenia study. Furthermore, these genes mapped to four of the 14 presently identified pathways. Several of the SNPs assigned to CTCF and CACNB2 have potential functional consequences, and a gene in close proximity to CACNB2, i.e. ARL5B, was identified as a potential gene of interest. Application of the present hierarchical approach thus allowed: (1) identification of novel biological gene-sets or pathways with potential involvement in the etiology of schizophrenia, as well as replication of these findings in an independent cohort; (2) detection of genes of interest for future follow-up studies; and (3) the highlighting of novel genes in previously reported candidate regions for schizophrenia.

Integrative transcriptome network analysis of iPSC-derived neurons from schizophrenia and schizoaffective disorder patients with 22q11.2 deletion

“…Several studies have provided support to the hypothesis by showing increased brain Bax/Bcl-2 ratios and decreased levels of Bcl-2 and GSK3 [114–116]. In addition, a comprehensive integrated pathway analysis of GWAS and gene expression data also pointed to aberrant apoptosis as a potential cause of SZ [110]. In our study, we found similar evidence.…”

Genetic Sources of Subcomponents of Event-Related Potential in the Dimension of Psychosis Analyzed From the B-SNIP Study

“…Findings from the current study point to converging evidence from pathway-based studies that identified similar biological mechanisms including axon guidance (91-93), cell adhesion (94, 95), inflammation and immune system (96) associated with SZ risk. A recent BSNIP resting fMRI-genetic study (32) using Para-ICA identified similar processes including developmental neurogenesis, axon guidance, synaptic and cadherin cell adhesion, immune response, nervous system development, ceramide and sphingosine pathways mediating aberrant default mode activity in psychosis.…”

The Future is The Past: Methylation QTLs in Schizophrenia

“…These findings point to a potential mechanism of action underlying meQTL function and molecular consequences. In support of a role in SCZ, CTCF has been recently identified in an integrated pathway approach for pathways and genes affected in SCZ [75]. Together, these findings suggest a regulatory role for fetal meQTLs and highlight with CTCF an important mechanism connecting genomic variation to genomic function.…”