title: Connecting myelin-related and synaptic dysfunction in schizophrenia with SNP-rich gene expression hubs.
abstract: Combining genome-wide mapping of SNP-rich regions in schizophrenics and gene expression data in all brain compartments across the human life span revealed that genes with promoters most frequently mutated in schizophrenia are expression hubs interacting with far more genes than the rest of the genome. We summed up the differentially methylated "expression neighbors" of genes that fall into one of 108 distinct schizophrenia-associated loci with high number of SNPs. Surprisingly, the number of expression neighbors of the genes in these loci were 35 times higher for the positively correlating genes (32 times higher for the negatively correlating ones) than for the rest of the ~16000 genes. While the genes in the 108 loci have little known impact in schizophrenia, we identified many more known schizophrenia-related important genes with a high degree of connectedness (e.g. MOBP, SYNGR1 and DGCR6), validating our approach. Both the most connected positive and negative hubs affected synapse-related genes the most, supporting the synaptic origin of schizophrenia. At least half of the top genes in both the correlating and anti-correlating categories are cancer-related, including oncogenes (RRAS and ALDOA), providing further insight into the observed inverse relationship between the two diseases.
authors.affiliation: CEITEC - Central European Institute of Technology, Masaryk University, 62500 Brno, Czech Republic.
authors.forename: Hedi
authors.initials: H
authors.lastname: Hegyi
mesh_terms: D001921:Brain / Q000378:metabolism; D019175:DNA Methylation; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D053263:Gene Regulatory Networks / Q000235:genetics; D056426:Genetic Loci; D006801:Humans; D009185:Myelin Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012559:Schizophrenia / Q000235:genetics / Q000473:pathology*; D013569:Synapses / Q000378:metabolism*; D062805:Synaptogyrins / Q000235:genetics / Q000378:metabolism
chemical_list: C101273:DGCR6 protein, human; D016326:Extracellular Matrix Proteins; C560487:MOBP protein, human; D009185:Myelin Proteins; D009687:Nuclear Proteins; C507923:SYNGR1 protein, human; D062805:Synaptogyrins