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.
Highlights
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
Protein-protein interaction and other high-throughput experiments in the post-genomic era have revealed that genes tend to form complex, scale-free networks where most genes have a few connections with others and a few have a high number of interactions, commonly referred to as “hubs”, establishing them as important central genes in these gene networks[1]
Myelin is dysfunctional in schizophrenia[49] and this dysfunctionality leads to changes in synaptic formation and function, another hallmark of schizophrenia[49]
Summary
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. Measurements found only a weak correlation between disease genes and hubs, e.g. Barabasi et al.[2] found that disease genes have 32% more interactions with other proteins than non-disease genes, arguing that genetic mutations in topologically central, widely expressed genes are more likely to result in severe impairment of normal development, leading to lethality in utero and eventual deletion from the population[2] This is apparently not the case in schizophrenia, a disease that steadily affects about one percent of the population despite the lower fecundity of the affected individuals[3]. Ranking the genes for the hypermethylated probes of the positively correlating gene pairs identified the top gene as SYNGR1, a synapse-related gene whose regulatory region overlaps with one of the 108 SNP-rich loci in ref
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