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Connecting myelin-related and synaptic dysfunction in schizophrenia with SNP-rich gene expression hubs

View Article: PubMed Central - PubMed

ABSTRACT

35 times32 times: 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 higher for the positively correlating genes ( 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.

No MeSH data available.


(A) All positively correlating genes in the 108 loci. The network is again centered on SYNGR1. The red-colored edges show correlations with SYNGR1. (B) All the genes in the 108 loci that correlate negatively with MOBP (edges colored red) or one another (grey edges). (C) The combined network in (A and B). All light green-colored genes correlate positively with SYNGR1 and negatively with MOBP (edges show in red in both cases). The purple-colored and turquoise-colored genes correlate only with MOBP or SYNGR1 (of the two), respectively.
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f4: (A) All positively correlating genes in the 108 loci. The network is again centered on SYNGR1. The red-colored edges show correlations with SYNGR1. (B) All the genes in the 108 loci that correlate negatively with MOBP (edges colored red) or one another (grey edges). (C) The combined network in (A and B). All light green-colored genes correlate positively with SYNGR1 and negatively with MOBP (edges show in red in both cases). The purple-colored and turquoise-colored genes correlate only with MOBP or SYNGR1 (of the two), respectively.

Mentions: We repeated the selection process replacing the Malacards-genes with the 108-loci genes. This resulted in a similar number of interacting genes that correlate positively with SYNGR1 (50 genes) and negatively with MOBP (48 genes). They share 39 common genes (Fig. 4). Biological processes derived from a Gene Ontology44 analysis of the shared genes either in the Malacards set or the 108-loci set and in both cases shared between SYNGR1 and MOBP and significantly enriched (p-value < 0.05) for both sets are shown in Table 3. For both gene sets the top two biological processes with the highest significance are “synaptic transmission” and “modulation of synaptic transmission”.


Connecting myelin-related and synaptic dysfunction in schizophrenia with SNP-rich gene expression hubs
(A) All positively correlating genes in the 108 loci. The network is again centered on SYNGR1. The red-colored edges show correlations with SYNGR1. (B) All the genes in the 108 loci that correlate negatively with MOBP (edges colored red) or one another (grey edges). (C) The combined network in (A and B). All light green-colored genes correlate positively with SYNGR1 and negatively with MOBP (edges show in red in both cases). The purple-colored and turquoise-colored genes correlate only with MOBP or SYNGR1 (of the two), respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5382542&req=5

f4: (A) All positively correlating genes in the 108 loci. The network is again centered on SYNGR1. The red-colored edges show correlations with SYNGR1. (B) All the genes in the 108 loci that correlate negatively with MOBP (edges colored red) or one another (grey edges). (C) The combined network in (A and B). All light green-colored genes correlate positively with SYNGR1 and negatively with MOBP (edges show in red in both cases). The purple-colored and turquoise-colored genes correlate only with MOBP or SYNGR1 (of the two), respectively.
Mentions: We repeated the selection process replacing the Malacards-genes with the 108-loci genes. This resulted in a similar number of interacting genes that correlate positively with SYNGR1 (50 genes) and negatively with MOBP (48 genes). They share 39 common genes (Fig. 4). Biological processes derived from a Gene Ontology44 analysis of the shared genes either in the Malacards set or the 108-loci set and in both cases shared between SYNGR1 and MOBP and significantly enriched (p-value < 0.05) for both sets are shown in Table 3. For both gene sets the top two biological processes with the highest significance are “synaptic transmission” and “modulation of synaptic transmission”.

View Article: PubMed Central - PubMed

ABSTRACT

35 times32 times: 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 &ldquo;expression neighbors&rdquo; 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 higher for the positively correlating genes ( 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.

No MeSH data available.