Limits...
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.


Related in: MedlinePlus

Gene networks of hub genes generated from hypermethylated Malacards-annotated genes.(A) SYNGR1-centered, positively correlating gene network. The red-colored edges show correlations with SYNGR1. (B) Negatively correlating gene network, centered on MOBP. All the red-colored edges show negative correlations with MOBP. All the other pairwise negative correlations are shown in grey. The purple-colored genes overlap with 108 highly mutated genomic loci in schizophrenics (see text for details). (C) The combined network in (A and B). All light green-colored genes correlate positively with SYNGR1 and negatively with MOBP. The purple-colored and turquoise-colored genes correlate only with MOBP or SYNGR1, respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC5382542&req=5

f3: Gene networks of hub genes generated from hypermethylated Malacards-annotated genes.(A) SYNGR1-centered, positively correlating gene network. The red-colored edges show correlations with SYNGR1. (B) Negatively correlating gene network, centered on MOBP. All the red-colored edges show negative correlations with MOBP. All the other pairwise negative correlations are shown in grey. The purple-colored genes overlap with 108 highly mutated genomic loci in schizophrenics (see text for details). (C) The combined network in (A and B). All light green-colored genes correlate positively with SYNGR1 and negatively with MOBP. The purple-colored and turquoise-colored genes correlate only with MOBP or SYNGR1, respectively.

Mentions: The existence of the two kinds of hub genes with high numbers of positive or negative correlating partners raises the question about their functionality and the underlying neurobiological pathways: are they related or do they form mostly separate networks? To answer this question we constructed three gene networks (Fig. 3): two representing the positive and negative correlations only for SYNGR1 and MOBP, respectively (Fig. 3a,b), and one (Fig. 3c) showing a combined network of the two. We chose SYNGR1 for the positive hub for it is the top ranking gene in Table 1 and is also located in one of the PGC regions whereas we chose MOBP because it ranks highly among the anti-correlating genes, indicating a putative regulatory function, which, however, has not been observed yet experimentally.


Connecting myelin-related and synaptic dysfunction in schizophrenia with SNP-rich gene expression hubs
Gene networks of hub genes generated from hypermethylated Malacards-annotated genes.(A) SYNGR1-centered, positively correlating gene network. The red-colored edges show correlations with SYNGR1. (B) Negatively correlating gene network, centered on MOBP. All the red-colored edges show negative correlations with MOBP. All the other pairwise negative correlations are shown in grey. The purple-colored genes overlap with 108 highly mutated genomic loci in schizophrenics (see text for details). (C) The combined network in (A and B). All light green-colored genes correlate positively with SYNGR1 and negatively with MOBP. The purple-colored and turquoise-colored genes correlate only with MOBP or SYNGR1, respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f3: Gene networks of hub genes generated from hypermethylated Malacards-annotated genes.(A) SYNGR1-centered, positively correlating gene network. The red-colored edges show correlations with SYNGR1. (B) Negatively correlating gene network, centered on MOBP. All the red-colored edges show negative correlations with MOBP. All the other pairwise negative correlations are shown in grey. The purple-colored genes overlap with 108 highly mutated genomic loci in schizophrenics (see text for details). (C) The combined network in (A and B). All light green-colored genes correlate positively with SYNGR1 and negatively with MOBP. The purple-colored and turquoise-colored genes correlate only with MOBP or SYNGR1, respectively.
Mentions: The existence of the two kinds of hub genes with high numbers of positive or negative correlating partners raises the question about their functionality and the underlying neurobiological pathways: are they related or do they form mostly separate networks? To answer this question we constructed three gene networks (Fig. 3): two representing the positive and negative correlations only for SYNGR1 and MOBP, respectively (Fig. 3a,b), and one (Fig. 3c) showing a combined network of the two. We chose SYNGR1 for the positive hub for it is the top ranking gene in Table 1 and is also located in one of the PGC regions whereas we chose MOBP because it ranks highly among the anti-correlating genes, indicating a putative regulatory function, which, however, has not been observed yet experimentally.

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.


Related in: MedlinePlus