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Protein-protein interaction analysis highlights additional loci of interest for multiple sclerosis.

Ragnedda G, Disanto G, Giovannoni G, Ebers GC, Sotgiu S, Ramagopalan SV - PLoS ONE (2012)

Bottom Line: Using the Disease Association Protein-Protein Link Evaluator tool we found that direct interactions among genetic products were significantly higher than expected by chance when considering both significant regions alone (p<0.0002) and significant plus suggestive (p<0.007).Using the gene portal BioGPS, we tested the expression of these genes in 24 different tissues and found the highest values among immune-related cells as compared to non-immune tissues (p<0.001).A gene ontology analysis confirmed the immune-related functions of these genes.

View Article: PubMed Central - PubMed

Affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.

ABSTRACT
Genetic factors play an important role in determining the risk of multiple sclerosis (MS). The strongest genetic association in MS is located within the major histocompatibility complex class II region (MHC), but more than 50 MS loci of modest effect located outside the MHC have now been identified. However, the relative candidate genes that underlie these associations and their functions are largely unknown. We conducted a protein-protein interaction (PPI) analysis of gene products coded in loci recently reported to be MS associated at the genome-wide significance level and in loci suggestive of MS association. Our aim was to identify which suggestive regions are more likely to be truly associated, which genes are mostly implicated in the PPI network and their expression profile. From three recent independent association studies, SNPs were considered and divided into significant and suggestive depending on the strength of the statistical association. Using the Disease Association Protein-Protein Link Evaluator tool we found that direct interactions among genetic products were significantly higher than expected by chance when considering both significant regions alone (p<0.0002) and significant plus suggestive (p<0.007). The number of genes involved in the network was 43. Of these, 23 were located within suggestive regions and many of them directly interacted with proteins coded within significant regions. These included genes such as SYK, IL-6, CSF2RB, FCLR3, EIF4EBP2 and CHST12. Using the gene portal BioGPS, we tested the expression of these genes in 24 different tissues and found the highest values among immune-related cells as compared to non-immune tissues (p<0.001). A gene ontology analysis confirmed the immune-related functions of these genes. In conclusion, loci currently suggestive of MS association interact with and have similar expression profiles and function as those significantly associated, highlighting the fact that more common variants remain to be found to be associated to MS.

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Related in: MedlinePlus

Direct connections among gene products from MS significant regions.Colours indicate significance of participation in the PPI network.
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pone-0046730-g001: Direct connections among gene products from MS significant regions.Colours indicate significance of participation in the PPI network.

Mentions: Our first aim was to assess the extent of PPI interactions among genes located within genomic regions with definite association with MS susceptibility. We therefore submitted into DAPPLE the 67 SNPs with genome-wide significant association with MS risk. There were a total of 75 proteins participating in the direct network with 104 direct interactions (expected direct interactions = 61, p<0.0002) (Table 1, Figure 1 and Table S1). The mean associated protein direct connectivity was 2.7 (expected = 1.7, p<0.0002). The mean associated protein indirect connectivity was 52.2 (expected = 43.8, p = 0.04) and the mean common interactor connectivity was 4.5. (expected = 3.9, p = 0.0002). The total number of genes implicated in the network was 215 (Table S1). The total number of genes that had more connections than expected by chance (genes to prioritize) was 22 and included previously shown putative candidate genes such as IL-12A, SOCS-1, CBLB, MALT-1, IL-22RA, MAPK-1 and IL-7R.


Protein-protein interaction analysis highlights additional loci of interest for multiple sclerosis.

Ragnedda G, Disanto G, Giovannoni G, Ebers GC, Sotgiu S, Ramagopalan SV - PLoS ONE (2012)

Direct connections among gene products from MS significant regions.Colours indicate significance of participation in the PPI network.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3475710&req=5

pone-0046730-g001: Direct connections among gene products from MS significant regions.Colours indicate significance of participation in the PPI network.
Mentions: Our first aim was to assess the extent of PPI interactions among genes located within genomic regions with definite association with MS susceptibility. We therefore submitted into DAPPLE the 67 SNPs with genome-wide significant association with MS risk. There were a total of 75 proteins participating in the direct network with 104 direct interactions (expected direct interactions = 61, p<0.0002) (Table 1, Figure 1 and Table S1). The mean associated protein direct connectivity was 2.7 (expected = 1.7, p<0.0002). The mean associated protein indirect connectivity was 52.2 (expected = 43.8, p = 0.04) and the mean common interactor connectivity was 4.5. (expected = 3.9, p = 0.0002). The total number of genes implicated in the network was 215 (Table S1). The total number of genes that had more connections than expected by chance (genes to prioritize) was 22 and included previously shown putative candidate genes such as IL-12A, SOCS-1, CBLB, MALT-1, IL-22RA, MAPK-1 and IL-7R.

Bottom Line: Using the Disease Association Protein-Protein Link Evaluator tool we found that direct interactions among genetic products were significantly higher than expected by chance when considering both significant regions alone (p<0.0002) and significant plus suggestive (p<0.007).Using the gene portal BioGPS, we tested the expression of these genes in 24 different tissues and found the highest values among immune-related cells as compared to non-immune tissues (p<0.001).A gene ontology analysis confirmed the immune-related functions of these genes.

View Article: PubMed Central - PubMed

Affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.

ABSTRACT
Genetic factors play an important role in determining the risk of multiple sclerosis (MS). The strongest genetic association in MS is located within the major histocompatibility complex class II region (MHC), but more than 50 MS loci of modest effect located outside the MHC have now been identified. However, the relative candidate genes that underlie these associations and their functions are largely unknown. We conducted a protein-protein interaction (PPI) analysis of gene products coded in loci recently reported to be MS associated at the genome-wide significance level and in loci suggestive of MS association. Our aim was to identify which suggestive regions are more likely to be truly associated, which genes are mostly implicated in the PPI network and their expression profile. From three recent independent association studies, SNPs were considered and divided into significant and suggestive depending on the strength of the statistical association. Using the Disease Association Protein-Protein Link Evaluator tool we found that direct interactions among genetic products were significantly higher than expected by chance when considering both significant regions alone (p<0.0002) and significant plus suggestive (p<0.007). The number of genes involved in the network was 43. Of these, 23 were located within suggestive regions and many of them directly interacted with proteins coded within significant regions. These included genes such as SYK, IL-6, CSF2RB, FCLR3, EIF4EBP2 and CHST12. Using the gene portal BioGPS, we tested the expression of these genes in 24 different tissues and found the highest values among immune-related cells as compared to non-immune tissues (p<0.001). A gene ontology analysis confirmed the immune-related functions of these genes. In conclusion, loci currently suggestive of MS association interact with and have similar expression profiles and function as those significantly associated, highlighting the fact that more common variants remain to be found to be associated to MS.

Show MeSH
Related in: MedlinePlus