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Accounting for eXentricities: analysis of the X chromosome in GWAS reveals X-linked genes implicated in autoimmune diseases.

Chang D, Gao F, Slavney A, Ma L, Waldman YY, Sams AJ, Billing-Ross P, Madar A, Spritz R, Keinan A - PLoS ONE (2014)

Bottom Line: We associated several X-linked genes with disease risk, among which (1) ARHGEF6 is associated with Crohn's disease and replicated in a study of ulcerative colitis, another inflammatory bowel disease (IBD).These and other X-linked genes that we associated with AID tend to be highly expressed in tissues related to immune response, participate in major immune pathways, and display differential gene expression between males and females.Combined, the results demonstrate the importance of the X chromosome in autoimmunity, reveal the potential of extensive XWAS, even based on existing data, and provide the tools and incentive to properly include the X chromosome in future studies.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, New York, United States of America; Program in Computational Biology and Medicine, Cornell University, Ithaca, New York, United States of America.

ABSTRACT
Many complex human diseases are highly sexually dimorphic, suggesting a potential contribution of the X chromosome to disease risk. However, the X chromosome has been neglected or incorrectly analyzed in most genome-wide association studies (GWAS). We present tailored analytical methods and software that facilitate X-wide association studies (XWAS), which we further applied to reanalyze data from 16 GWAS of different autoimmune and related diseases (AID). We associated several X-linked genes with disease risk, among which (1) ARHGEF6 is associated with Crohn's disease and replicated in a study of ulcerative colitis, another inflammatory bowel disease (IBD). Indeed, ARHGEF6 interacts with a gastric bacterium that has been implicated in IBD. (2) CENPI is associated with three different AID, which is compelling in light of known associations with AID of autosomal genes encoding centromere proteins, as well as established autosomal evidence of pleiotropy between autoimmune diseases. (3) We replicated a previous association of FOXP3, a transcription factor that regulates T-cell development and function, with vitiligo; and (4) we discovered that C1GALT1C1 exhibits sex-specific effect on disease risk in both IBDs. These and other X-linked genes that we associated with AID tend to be highly expressed in tissues related to immune response, participate in major immune pathways, and display differential gene expression between males and females. Combined, the results demonstrate the importance of the X chromosome in autoimmunity, reveal the potential of extensive XWAS, even based on existing data, and provide the tools and incentive to properly include the X chromosome in future studies.

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Interactome of X-linked disease risk genes.All 22 X-linked protein-coding genes that showed evidence of association and replication (Figure 1) are denoted by black diamonds and are presented together with genes that interact with them (grey circles) (Materials and Methods). Physical interactions refer to documented protein-protein interactions. Genetic interactions represent genes where perturbations to one gene affect another. Predicted interactions were obtained from orthology to interactions present in other organisms [159]. All but four of these 22 genes share interacting partners according to these known and predicted interactions. Results of a pathway analysis based on this interactome are presented in Table 5.
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pone-0113684-g004: Interactome of X-linked disease risk genes.All 22 X-linked protein-coding genes that showed evidence of association and replication (Figure 1) are denoted by black diamonds and are presented together with genes that interact with them (grey circles) (Materials and Methods). Physical interactions refer to documented protein-protein interactions. Genetic interactions represent genes where perturbations to one gene affect another. Predicted interactions were obtained from orthology to interactions present in other organisms [159]. All but four of these 22 genes share interacting partners according to these known and predicted interactions. Results of a pathway analysis based on this interactome are presented in Table 5.

Mentions: Third, we built an “interactome” by considering this set of 22 protein-coding genes along with genes they interact with in either protein-protein or genetic interactions (Materials and Methods). We found that 18 of these 22 genes are included in the same interaction network (Figure 4), which further supports that they interact with each other. In a pathway enrichment analysis of the resulting interactome (i.e. all genes in Figure 4), several of the significantly enriched pathways relate to immune response or specific immune-related disorders or diseases (Table 5). Another enriched pathway is that underlying lupus, which is a systemic AID. While no dataset for lupus was included in our study, the interactome is potentially enriched for genes in that pathway due to pleiotropy of genes between AID. Other significantly enriched pathways include the regulation of actin cytoskeleton, which can influence the morphology and movement of T-cells, as well as the TGF-beta signaling and ECF-receptor interaction pathways, both of which can mediate apoptosis [110], [111]. Finally, the significantly enriched Wnt signaling pathway is generally involved in cell development processes, such as cell-fate determination and cell differentiation [112]. It also plays a role in T-cell and B-cell proliferation and migration, as well as modulation of antigen presenting cells such as dendritic cells [113].


Accounting for eXentricities: analysis of the X chromosome in GWAS reveals X-linked genes implicated in autoimmune diseases.

Chang D, Gao F, Slavney A, Ma L, Waldman YY, Sams AJ, Billing-Ross P, Madar A, Spritz R, Keinan A - PLoS ONE (2014)

Interactome of X-linked disease risk genes.All 22 X-linked protein-coding genes that showed evidence of association and replication (Figure 1) are denoted by black diamonds and are presented together with genes that interact with them (grey circles) (Materials and Methods). Physical interactions refer to documented protein-protein interactions. Genetic interactions represent genes where perturbations to one gene affect another. Predicted interactions were obtained from orthology to interactions present in other organisms [159]. All but four of these 22 genes share interacting partners according to these known and predicted interactions. Results of a pathway analysis based on this interactome are presented in Table 5.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4257614&req=5

pone-0113684-g004: Interactome of X-linked disease risk genes.All 22 X-linked protein-coding genes that showed evidence of association and replication (Figure 1) are denoted by black diamonds and are presented together with genes that interact with them (grey circles) (Materials and Methods). Physical interactions refer to documented protein-protein interactions. Genetic interactions represent genes where perturbations to one gene affect another. Predicted interactions were obtained from orthology to interactions present in other organisms [159]. All but four of these 22 genes share interacting partners according to these known and predicted interactions. Results of a pathway analysis based on this interactome are presented in Table 5.
Mentions: Third, we built an “interactome” by considering this set of 22 protein-coding genes along with genes they interact with in either protein-protein or genetic interactions (Materials and Methods). We found that 18 of these 22 genes are included in the same interaction network (Figure 4), which further supports that they interact with each other. In a pathway enrichment analysis of the resulting interactome (i.e. all genes in Figure 4), several of the significantly enriched pathways relate to immune response or specific immune-related disorders or diseases (Table 5). Another enriched pathway is that underlying lupus, which is a systemic AID. While no dataset for lupus was included in our study, the interactome is potentially enriched for genes in that pathway due to pleiotropy of genes between AID. Other significantly enriched pathways include the regulation of actin cytoskeleton, which can influence the morphology and movement of T-cells, as well as the TGF-beta signaling and ECF-receptor interaction pathways, both of which can mediate apoptosis [110], [111]. Finally, the significantly enriched Wnt signaling pathway is generally involved in cell development processes, such as cell-fate determination and cell differentiation [112]. It also plays a role in T-cell and B-cell proliferation and migration, as well as modulation of antigen presenting cells such as dendritic cells [113].

Bottom Line: We associated several X-linked genes with disease risk, among which (1) ARHGEF6 is associated with Crohn's disease and replicated in a study of ulcerative colitis, another inflammatory bowel disease (IBD).These and other X-linked genes that we associated with AID tend to be highly expressed in tissues related to immune response, participate in major immune pathways, and display differential gene expression between males and females.Combined, the results demonstrate the importance of the X chromosome in autoimmunity, reveal the potential of extensive XWAS, even based on existing data, and provide the tools and incentive to properly include the X chromosome in future studies.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, New York, United States of America; Program in Computational Biology and Medicine, Cornell University, Ithaca, New York, United States of America.

ABSTRACT
Many complex human diseases are highly sexually dimorphic, suggesting a potential contribution of the X chromosome to disease risk. However, the X chromosome has been neglected or incorrectly analyzed in most genome-wide association studies (GWAS). We present tailored analytical methods and software that facilitate X-wide association studies (XWAS), which we further applied to reanalyze data from 16 GWAS of different autoimmune and related diseases (AID). We associated several X-linked genes with disease risk, among which (1) ARHGEF6 is associated with Crohn's disease and replicated in a study of ulcerative colitis, another inflammatory bowel disease (IBD). Indeed, ARHGEF6 interacts with a gastric bacterium that has been implicated in IBD. (2) CENPI is associated with three different AID, which is compelling in light of known associations with AID of autosomal genes encoding centromere proteins, as well as established autosomal evidence of pleiotropy between autoimmune diseases. (3) We replicated a previous association of FOXP3, a transcription factor that regulates T-cell development and function, with vitiligo; and (4) we discovered that C1GALT1C1 exhibits sex-specific effect on disease risk in both IBDs. These and other X-linked genes that we associated with AID tend to be highly expressed in tissues related to immune response, participate in major immune pathways, and display differential gene expression between males and females. Combined, the results demonstrate the importance of the X chromosome in autoimmunity, reveal the potential of extensive XWAS, even based on existing data, and provide the tools and incentive to properly include the X chromosome in future studies.

Show MeSH
Related in: MedlinePlus