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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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Three X-linked disease risk genes show high expression in immune-related tissues and cells.ARHGEF6 (a), IL13RA1 (b), and ITM2A (c) show expression greater than 4 standard deviations above the average expression of these genes in T-cells (highest in CD4+ in purple), CD14+ monocytes (blue), and the thymus (red), respectively. Y-axis follows the respective tissues from Figure 2 and x-axis denotes a z-score for the deviation of expression in each tissue from the average expression of that gene. The title of each panel includes the name of the gene and the tissue with the highest expression for that gene.
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pone-0113684-g003: Three X-linked disease risk genes show high expression in immune-related tissues and cells.ARHGEF6 (a), IL13RA1 (b), and ITM2A (c) show expression greater than 4 standard deviations above the average expression of these genes in T-cells (highest in CD4+ in purple), CD14+ monocytes (blue), and the thymus (red), respectively. Y-axis follows the respective tissues from Figure 2 and x-axis denotes a z-score for the deviation of expression in each tissue from the average expression of that gene. The title of each panel includes the name of the gene and the tissue with the highest expression for that gene.

Mentions: We set out to explore in three analyses the biological function of our associated disease risk genes by considering all 22 protein-coding genes we discovered and replicated with any AID or other complex disease tested. First, we investigated the gene expression patterns of 13 of these genes for which we could obtain tissue-specific expression data (Materials and Methods). Three of these genes show the highest expression in cells and organs directly involved in the immune system (Figures 2–3): ARHGEF6 is most highly expressed in T-cells, IL13RA1 in CD14+ monocytes, and ITM2A in the thymus (in which T-cells develop). Three of the remaining genes, MCF2 (associated with vitiligo), NAP1L2 and TMEM35 (associated with ALS), exhibit the highest expression levels in the pineal gland (Figure 2). The pineal gland produces and secretes melatonin, which interacts with the immune system [102], [103] and has been implicated in both vitiligo and ALS [102], [104]–[108], as well as suggested as a possible treatment for ALS [109].


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)

Three X-linked disease risk genes show high expression in immune-related tissues and cells.ARHGEF6 (a), IL13RA1 (b), and ITM2A (c) show expression greater than 4 standard deviations above the average expression of these genes in T-cells (highest in CD4+ in purple), CD14+ monocytes (blue), and the thymus (red), respectively. Y-axis follows the respective tissues from Figure 2 and x-axis denotes a z-score for the deviation of expression in each tissue from the average expression of that gene. The title of each panel includes the name of the gene and the tissue with the highest expression for that gene.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0113684-g003: Three X-linked disease risk genes show high expression in immune-related tissues and cells.ARHGEF6 (a), IL13RA1 (b), and ITM2A (c) show expression greater than 4 standard deviations above the average expression of these genes in T-cells (highest in CD4+ in purple), CD14+ monocytes (blue), and the thymus (red), respectively. Y-axis follows the respective tissues from Figure 2 and x-axis denotes a z-score for the deviation of expression in each tissue from the average expression of that gene. The title of each panel includes the name of the gene and the tissue with the highest expression for that gene.
Mentions: We set out to explore in three analyses the biological function of our associated disease risk genes by considering all 22 protein-coding genes we discovered and replicated with any AID or other complex disease tested. First, we investigated the gene expression patterns of 13 of these genes for which we could obtain tissue-specific expression data (Materials and Methods). Three of these genes show the highest expression in cells and organs directly involved in the immune system (Figures 2–3): ARHGEF6 is most highly expressed in T-cells, IL13RA1 in CD14+ monocytes, and ITM2A in the thymus (in which T-cells develop). Three of the remaining genes, MCF2 (associated with vitiligo), NAP1L2 and TMEM35 (associated with ALS), exhibit the highest expression levels in the pineal gland (Figure 2). The pineal gland produces and secretes melatonin, which interacts with the immune system [102], [103] and has been implicated in both vitiligo and ALS [102], [104]–[108], as well as suggested as a possible treatment for ALS [109].

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