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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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X-linked genes associated with autoimmune disease risk.All genes that showed evidence of association in a gene-based test and replication, including suggestive replication in any other dataset (see main text) are presented for the a) FMS.comb b) FMF.comb c) FM02 and d) sex-differentiated effect size tests (Materials and Methods). X-axis denotes the different datasets, with their names following the notation from Table 1. Y-axis displays the different gene names. For each gene, the more significant p-value of the truncated tail strength and truncated product methods is displayed on a −log10 scale according to the enclosed color scale. A “*” represents the discovery dataset and “**” indicates datasets in which replication is significant after correcting for the number of genes tested for replication. These appear in grey when the discovery and replication are in datasets of the same disease (or across the related Crohn's disease and ulcerative colitis). Numerical values corresponding to this figure are presented in Tables 2–3.
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pone-0113684-g001: X-linked genes associated with autoimmune disease risk.All genes that showed evidence of association in a gene-based test and replication, including suggestive replication in any other dataset (see main text) are presented for the a) FMS.comb b) FMF.comb c) FM02 and d) sex-differentiated effect size tests (Materials and Methods). X-axis denotes the different datasets, with their names following the notation from Table 1. Y-axis displays the different gene names. For each gene, the more significant p-value of the truncated tail strength and truncated product methods is displayed on a −log10 scale according to the enclosed color scale. A “*” represents the discovery dataset and “**” indicates datasets in which replication is significant after correcting for the number of genes tested for replication. These appear in grey when the discovery and replication are in datasets of the same disease (or across the related Crohn's disease and ulcerative colitis). Numerical values corresponding to this figure are presented in Tables 2–3.

Mentions: We detected 54 unique genes that passed the initial discovery criterion in one or more of the 16 datasets. Of these, 38 genes were significant based on the FM02 test, 22 based on the FMF.comb test, and 34 in the FMS.comb test (Tables S3, S4), with overlap between the three tests due to their statistical dependence. For 42 of these 54 genes, we had an independent dataset for the same or related disease with which to attempt replication. Of these 42 genes, 5 (12%) successfully replicated, with 3 of the 5 both discovered and replicated based on more than one of the three tests (Figure 1a–c and Table 2). These include 3 genes (FOXP3, PPP1R3F and GAGE10) in LD for the FM02 test and 3 genes (PPP1R3F, GAGE12H and GAGE10) in LD for the FMS.comb test that are associated with vitiligo. To reduce the level of LD, we repeated the gene-based testing without the flanking region of 15 kb around each gene. All genes still successfully replicated in this case, though it remains unclear whether these represent independent signals or remain in LD with the same—likely unobserved—causal variant(s).


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)

X-linked genes associated with autoimmune disease risk.All genes that showed evidence of association in a gene-based test and replication, including suggestive replication in any other dataset (see main text) are presented for the a) FMS.comb b) FMF.comb c) FM02 and d) sex-differentiated effect size tests (Materials and Methods). X-axis denotes the different datasets, with their names following the notation from Table 1. Y-axis displays the different gene names. For each gene, the more significant p-value of the truncated tail strength and truncated product methods is displayed on a −log10 scale according to the enclosed color scale. A “*” represents the discovery dataset and “**” indicates datasets in which replication is significant after correcting for the number of genes tested for replication. These appear in grey when the discovery and replication are in datasets of the same disease (or across the related Crohn's disease and ulcerative colitis). Numerical values corresponding to this figure are presented in Tables 2–3.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0113684-g001: X-linked genes associated with autoimmune disease risk.All genes that showed evidence of association in a gene-based test and replication, including suggestive replication in any other dataset (see main text) are presented for the a) FMS.comb b) FMF.comb c) FM02 and d) sex-differentiated effect size tests (Materials and Methods). X-axis denotes the different datasets, with their names following the notation from Table 1. Y-axis displays the different gene names. For each gene, the more significant p-value of the truncated tail strength and truncated product methods is displayed on a −log10 scale according to the enclosed color scale. A “*” represents the discovery dataset and “**” indicates datasets in which replication is significant after correcting for the number of genes tested for replication. These appear in grey when the discovery and replication are in datasets of the same disease (or across the related Crohn's disease and ulcerative colitis). Numerical values corresponding to this figure are presented in Tables 2–3.
Mentions: We detected 54 unique genes that passed the initial discovery criterion in one or more of the 16 datasets. Of these, 38 genes were significant based on the FM02 test, 22 based on the FMF.comb test, and 34 in the FMS.comb test (Tables S3, S4), with overlap between the three tests due to their statistical dependence. For 42 of these 54 genes, we had an independent dataset for the same or related disease with which to attempt replication. Of these 42 genes, 5 (12%) successfully replicated, with 3 of the 5 both discovered and replicated based on more than one of the three tests (Figure 1a–c and Table 2). These include 3 genes (FOXP3, PPP1R3F and GAGE10) in LD for the FM02 test and 3 genes (PPP1R3F, GAGE12H and GAGE10) in LD for the FMS.comb test that are associated with vitiligo. To reduce the level of LD, we repeated the gene-based testing without the flanking region of 15 kb around each gene. All genes still successfully replicated in this case, though it remains unclear whether these represent independent signals or remain in LD with the same—likely unobserved—causal variant(s).

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