MOESM9 of Mitochondrial DNA variants correlate with symptoms in myalgic encephalomyelitis/chronic fatigue syndrome

Additional file 9: Figure S3. Quantile–quantile plots of symptoms significantly associated with mtDNA SNPs

MOESM11 of Mitochondrial DNA variants correlate with symptoms in myalgic encephalomyelitis/chronic fatigue syndrome

Additional file 11: Figure S5. Comparison of HPUI distribution between individuals with acute and gradual CFS onset

MOESM10 of Mitochondrial DNA variants correlate with symptoms in myalgic encephalomyelitis/chronic fatigue syndrome

Additional file 10: Figure S4. Boxplots of SF-36/DSQ symptom scores associated with mtDNA alleles

Accounting for eXentricities: Analysis of the X Chromosome in GWAS Reveals X-Linked Genes Implicated in Autoimmune Diseases

<div><p>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) <i>ARHGEF6</i> 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) <i>CENPI</i> 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 <i>FOXP3</i>, a transcription factor that regulates T-cell development and function, with vitiligo; and (4) we discovered that <i>C1GALT1C1</i> 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.</p></div

Gene-based associations replicating in other diseases.

<p>All genes with a discovery nominal P<1×10⁻³ that also replicated in a dataset of a <i>different</i> disease (see main text). The table mirrors <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0113684#pone-0113684-t002" target="_blank">Table 2</a>, with the only difference being whether replication is in the same disease (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0113684#pone-0113684-t002" target="_blank">Table 2</a>) or a different one (this table). Cases in which the same association is replicated in multiple datasets span several rows.</p><p>Gene-based associations replicating in other diseases.</p

Interactome of X-linked disease risk genes.

<p>All 22 X-linked protein-coding genes that showed evidence of association and replication (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0113684#pone-0113684-g001" target="_blank">Figure 1</a>) are denoted by black diamonds and are presented together with genes that interact with them (grey circles) (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0113684#s3" target="_blank">Materials and Methods</a>). <i>Physical interactions</i> refer to documented protein-protein interactions. <i>Genetic interactions</i> represent genes where perturbations to one gene affect another. <i>Predicted interactions</i> were obtained from orthology to interactions present in other organisms <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0113684#pone.0113684-WardeFarley1" target="_blank">[159]</a>. 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 <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0113684#pone-0113684-t005" target="_blank">Table 5</a>.</p

Gene-based associations replicating in similar diseases.

<p>All genes with a discovery nominal P<1×10⁻³ (in <i>Discovery dataset</i>) that also replicated in a dataset of the same or similar disease (<i>Replicated dataset</i>). Results are presented for each of the 3 tests of association, as well as for the test of sex-differential effect size, as indicated by titles in the table. For both discovery and replication, p-values of both methods of gene-based testing (truncated tail strength and truncated product) are presented. Combined p-values (last column) were calculated using Fisher's method.</p><p>Gene-based associations replicating in similar diseases.</p

Gene set associations.

<p>Three curated gene sets were tested for association with disease risk. Displayed are datasets for which P<0.05 for association with the gene set indicated in header rows (XY homologs, Panther, KEGG/GO; <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0113684#s3" target="_blank">Materials and Methods</a>). Bold p-values indicate significant associations after multiple testing correction. P-values are the minimum between that based on the truncated tail strength method and the one based on the truncated product method. Results for all datasets and tests are presented in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0113684#pone.0113684.s012" target="_blank">Table S7</a>.</p><p>Gene set associations.</p