Meta-analysis of shared genetic architecture across ten pediatric autoimmune diseases

Abstract

Genome-wide association studies (GWASs) have identified hundreds of susceptibility genes, including shared associations across clinically distinct autoimmune diseases. We performed an inverse χ2 meta-analysis across ten pediatric-age-of-onset autoimmune diseases (pAIDs) in a case-control study including more than 6,035 cases and 10,718 shared population-based controls. We identified 27 genome-wide significant loci associated with one or more pAIDs, mapping to in silico–replicated autoimmune-associated genes (including IL2RA) and new candidate loci with established immunoregulatory functions such as ADGRL2, TENM3, ANKRD30A, ADCY7 and CD40LG. The pAID-associated single-nucleotide polymorphisms (SNPs) were functionally enriched for deoxyribonuclease (DNase)-hypersensitivity sites, expression quantitative trait loci (eQTLs), microRNA (miRNA)-binding sites and coding variants. We also identified biologically correlated, pAID-associated candidate gene sets on the basis of immune cell expression profiling and found evidence of genetic sharing. Network and protein-interaction analyses demonstrated converging roles for the signaling pathways of type 1, 2 and 17 helper T cells (TH1, TH2 and TH17), JAK-STAT, interferon and interleukin in multiple autoimmune diseases.

Tie2 protects the vasculature against thrombus formation in systemic inflammation

“…In contrast, understanding of how the endothelium, which undergoes profound changes in response to systemic inflamma- (34,35). One hundred and seventy-three of the 202 hits in sepsis DIC (P value cutoff ≤ 0.05, Figure 1A) formed distinct interacting protein clusters that were highly enriched in pathways associated with coagulation, vascular function, complement, and endothelial inflammation ( Figure 1C).…”

Common susceptibility variants are shared between schizophrenia and psoriasis in the Han Chinese population

“…[19][20][21][22][23][24][25][26] This trend appears to be even more pronounced in diseases of autoimmune origin. 27 In this light, we tested our hypothesis of a shared genetic basis of schizophrenia and psoriasis using large cohorts previously studied in independent GWAS.…”

Genome-wide association study of clinical parameters in immunoglobulin light chain amyloidosis in three patient cohorts

“…The three data sets were combined in meta-analysis and heterogeneity was assessed by the I by standard error. 4 Long-range promoter contacts were probed by high-resolution capture Hi-C in GM12878 cells.…”