Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci

Abstract

We simultaneously investigated the genetic landscape of ankylosing spondylitis, Crohn's disease, psoriasis, primary sclerosing cholangitis and ulcerative colitis to investigate pleiotropy and the relationship between these clinically related diseases. Using high-density genotype data from more than 86,000 individuals of European-ancestry we identified 244 independent multi-disease signals including 27 novel genome-wide significant susceptibility loci and 3 unreported shared risk loci. Complex pleiotropy was supported when contrasting multi-disease signals with expression data sets from human, rat and mouse, and epigenetic and expressed enhancer profiles. The comorbidities among the five immune diseases were best explained by biological pleiotropy rather than heterogeneity (a subgroup of cases that is genetically identical to another disease, possibly due to diagnostic misclassification, molecular subtypes, or excessive comorbidity). In particular, the strong comorbidity between primary sclerosing cholangitis and inflammatory bowel disease is likely the result of a unique disease, which is genetically distinct from classical inflammatory bowel disease phenotypes.

10 Years of GWAS Discovery: Biology, Function, and Translation

“…[20][21][22] In the case of auto-immune diseases, evidence implies that at some loci, the same causal variants are driving the observations of associations across diseases. [23][24][25] Fourth, analytical methods that estimate genetic correlations from GWAS data have provided evidence for widespread pleiotropy. 20,26 The corollary of pervasive pleiotropy for complex traits is that the paradigm of ''one gene, one function, one trait'' is the wrong way to view genetic variation in the human genome (and the same applies for studying disease in experimental organisms).…”

“…A recent cross-disease study involving the conditions ankylosing spondylitis (AS [MIM: 106300]), inflammatory bowel disease (IBD [MIM: 266600]), primary sclerosing cholangitis (MIM: 613806), and psoriasis identified without any further genotyping 30 new loci at genome-wide significance. 24 Transethnic studies have demonstrated substantial genetic overlap between ethnically remote populations; 106 109 The SNP leads to loss of the transmembrane domain of the receptor, and the risk SNP for MS (protective for AS) leads to increased serum soluble TNF receptor. 110 TNF inhibition, including by decoy TNF receptor therapies, is highly effective for AS and many other immune-mediated diseases, but its use can be complicated by de novo development of MS, and in MS itself, it can exacerbate disease.…”

Systematic Analysis of GWAS Data Reveals Genomic Hotspots for Shared Mechanisms between Neurodegenerative Diseases

“…Such pleiotropic variants are particularly interesting, as the functional impact of a SNP on one or several genes may provide clues about the underlying molecular mechanism. For example, a significant overlap of shared genetic variants and pathways has been detected in immune-mediated diseases, suggesting extensive pleiotropic effects [6][7][8]. These shared genetics variants linked to pathways are ideally suited to identify candidate mechanisms underlying a "shared aetiology" of different diseases.…”

The role of human CD1c+ DCs at activating innate and adaptive immune responses

“…Genome-wide association studies (GWAS) have identified several other genes other than HLA-B*27 are associated with AS pathology including IL23R, TYK2, JAK2, STAT3 and IL12B (encodes for IL-12p40 subunit) suggest the importance of IL-23 signalling in AS pathology (Cortes et al, 2015, Ellinghaus et al, 2016, International Genetics of Ankylosing Spondylitis et al, 2013. Given the importance of IL-23 in maintaining memory Th17 cells (Wilson et al, 2007), these studies implicated that IL-23-Th17 axis in AS pathology.…”

“…GWAS have identified several other genes other than HLA-B*27 are associated with AS pathology including IL23R, TYK2, JAK2, STAT3 and IL12B (encodes for IL-12p40 subunit) suggest the importance of IL-23 signalling in AS pathology (Cortes et al, 2015, Ellinghaus et al, 2016, International Genetics of Ankylosing Spondylitis et al, 2013. Furthermore, a proof-of-concept clinical trial of ustekinumab (IL-12p40 neutralising monoclonal antibody) was recently conducted and demonstrated effectiveness in AS patients (Poddubnyy et al, 2014).…”