A cross-disease meta-GWAS identifies four new susceptibility loci shared between systemic sclerosis and Crohn's disease

Abstract

Genome-wide association studies (GWASs) have identified a number of genetic risk loci associated with systemic sclerosis (SSc) and Crohn's disease (CD), some of which confer susceptibility to both diseases. In order to identify new risk loci shared between these two immune-mediated disorders, we performed a cross-disease meta-analysis including GWAS data from 5,734 SSc patients, 4,588 CD patients and 14,568 controls of European origin. We identified 4 new loci shared between SSc and CD, IL12RB2, IRF1/SLC22A5, STAT3 and an intergenic locus at 6p21.31. Pleiotropic variants within these loci showed opposite allelic effects in the two analysed diseases and all of them showed a significant effect on gene expression. In addition, an enrichment in the IL-12 family and type I interferon signaling pathways was observed among the set of SSc-CD common genetic risk loci. In conclusion, through the first cross-disease meta-analysis of SSc and CD, we identified genetic variants with pleiotropic effects on two clinically distinct immune-mediated disorders. The fact that all these pleiotropic SNPs have opposite allelic effects in SSc and CD reveals the complexity of the molecular mechanisms by which polymorphisms affect diseases.

Figure 1

Schema of the study design.

Figure 2

Manhattan plot representing the results of the cross-disease meta-analysis including systemic sclerosis and Crohn’s disease, considering same allelic effects (A) and opposite allelic effects (B). Loci selected for replication are marked in black. Significance threshold at genome-wide level is marked with a red line. Established significance threshold for the cross-disease meta-analysis (p < 1 × 10⁻⁵) is marked with a blue line.

Figure 3

STRING protein-protein interaction network connectivity among genetic risk loci shared between systemic sclerosis and Crohn’s disease.