Genome-Wide Association Study (GWAS) Uncovers Novel Mechanisms and Potential Therapeutic Targets for IgA Vasculitis

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Background: IgA vasculitis (IgAV) is an immune complex-mediated leukocytoclastic vasculitis characterized by vascular deposition of IgA-containing immune complexes in the skin, gastrointestinal and glomerular capillaries. The exact pathogenic mechanisms of IgAV remain unclear and thus there are presently no targeted treatments. Methods: We conducted a GWAS for IgAV in 8,098 individuals of European and East Asian ancestries including 2,170 IgAV cases and 5,928 controls. We performed meta-analysis with dense imputation and fine-mapping of significant loci, followed by proteome-wide association studies (PWAS) and transcriptome-wide association studies. Whole blood RNA-seq data from 255 IgAV cases with matched genotype data were used for genome-wide expression QTL (eQTL) mapping. By integrative analysis of genetic and transcriptomic data, we investigated the consequences of IgAV risk alleles on gene function and regulation. Results: In GWAS, we detected 3 genome-wide significant loci for IgAV. We confirmed a strong effect of the HLA locus (OR=1.55, P= 1.1x10-25) and we identified two novel non-HLA loci at chr.19q13.42 (OR=1.51, P=1.0x10-20) and chr.2q37.1 (OR=1.34, P= 2.2x10-09) loci. The HLA fine-mapping identified HLA-DRB1 as the most likely culprit gene, with amino-acid position 11 conveying the greatest risk. The chr.19q13.42 locus colocalized with the eQTL for FCAR (PP4=0.95), encoding the Fc α IgA receptor (CD89), with the risk allele being associated with increased FCAR expression in myeloid cells (Pfdr-adjusted =1.6x10-09). Blood mRNA levels of FCAR in IgAV patients were 1.5-fold higher vs. controls (P=5.1x10-09). Four upstream regulators for FCAR differentially activated in IgAV cases vs. controls were identified using ARACNe3-based master regulator analysis. By PWAS, we additionally identified a distinct proteome-wide significant signal at the 1q21.3 locus that was suggestive in GWAS, and for which the risk allele was associated with increased blood levels of soluble IL6R. Conclusions: Our genetic findings implicate roles for CD89 and IL6R in the pathogenesis of IgAV and nominate these genes and related pathways for future therapeutic targeting.

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