Genome-wide studies define genetic mechanisms of IgA vasculitis

IgA vasculitis is a pediatric disease with skin and systemic manifestations. Here, we conduct genome, transcriptome, and proteome-wide association studies in 2170 IgA vasculitis cases and 5928 controls, generate IgA vasculitis-specific maps of gene expression and splicing from blood of 255 pediatric cases, and reconstruct myeloid-specific regulatory networks to define disease master regulators modulated by the identified genes. We observe significant association at the HLA-DRB1 locus (OR = 1.55, P = 1.1 × 10−25) and fine-map specific amino-acid risk substitutions in DRβ1. We find two novel non-HLA associated loci: FCAR (OR = 1.51, P = 1.0 × 10−20), encoding a myeloid IgA receptor FcαR, and INPP5D (OR = 1.34, P = 2.2 × 10−09), encoding an inhibitor of FcαR signalling. The FCAR risk locus co-localizes with a cis-eQTL that increases FCAR expression; the risk alleles disrupt a PRDM1 binding motif within a myeloid enhancer of FCAR. Another risk locus is associated with higher genetically predicted levels of plasma IL6R. The IL6R risk haplotype carries a missense variant contributing to accelerated cleavage of IL6R into a soluble form. Applying network-based approaches to blood single cell transcriptomes, we predict, independently replicate, and experimentally validate 21 IgA vasculitis master regulators co-modulated by FCAR, INPP5D and IL6R signalling in myeloid cells. IgA vasculitis is a pediatric disease with skin and systemic manifestations. Here, the authors use multiomic data to examine the genetic mechanisms of IgA vasculitis and find therapeutically relevant immune pathways and molecular drivers.