Leveraging pleiotropy identifies common-variant associations with selective IgA deficiency

Abstract

Selective IgA deficiency (SIgAD) is the most common inborn error of immunity (IEI). Unlike many IEIs, evidence of a role for highly penetrant rare variants in SIgAD is lacking. Previous SIgAD studies have had limited power to identify common variants due to their small sample size. We overcame this problem first through meta-analysis of two existing GWAS. This identified four novel common-variant associations and enrichment of SIgAD-associated variants in genes linked to Mendelian IEIs. SIgAD showed evidence of shared genetic architecture with serum IgA and a number of immune-mediated diseases. We leveraged this pleiotropy through the conditional false discovery rate procedure, conditioning our SIgAD meta-analysis on large GWAS of asthma and rheumatoid arthritis, and our own meta-analysis of serum IgA. This identified an additional 18 variants, increasing the number of known SIgAD-associated variants to 27 and strengthening the evidence for a polygenic, common-variant aetiology for SIgAD.