Common variants at PVT1, ATG13–AMBRA1, AHI1 and CLEC16A are associated with selective IgA deficiency

Selective immunoglobulin A deficiency (IgAD) is the most common primary immunodeficiency in Europeans. Our GWAS meta-analysis of 1,635 IgAD patients and 4,852 controls identified four new significant (P < 5x10(−8)) loci and association with a rare IFIH1 variant (Ile923Val). Peak novel variants (PVT1 P = 4.3x10(−11), ATG13–AMBRA1 P = 6.7x10(−10), AHI1 P = 8.4x10(−10) and CLEC16A P = 1.4x10(−9)) overlapped with autoimmune markers (3/4) and correlated with 21 putative regulatory variants, including eQTLs for AHI1 and DEXI and DNase hypersensitivity in FOXP3+ T regulatory cells. A pathway analysis of the meta-analysis results showed a striking association with the KEGG pathway for IgA production (pathway P < 0.0001): where 22 of 30 annotated pathway genes contained at least one variant with a P-value ≤0.05 in the IgAD meta-analysis. These data suggest that a complex network of genetic effects, including genes known to influence the biology of IgA production, contribute to IgAD.