To understand the genetic predisposition to selective immunoglobulin A deficiency (IgAD), we performed a genome-wide association study in 430 affected individuals (cases) from Sweden and Iceland and 1,090 ethnically matched controls, and we performed replication studies in two independent European cohorts. In addition to the known association of HLA with IgAD, we identified association with a nonsynonymous variant in IFIH1 (rs1990760G>A, P = 7.3 × 10−10) which was previously associated with type 1 diabetes and systemic lupus erythematosus. Variants in CLEC16A, another known autoimmunity locus, showed suggestive evidence for association (rs6498142C>G, P = 1.8 × 10−7), and 29 additional loci were identified with P < 5 × 10−5. A survey in IgAD of 118 validated non-HLA autoimmunity loci indicated a significant enrichment for association with autoimmunity loci as compared to non-autoimmunity loci (P = 9.0 × 10−4) or random SNPs across the genome (P < 0.0001). These findings support the hypothesis that autoimmune mechanisms may contribute to the pathogenesis of IgAD.
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We are grateful to the individuals with IgAD and their physicians for their contributions to this work. These studies were supported by the US National Institutes of Health (U19 AI067152 and AR043274), the Swedish Research Council, the European Research Council (242551-ImmunoSwitch) and EURO-PADnet grant 201549. Genentech, Inc. provided partial funding for the GWAS studies. Financial support was also provided through the regional agreement on medical training and clinical research the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet between the Stockholm county council and the Karolinska Institute. R.C.F. was supported by a fellowship from the Fundação para a Ciência e Tecnologia, Portugal (SFRH/BD/16281/2004). The population allele and genotype frequencies were obtained from a data source funded by the Nordic Center of Excellence in Disease Genetics based on regional samples from Finland and Sweden. The Helsinki 4 study was supported by the Yale Center for Human Genetics and Genomics and the Yale Program on Neurogenetics and US National Institutes of Health grants R01NS057756 and U24 NS051869.
R.R.G., V.G., W.O., H.F.K. and T.W.B. are full-time employees of Genentech, Inc.
Supplementary Figures 1–3, Supplementary Tables 1–8 and Supplementary Note (PDF 3665 kb)
Additional genomic regions showing suggestive evidence for association with IgAD. (XLS 32 kb)
Genetic association of previously validated non-HLA autoimmunity loci in IgA. (XLS 79 kb)
Genetic association of loci associated with non-autoimmune phenotypes in IgAD. (XLS 26 kb)
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