Selective immunoglobulin A deficiency (IgAD) is the most common primary immunodeficiency in Europeans. Our genome-wide association study (GWAS) meta-analysis of 1,635 patients with IgAD and 4,852 controls identified four new significant (P < 5 × 10-8) loci and association with a rare IFIH1 variant (p.Ile923Val). Peak new variants (PVT1, P = 4.3 × 10-11; ATG13-AMBRA1, P = 6.7 × 10-10; AHI1, P = 8.4 × 10-10; CLEC16A, P = 1.4 × 10-9) overlapped with autoimmune markers (3/4) and correlated with 21 putative regulatory variants, including expression quantitative trait loci (eQTLs) for AHI1 and DEXI and DNase hypersensitivity sites in FOXP3+ regulatory T cells. Pathway analysis of the meta-analysis results showed striking association with the KEGG pathway for IgA production (pathway P < 0.0001), with 22 of the 30 annotated pathway genes containing at least one variant with P ≤ 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, contributes to IgAD.

Central European Institute of Technology Masaryk University Brno Czech Republic

Department of Biochemistry School of Medicine University of California Davis Davis California USA

Department of Bioinformatics and Computational Biology Genentech Inc South San Francisco California USA

Department of Clinical Immunology and Allergy Faculty of Medicine Masaryk University St Anne's University Hospital Brno Czech Republic

Department of Human Genetics Genentech Inc South San Francisco California USA

Department of Immunology Hospital San Pedro de Alcántara Cáceres Spain

Department of Immunology Instituto de Investigación Sanitaria del Hospital Clínico San Carlos IdISSC Madrid Spain

Department of Infectious Diseases University of Gothenburg Gothenburg Sweden

Division of Clinical Immunology and Transfusion Medicine Karolinska Institutet Stockholm Sweden

Institute for Molecular Medicine A Nocivelli Department of Clinical and Experimental Sciences University of Brescia Spedali Civili di Brescia Brescia Italy

Instituto de Parasitología y Biomedicina López Neyra CSIC Granada Spain

Juvenile Diabetes Research Foundation Wellcome Trust Diabetes and Inflammation Laboratory Cambridge Institute for Medical Research Cambridge UK

Molecular Genetics Laboratory Centre for Cardiovascular Surgery and Transplantation Brno Czech Republic

Pediatrics Clinic Department of Clinical and Experimental Sciences University of Brescia Spedali Civili di Brescia Brescia Italy

Research Centre for Toxic Compounds in the Environment Faculty of Science Masaryk University Brno Czech Republic

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