title: Common variants at PVT1, ATG13-AMBRA1, AHI1 and CLEC16A are associated with selective IgA deficiency.
abstract: 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.
authors.affiliation: Department of Human Genetics, Genentech, Inc., South San Francisco, California, USA.
authors.forename: Paola G
authors.initials: PG
authors.lastname: Bronson
authors.affiliation: Department of Human Genetics, Genentech, Inc., South San Francisco, California, USA.
authors.forename: Diana
authors.initials: D
authors.lastname: Chang
authors.affiliation: Department of Bioinformatics and Computational Biology, Genentech, Inc., South San Francisco, California, USA.
authors.forename: Tushar
authors.initials: T
authors.lastname: Bhangale
authors.affiliation: Department of Biochemistry, School of Medicine, University of California, Davis, Davis, California, USA.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Seldin
authors.affiliation: Department of Human Genetics, Genentech, Inc., South San Francisco, California, USA.
authors.forename: Ward
authors.initials: W
authors.lastname: Ortmann
authors.affiliation: Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, Cambridge, UK.
authors.forename: Ricardo C
authors.initials: RC
authors.lastname: Ferreira
authors.affiliation: Department of Immunology, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, IdISSC, Madrid, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Urcelay
authors.affiliation: Department of Immunology, Hospital San Pedro de Alcántara, Cáceres, Spain.
authors.forename: Luis Fernández
authors.initials: LF
authors.lastname: Pereira
authors.affiliation: Instituto de Parasitología y Biomedicina López-Neyra, CSIC, Granada, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Martin
authors.affiliation: Pediatrics Clinic, Department of Clinical and Experimental Sciences, University of Brescia, Spedali Civili di Brescia, Brescia, Italy.|Institute for Molecular Medicine, A. Nocivelli, Department of Clinical and Experimental Sciences, University of Brescia, Spedali Civili di Brescia, Brescia, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Plebani
authors.affiliation: Pediatrics Clinic, Department of Clinical and Experimental Sciences, University of Brescia, Spedali Civili di Brescia, Brescia, Italy.|Institute for Molecular Medicine, A. Nocivelli, Department of Clinical and Experimental Sciences, University of Brescia, Spedali Civili di Brescia, Brescia, Italy.
authors.forename: Vassilios
authors.initials: V
authors.lastname: Lougaris
authors.affiliation: Department of Infectious Diseases, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Vanda
authors.initials: V
authors.lastname: Friman
authors.affiliation: Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, Brno, Czech Republic.|Central European Institute of Technology, Masaryk University, Brno, Czech Republic.
authors.forename: Tomáš
authors.initials: T
authors.lastname: Freiberger
authors.affiliation: Department of Clinical Immunology and Allergy, Faculty of Medicine, Masaryk University, St. Anne's University Hospital, Brno, Czech Republic.
authors.forename: Jiri
authors.initials: J
authors.lastname: Litzman
authors.affiliation: Department of Clinical Immunology and Allergy, Faculty of Medicine, Masaryk University, St. Anne's University Hospital, Brno, Czech Republic.|Research Centre for Toxic Compounds in the Environment, Faculty of Science, Masaryk University, Brno, Czech Republic.
authors.forename: Vojtech
authors.initials: V
authors.lastname: Thon
authors.affiliation: Division of Clinical Immunology and Transfusion Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Qiang
authors.identifier: 0000-0003-1990-8804
authors.initials: Q
authors.lastname: Pan-Hammarström
authors.affiliation: Division of Clinical Immunology and Transfusion Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Lennart
authors.initials: L
authors.lastname: Hammarström
authors.affiliation: Department of Human Genetics, Genentech, Inc., South San Francisco, California, USA.
authors.forename: Robert R
authors.initials: RR
authors.lastname: Graham
authors.affiliation: Department of Human Genetics, Genentech, Inc., South San Francisco, California, USA.
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Behrens
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D033942:Adaptor Proteins, Vesicular Transport; D000071183:Autophagy-Related Proteins / Q000235:genetics; D015331:Cohort Studies; D053263:Gene Regulatory Networks; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D017098:IgA Deficiency / Q000235:genetics*; D037181:Lectins, C-Type / Q000235:genetics; D009004:Monosaccharide Transport Proteins / Q000235:genetics; D062085:RNA, Long Noncoding / Q000235:genetics
chemical_list: C487178:AHI1 protein, human; C553334:AMBRA1 protein, human; C534291:ATG13 protein, human; D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000071183:Autophagy-Related Proteins; C522505:CLEC16A protein, human; D037181:Lectins, C-Type; D009004:Monosaccharide Transport Proteins; C521123:PVT1 long-non-coding RNA, human; D062085:RNA, Long Noncoding