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

Paola G. Bronson, Diana Chang, Tushar Bhangale, Michael F Seldin, Ward Ortmann, Ricardo C. Ferreira, Elena Urcelay, Luis Fernández Pereira, Javier Martin, Alessandro Plebani, Vassilios Lougaris, Vanda Friman, Tomáš Freiberger, Jiri Litzman, Vojtech Thon, Qiang Pan-Hammarström, Lennart Hammarström, Robert R. Graham, Timothy W. Behrens

Research output: Contribution to journalArticle

28 Scopus citations

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 â '8) loci and association with a rare IFIH1 variant (p.Ile923Val). Peak new variants (PVT1, P = 4.3 × 10 â '11; ATG13-AMBRA1, P = 6.7 × 10 â '10; AHI1, P = 8.4 × 10 â '10; CLEC16A, P = 1.4 × 10 â '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.

Original languageEnglish (US)
Pages (from-to)1425-1429
Number of pages5
JournalNature Genetics
Volume48
Issue number11
DOIs
StatePublished - Nov 1 2016

ASJC Scopus subject areas

  • Genetics

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    Bronson, P. G., Chang, D., Bhangale, T., Seldin, M. F., Ortmann, W., Ferreira, R. C., Urcelay, E., Pereira, L. F., Martin, J., Plebani, A., Lougaris, V., Friman, V., Freiberger, T., Litzman, J., Thon, V., Pan-Hammarström, Q., Hammarström, L., Graham, R. R., & Behrens, T. W. (2016). Common variants at PVT1, ATG13-AMBRA1, AHI1 and CLEC16A are associated with selective IgA deficiency. Nature Genetics, 48(11), 1425-1429. https://doi.org/10.1038/ng.3675