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

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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

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IgA Deficiency
Immunoglobulin A
Meta-Analysis
Deoxyribonucleases
Quantitative Trait Loci
Genome-Wide Association Study
Regulatory T-Lymphocytes
Genes
Hypersensitivity

ASJC Scopus subject areas

  • Genetics

Cite this

Bronson, P. G., Chang, D., Bhangale, T., Seldin, M. F., Ortmann, W., Ferreira, R. C., ... 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

Common variants at PVT1, ATG13-AMBRA1, AHI1 and CLEC16A are associated with selective IgA deficiency. / Bronson, Paola G.; Chang, Diana; Bhangale, Tushar; Seldin, Michael F; Ortmann, Ward; Ferreira, Ricardo C.; Urcelay, Elena; Pereira, Luis Fernández; Martin, Javier; Plebani, Alessandro; Lougaris, Vassilios; Friman, Vanda; Freiberger, Tomáš; Litzman, Jiri; Thon, Vojtech; Pan-Hammarström, Qiang; Hammarström, Lennart; Graham, Robert R.; Behrens, Timothy W.

In: Nature Genetics, Vol. 48, No. 11, 01.11.2016, p. 1425-1429.

Research output: Contribution to journalArticle

Bronson, PG, Chang, D, Bhangale, T, Seldin, MF, Ortmann, W, Ferreira, RC, Urcelay, E, Pereira, LF, Martin, J, Plebani, A, Lougaris, V, Friman, V, Freiberger, T, Litzman, J, Thon, V, Pan-Hammarström, Q, Hammarström, L, Graham, RR & Behrens, TW 2016, 'Common variants at PVT1, ATG13-AMBRA1, AHI1 and CLEC16A are associated with selective IgA deficiency', Nature Genetics, vol. 48, no. 11, pp. 1425-1429. https://doi.org/10.1038/ng.3675
Bronson, Paola G. ; Chang, Diana ; Bhangale, Tushar ; Seldin, Michael F ; Ortmann, Ward ; Ferreira, Ricardo C. ; Urcelay, Elena ; Pereira, Luis Fernández ; Martin, Javier ; Plebani, Alessandro ; Lougaris, Vassilios ; Friman, Vanda ; Freiberger, Tomáš ; Litzman, Jiri ; Thon, Vojtech ; Pan-Hammarström, Qiang ; Hammarström, Lennart ; Graham, Robert R. ; Behrens, Timothy W. / Common variants at PVT1, ATG13-AMBRA1, AHI1 and CLEC16A are associated with selective IgA deficiency. In: Nature Genetics. 2016 ; Vol. 48, No. 11. pp. 1425-1429.
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AU - Seldin, Michael F

AU - Ortmann, Ward

AU - Ferreira, Ricardo C.

AU - Urcelay, Elena

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AU - Behrens, Timothy W.

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