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

doi:10.1038/ng.3675

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

Biochemistry and Molecular Medicine

Research output: Contribution to journal › Article › peer-review

30 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 language	English (US)
Pages (from-to)	1425-1429
Number of pages	5
Journal	Nature Genetics
Volume	48
Issue number	11
DOIs	https://doi.org/10.1038/ng.3675
State	Published - 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

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 journal › Article › peer-review

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

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AU - Seldin, Michael F

AU - Ortmann, Ward

AU - Ferreira, Ricardo C.

AU - Urcelay, Elena

AU - Pereira, Luis Fernández

AU - Martin, Javier

AU - Plebani, Alessandro

AU - Lougaris, Vassilios

AU - Friman, Vanda

AU - Freiberger, Tomáš

AU - Litzman, Jiri

AU - Thon, Vojtech

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AU - Graham, Robert R.

AU - Behrens, Timothy W.

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