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 | |
| State | Published - Nov 1 2016 |
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ASJC Scopus subject areas
- Genetics
Cite this
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
}
TY - JOUR
T1 - Common variants at PVT1, ATG13-AMBRA1, AHI1 and CLEC16A are associated with selective IgA deficiency
AU - Bronson, Paola G.
AU - Chang, Diana
AU - Bhangale, Tushar
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
AU - Pan-Hammarström, Qiang
AU - Hammarström, Lennart
AU - Graham, Robert R.
AU - Behrens, Timothy W.
PY - 2016/11/1
Y1 - 2016/11/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84990987996&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84990987996&partnerID=8YFLogxK
U2 - 10.1038/ng.3675
DO - 10.1038/ng.3675
M3 - Article
C2 - 27723758
AN - SCOPUS:84990987996
VL - 48
SP - 1425
EP - 1429
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
IS - 11
ER -