Abstract
Immunoglobulins are the effector molecules of the adaptive humoral immune system. In a genome-wide association study of 19,219 individuals, we found 38 new variants and replicated 5 known variants associating with IgA, IgG or IgM levels or with composite immunoglobulin traits, accounted for by 32 loci. Variants at these loci also affect the risk of autoimmune diseases and blood malignancies and influence blood cell development. Notable associations include a rare variant at RUNX3 decreasing IgA levels by shifting isoform proportions (rs188468174[C>T]: P = 8.3 × 10−55, β = −0.90 s.d.), a rare in-frame deletion in FCGR2B abolishing IgG binding to the encoded receptor (p.Asn106del: P = 4.2 × 10−8, β = 1.03 s.d.), four IGH locus variants influencing class switching, and ten new associations with the HLA region. Our results provide new insight into the regulation of humoral immunity.
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Acknowledgements
We thank all study participants and the staff at the Icelandic Patient Recruitment Center and the deCODE genetics core facilities. We are indebted to the blood donors and staff at Lundatappen who participated in the project.
This work was supported by research grants from the Swedish Foundation for Strategic Research (KF10-0009, B.N.), the Marianne and Marcus Wallenberg Foundation (2010.0112, B.N.), the Knut and Alice Wallenberg Foundation (2012.0193, B.N.) and the Swedish Research Council (2012-1753, B.N.).
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S.J., D.F.G., U.T., I.J., B.N. and K.S. coordinated and designed the study. G.I.E., B.R.L., I.O., O.S., H.H. and I.J. coordinated and managed collection of samples and ascertainment of phenotype data in Iceland. A.L.d.L.P., E.E., E.J., R.A., U.G., M.H. and Å.J. collected samples and phenotype data in Sweden. S.J., G.Th., B.V.H., S.A.G., A.G., A.S., L.S., A.O., S.O., A.L.d.L.P., B.S., M.A., G.S., G.M., P.S., D.F.G., A.-K.W., I.J. and B.N. carried out statistical and bioinformatic analyses of genetic data. A.L.d.L.P., B.S., E.E., A.J., G.V., R.P., M.W., A.E.H.B. and G.D. carried out functional experiments and analysis. S.J., A.-K.W., I.J., B.N. and K.S. drafted the manuscript. All authors contributed to the final manuscript.
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S.J., G.S., S.A.G., A.G., B.V.H., H.H., A.J., A.O., S.O., A.S., L.S., G.M., P.S., G.Th., D.F.G., U.T., I.J. and K.S. are employees of deCODE Genetics/Amgen, Inc.
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Supplementary Text and Figures
Supplementary Figures 1–8, Supplementary Tables 1–4, 6–10, 12, 14–17 and 20, and Supplementary Note (PDF 6796 kb)
Supplementary Table 5
Association of the 43 novel and confirmed immunoglobulin variants with each of the nine immunoglobulin traits in the Icelandic data. (XLSX 27 kb)
Supplementary Table 11
Immune-related mouse phenotypes for 310 immunoglobulin locus genes. (XLSX 21 kb)
Supplementary Table 13
Association of 43 immunoglobulin lead SNPs with frequencies of eight B cell populations in peripheral blood from healthy Swedish individuals. (XLSX 27 kb)
Supplementary Table 18
Correlation (linkage disequilibrium, r2) matrix of classical HLA alleles and SNPs in the HLA region with significant association with one or more immunoglobulin traits in Iceland. (XLSX 19 kb)
Supplementary Table 19
Meta-analysis results for immunoglobulin traits showing all variants with combined P value below 1 × 10−6. (XLSX 2978 kb)
Supplementary Table 21
The basis for selection of candidate genes. (XLSX 20 kb)
Supplementary Table 22
Genes overlapping the defined locus region at novel and previously reported immunoglobulin-associated loci. (XLSX 23 kb)
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Jonsson, S., Sveinbjornsson, G., de Lapuente Portilla, A. et al. Identification of sequence variants influencing immunoglobulin levels. Nat Genet 49, 1182–1191 (2017). https://doi.org/10.1038/ng.3897
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DOI: https://doi.org/10.1038/ng.3897
