Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Identification of sequence variants influencing immunoglobulin levels

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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Heat map showing association of each of the new and reported immunoglobulin sentinel variants with all nine immunoglobulin traits.
Figure 2: Expression of candidate genes in hematopoietic cell types.
Figure 3: rs188468174 increases transcriptional activity at the RUNX3 P1 promoter, leading to increased expression of the long transcript without affecting total RUNX3 expression and to reduced IgA levels.
Figure 4: In-frame deletion of a predicted N-glycosylation site, p.Asn106del, in FCGR2B abolishes IgG binding to the encoded receptor but has minor effects on glycosylation.

Accession codes

Primary accessions

Gene Expression Omnibus

Referenced accessions

Gene Expression Omnibus

NCBI Reference Sequence

Protein Data Bank

References

  1. Stavnezer, J., Guikema, J.E. & Schrader, C.E. Mechanism and regulation of class switch recombination. Annu. Rev. Immunol. 26, 261–292 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Yoshida, T. et al. Memory B and memory plasma cells. Immunol. Rev. 237, 117–139 (2010).

    Article  CAS  PubMed  Google Scholar 

  3. Vincent, F.B., Morand, E.F., Schneider, P. & Mackay, F. The BAFF/APRIL system in SLE pathogenesis. Nat. Rev. Rheumatol. 10, 365–373 (2014).

    Article  CAS  PubMed  Google Scholar 

  4. Bronson, P.G. et al. Common variants at PVT1, ATG13AMBRA1, AHI1 and CLEC16A are associated with selective IgA deficiency. Nat. Genet. 48, 1425–1429 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Keller, M.D. et al. Mutation in IRF2BP2 is responsible for a familial form of common variable immunodeficiency disorder. J. Allergy Clin. Immunol. 138, 544–550 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Orange, J.S. et al. Genome-wide association identifies diverse causes of common variable immunodeficiency. J. Allergy Clin. Immunol. 127, 1360–1367 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Swaminathan, B. et al. Variants in ELL2 influencing immunoglobulin levels associate with multiple myeloma. Nat. Commun. 6, 7213 (2015).

    Article  PubMed  Google Scholar 

  8. Viktorin, A. et al. IgA measurements in over 12 000 Swedish twins reveal sex differential heritability and regulatory locus near CD30L. Hum. Mol. Genet. 23, 4177–4184 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Yang, C. et al. Genome-wide association study identifies TNFSF13 as a susceptibility gene for IgA in a South Chinese population in smokers. Immunogenetics 64, 747–753 (2012).

    Article  PubMed  CAS  Google Scholar 

  10. Yang, M. et al. Genome-wide scan identifies variant in TNFSF13 associated with serum IgM in a healthy Chinese male population. PLoS One 7, e47990 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Liao, M. et al. Genome-wide association study identifies common variants at TNFRSF13B associated with IgG level in a healthy Chinese male population. Genes Immun. 13, 509–513 (2012).

    Article  CAS  PubMed  Google Scholar 

  12. Granada, M. et al. A genome-wide association study of plasma total IgE concentrations in the Framingham Heart Study. J. Allergy Clin. Immunol. 129, 840–845 (2012).

  13. Weidinger, S. et al. Genome-wide scan on total serum IgE levels identifies FCER1A as novel susceptibility locus. PLoS Genet. 4, e1000166 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Moffatt, M.F. et al. A large-scale, consortium-based genomewide association study of asthma. N. Engl. J. Med. 363, 1211–1221 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Matthews, A.J., Zheng, S., DiMenna, L.J. & Chaudhuri, J. Regulation of immunoglobulin class-switch recombination: choreography of noncoding transcription, targeted DNA deamination, and long-range DNA repair. Adv. Immunol. 122, 1–57 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Sveinbjornsson, G. et al. Weighting sequence variants based on their annotation increases power of whole-genome association studies. Nat. Genet. 48, 314–317 (2016).

    Article  CAS  PubMed  Google Scholar 

  17. Emilsson, V. et al. Genetics of gene expression and its effect on disease. Nature 452, 423–428 (2008).

    Article  CAS  PubMed  Google Scholar 

  18. Westra, H.J. et al. Systematic identification of trans eQTLs as putative drivers of known disease associations. Nat. Genet. 45, 1238–1243 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Carithers, L.J. et al. A novel approach to high-quality postmortem tissue procurement: the GTEx Project. Biopreserv. Biobank. 13, 311–319 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Lappalainen, T. et al. Transcriptome and genome sequencing uncovers functional variation in humans. Nature 501, 506–511 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Köhler, S. et al. Construction and accessibility of a cross-species phenotype ontology along with gene annotations for biomedical research. F1000Res. 2, 30 (2013).

    Article  PubMed  Google Scholar 

  22. Eppig, J.T., Blake, J.A., Bult, C.J., Kadin, J.A. & Richardson, J.E. The Mouse Genome Database (MGD): facilitating mouse as a model for human biology and disease. Nucleic Acids Res. 43, D726–D736 (2015).

    Article  CAS  PubMed  Google Scholar 

  23. Amberger, J.S., Bocchini, C.A., Schiettecatte, F., Scott, A.F. & Hamosh, A. OMIM.org: Online Mendelian Inheritance in Man (OMIM®), an online catalog of human genes and genetic disorders. Nucleic Acids Res. 43, D789–D798 (2015).

    Article  CAS  PubMed  Google Scholar 

  24. Bossen, C. & Schneider, P. BAFF, APRIL and their receptors: structure, function and signaling. Semin. Immunol. 18, 263–275 (2006).

    Article  CAS  PubMed  Google Scholar 

  25. Chenery, A. et al. The retinoic acid–metabolizing enzyme Cyp26b1 regulates CD4 T cell differentiation and function. PLoS One 8, e72308 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Takeuchi, H., Yokota, A., Ohoka, Y. & Iwata, M. Cyp26b1 regulates retinoic acid–dependent signals in T cells and its expression is inhibited by transforming growth factor-β. PLoS One 6, e16089 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Capasso, M. Regulation of immune responses by proton channels. Immunology 143, 131–137 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Wang, J.H. et al. Aiolos regulates B cell activation and maturation to effector state. Immunity 9, 543–553 (1998).

    Article  CAS  PubMed  Google Scholar 

  29. Ma, S., Pathak, S., Trinh, L. & Lu, R. Interferon regulatory factors 4 and 8 induce the expression of Ikaros and Aiolos to down-regulate pre-B-cell receptor and promote cell-cycle withdrawal in pre-B-cell development. Blood 111, 1396–1403 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Merluzzi, S. et al. Mast cells enhance proliferation of B lymphocytes and drive their differentiation toward IgA-secreting plasma cells. Blood 115, 2810–2817 (2010).

    Article  CAS  PubMed  Google Scholar 

  31. Carotta, S. et al. The transcription factors IRF8 and PU.1 negatively regulate plasma cell differentiation. J. Exp. Med. 211, 2169–2181 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Costantino, C.M., Hang, H.C., Kent, S.C., Hafler, D.A. & Ploegh, H.L. Lysosomal cysteine and aspartic proteases are heterogeneously expressed and act redundantly to initiate human invariant chain degradation. J. Immunol. 180, 2876–2885 (2008).

    Article  CAS  PubMed  Google Scholar 

  33. Lin, S.C., Wortis, H.H. & Stavnezer, J. The ability of CD40L, but not lipopolysaccharide, to initiate immunoglobulin switching to immunoglobulin G1 is explained by differential induction of NF-κB/Rel proteins. Mol. Cell. Biol. 18, 5523–5532 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Ramachandran, S. et al. The RNF8/RNF168 ubiquitin ligase cascade facilitates class switch recombination. Proc. Natl. Acad. Sci. USA 107, 809–814 (2010).

    Article  CAS  PubMed  Google Scholar 

  35. Cerutti, A. et al. Engagement of CD153 (CD30 ligand) by CD30+ T cells inhibits class switch DNA recombination and antibody production in human IgD+ IgM+ B cells. J. Immunol. 165, 786–794 (2000).

    Article  CAS  PubMed  Google Scholar 

  36. Yi, Z., Lin, W.W., Stunz, L.L. & Bishop, G.A. Roles for TNF-receptor associated factor 3 (TRAF3) in lymphocyte functions. Cytokine Growth Factor Rev. 25, 147–156 (2014).

    Article  CAS  PubMed  Google Scholar 

  37. Welter, D. et al. The NHGRI GWAS Catalog, a curated resource of SNP–trait associations. Nucleic Acids Res. 42, D1001–D1006 (2014).

    Article  CAS  PubMed  Google Scholar 

  38. Pan-Hammarström, Q. et al. Reexamining the role of TACI coding variants in common variable immunodeficiency and selective IgA deficiency. Nat. Genet. 39, 429–430 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Ramirez-Alejo, N. & Santos-Argumedo, L. Innate defects of the IL-12/IFN-γ axis in susceptibility to infections by mycobacteria and Salmonella. J. Interferon Cytokine Res. 34, 307–317 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Hambleton, S. et al. IRF8 mutations and human dendritic-cell immunodeficiency. N. Engl. J. Med. 365, 127–138 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Stewart, G.S. et al. The RIDDLE syndrome protein mediates a ubiquitin-dependent signaling cascade at sites of DNA damage. Cell 136, 420–434 (2009).

    Article  CAS  PubMed  Google Scholar 

  42. Negro, R. et al. Overexpression of the autoimmunity-associated phosphatase PTPN22 promotes survival of antigen-stimulated CLL cells by selectively activating AKT. Blood 119, 6278–6287 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Rinaldi, A. et al. Genome-wide DNA profiling better defines the prognosis of chronic lymphocytic leukaemia. Br. J. Haematol. 154, 590–599 (2011).

    Article  PubMed  Google Scholar 

  44. Deambrogi, C. et al. Analysis of the REL, BCL11A, and MYCN proto-oncogenes belonging to the 2p amplicon in chronic lymphocytic leukemia. Am. J. Hematol. 85, 541–544 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Estécio, M.R. et al. RUNX3 promoter hypermethylation is frequent in leukaemia cell lines and associated with acute myeloid leukaemia inv(16) subtype. Br. J. Haematol. 169, 344–351 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Cameron, E.R. & Neil, J.C. The Runx genes: lineage-specific oncogenes and tumor suppressors. Oncogene 23, 4308–4314 (2004).

    Article  CAS  PubMed  Google Scholar 

  47. Roberts, K.G. et al. Genetic alterations activating kinase and cytokine receptor signaling in high-risk acute lymphoblastic leukemia. Cancer Cell 22, 153–166 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Novershtern, N. et al. Densely interconnected transcriptional circuits control cell states in human hematopoiesis. Cell 144, 296–309 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Boyd, K.D. et al. Mapping of chromosome 1p deletions in myeloma identifies FAM46C at 1p12 and CDKN2C at 1p32.3 as being genes in regions associated with adverse survival. Clin. Cancer Res. 17, 7776–7784 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Broyl, A. et al. Gene expression profiling for molecular classification of multiple myeloma in newly diagnosed patients. Blood 116, 2543–2553 (2010).

    Article  CAS  PubMed  Google Scholar 

  51. Chapman, M.A. et al. Initial genome sequencing and analysis of multiple myeloma. Nature 471, 467–472 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Zhan, F. et al. Gene-expression signature of benign monoclonal gammopathy evident in multiple myeloma is linked to good prognosis. Blood 109, 1692–1700 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Corces, M.R. et al. Lineage-specific and single-cell chromatin accessibility charts human hematopoiesis and leukemia evolution. Nat. Genet. 48, 1193–1203 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Bangsow, C. et al. The RUNX3 gene—sequence, structure and regulated expression. Gene 279, 221–232 (2001).

    Article  CAS  PubMed  Google Scholar 

  55. Watanabe, K. et al. Requirement for Runx proteins in IgA class switching acting downstream of TGF-β1 and retinoic acid signaling. J. Immunol. 184, 2785–2792 (2010).

    Article  CAS  PubMed  Google Scholar 

  56. Chung, D.D., Honda, K., Cafuir, L., McDuffie, M. & Wotton, D. The Runx3 distal transcript encodes an additional transcriptional activation domain. FEBS J. 274, 3429–3439 (2007).

    Article  CAS  PubMed  Google Scholar 

  57. Kheradpour, P. & Kellis, M. Systematic discovery and characterization of regulatory motifs in ENCODE TF binding experiments. Nucleic Acids Res. 42, 2976–2987 (2014).

    Article  CAS  PubMed  Google Scholar 

  58. Kersten, S., Reczek, P.R. & Noy, N. The tetramerization region of the retinoid X receptor is important for transcriptional activation by the receptor. J. Biol. Chem. 272, 29759–29768 (1997).

    Article  CAS  PubMed  Google Scholar 

  59. Seo, G.Y. et al. Retinoic acid acts as a selective human IgA switch factor. Hum. Immunol. 75, 923–929 (2014).

    Article  CAS  PubMed  Google Scholar 

  60. Okada, Y. et al. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature 506, 376–381 (2014).

    Article  CAS  PubMed  Google Scholar 

  61. Jostins, L. et al. Host–microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491, 119–124 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Gudbjartsson, D.F. et al. Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction. Nat. Genet. 41, 342–347 (2009).

    Article  CAS  PubMed  Google Scholar 

  63. Hester, A.G. et al. Relationship between a common variant in the fatty acid desaturase (FADS) cluster and eicosanoid generation in humans. J. Biol. Chem. 289, 22482–22489 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Joshi, H.J. & Gupta, R. Eukaryotic glycosylation: online methods for site prediction on protein sequences. Methods Mol. Biol. 1273, 127–137 (2015).

    Article  CAS  PubMed  Google Scholar 

  65. Hogarth, P.M. & Pietersz, G.A. Fc receptor-targeted therapies for the treatment of inflammation, cancer and beyond. Nat. Rev. Drug Discov. 11, 311–331 (2012).

    Article  CAS  PubMed  Google Scholar 

  66. de Lau, W. et al. Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling. Nature 476, 293–297 (2011).

    Article  CAS  PubMed  Google Scholar 

  67. Bruhns, P. et al. Specificity and affinity of human Fcγ receptors and their polymorphic variants for human IgG subclasses. Blood 113, 3716–3725 (2009).

    Article  CAS  PubMed  Google Scholar 

  68. Nimmerjahn, F., Gordan, S. & Lux, A. FcγR dependent mechanisms of cytotoxic, agonistic, and neutralizing antibody activities. Trends Immunol. 36, 325–336 (2015).

    Article  CAS  PubMed  Google Scholar 

  69. Papadakis, K.A. et al. Krüppel-like factor KLF10 regulates transforming growth factor receptor II expression and TGF-β signaling in CD8+ T lymphocytes. Am. J. Physiol. Cell Physiol. 308, C362–C371 (2015).

    Article  CAS  PubMed  Google Scholar 

  70. McKarns, S.C., Letterio, J.J. & Kaminski, N.E. Concentration-dependent bifunctional effect of TGF-β1 on immunoglobulin production: a role for Smad3 in IgA production in vitro. Int. Immunopharmacol. 3, 1761–1774 (2003).

    Article  CAS  PubMed  Google Scholar 

  71. Arechiga, A.F. et al. Cutting edge: the PTPN22 allelic variant associated with autoimmunity impairs B cell signaling. J. Immunol. 182, 3343–3347 (2009).

    Article  CAS  PubMed  Google Scholar 

  72. Oetke, C., Vinson, M.C., Jones, C. & Crocker, P.R. Sialoadhesin-deficient mice exhibit subtle changes in B- and T-cell populations and reduced immunoglobulin M levels. Mol. Cell. Biol. 26, 1549–1557 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Benson, M.J. et al. Cutting edge: the dependence of plasma cells and independence of memory B cells on BAFF and APRIL. J. Immunol. 180, 3655–3659 (2008).

    Article  CAS  PubMed  Google Scholar 

  74. Jabara, H.H., Weng, Y., Sannikova, T. & Geha, R.S. TRAF2 and TRAF3 independently mediate Ig class switching driven by CD40. Int. Immunol. 21, 477–488 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Ben-Ali, M. et al. Functional characterization of naturally occurring genetic variants in the human TLR1-2-6 gene family. Hum. Mutat. 32, 643–652 (2011).

    Article  CAS  PubMed  Google Scholar 

  76. Johnson, C.M. et al. Cutting edge: a common polymorphism impairs cell surface trafficking and functional responses of TLR1 but protects against leprosy. J. Immunol. 178, 7520–7524 (2007).

    Article  CAS  PubMed  Google Scholar 

  77. Lin, W.W., Hostager, B.S. & Bishop, G.A. TRAF3, ubiquitination, and B-lymphocyte regulation. Immunol. Rev. 266, 46–55 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Ohtsubo, T. et al. Identification of human MutY homolog (hMYH) as a repair enzyme for 2-hydroxyadenine in DNA and detection of multiple forms of hMYH located in nuclei and mitochondria. Nucleic Acids Res. 28, 1355–1364 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Yousif, A.S., Stanlie, A., Begum, N.A. & Honjo, T. Opinion: uracil DNA glycosylase (UNG) plays distinct and non-canonical roles in somatic hypermutation and class switch recombination. Int. Immunol. 26, 575–578 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Rölle, A. et al. IL-12-producing monocytes and HLA-E control HCMV-driven NKG2C+ NK cell expansion. J. Clin. Invest. 124, 5305–5316 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  81. Zhang, Y., Fear, D.J., Willis-Owen, S.A., Cookson, W.O. & Moffatt, M.F. Global gene regulation during activation of immunoglobulin class switching in human B cells. Sci. Rep. 6, 37988 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Frankowiack, M. et al. The higher frequency of IgA deficiency among Swedish twins is not explained by HLA haplotypes. Genes Immun. 16, 199–205 (2015).

    Article  CAS  PubMed  Google Scholar 

  83. Caffrey, M.F. & James, D.C. Human lymphocyte antigen association in ankylosing spondylitis. Nature 242, 121 (1973).

    Article  CAS  PubMed  Google Scholar 

  84. Brown, M.A., Kenna, T. & Wordsworth, B.P. Genetics of ankylosing spondylitis—insights into pathogenesis. Nat. Rev. Rheumatol. 12, 81–91 (2016).

    Article  CAS  PubMed  Google Scholar 

  85. Kenna, T.J., Hanson, A., Costello, M.E. & Brown, M.A. Functional genomics and its bench-to-bedside translation pertaining to the identified susceptibility alleles and loci in ankylosing spondylitis. Curr. Rheumatol. Rep. 18, 63 (2016).

    Article  PubMed  CAS  Google Scholar 

  86. Delaneau, O., Howie, B., Cox, A.J., Zagury, J.F. & Marchini, J. Haplotype estimation using sequencing reads. Am. J. Hum. Genet. 93, 687–696 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Howie, B.N., Donnelly, P. & Marchini, J. A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet. 5, e1000529 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Auton, A. et al. A global reference for human genetic variation. Nature 526, 68–74 (2015).

    Article  PubMed  CAS  Google Scholar 

  89. Alexander, D.H., Novembre, J. & Lange, K. Fast model-based estimation of ancestry in unrelated individuals. Genome Res. 19, 1655–1664 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Price, A.L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006).

    Article  CAS  PubMed  Google Scholar 

  91. Benonisdottir, S. et al. Epigenetic and genetic components of height regulation. Nat. Commun. 7, 13490 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Gudbjartsson, D.F. et al. Large-scale whole-genome sequencing of the Icelandic population. Nat. Genet. 47, 435–444 (2015).

    Article  CAS  PubMed  Google Scholar 

  93. Kong, A. et al. Detection of sharing by descent, long-range phasing and haplotype imputation. Nat. Genet. 40, 1068–1075 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Styrkarsdottir, U. et al. Nonsense mutation in the LGR4 gene is associated with several human diseases and other traits. Nature 497, 517–520 (2013).

    Article  CAS  PubMed  Google Scholar 

  95. Sveinbjornsson, G. et al. HLA class II sequence variants influence tuberculosis risk in populations of European ancestry. Nat. Genet. 48, 318–322 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. McLaren, W. et al. Deriving the consequences of genomic variants with the Ensembl API and SNP Effect Predictor. Bioinformatics 26, 2069–2070 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Flicek, P. et al. Ensembl 2012. Nucleic Acids Res. 40, D84–D90 (2012).

    Article  CAS  PubMed  Google Scholar 

  98. Pruitt, K.D., Tatusova, T., Brown, G.R. & Maglott, D.R. NCBI Reference Sequences (RefSeq): current status, new features and genome annotation policy. Nucleic Acids Res. 40, D130–D135 (2012).

    Article  CAS  PubMed  Google Scholar 

  99. Bulik-Sullivan, B.K. et al. LD Score regression distinguishes confounding from polygenicity in genome-wide association studies. Nat. Genet. 47, 291–295 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Rao, S.S. et al. A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping. Cell 159, 1665–1680 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Kundaje, A. et al. Integrative analysis of 111 reference human epigenomes. Nature 518, 317–330 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature 489, 57–74 (2012).

Download references

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.).

Author information

Authors and Affiliations

Authors

Contributions

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.

Corresponding authors

Correspondence to Ingileif Jonsdottir, Björn Nilsson or Kari Stefansson.

Ethics declarations

Competing interests

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.

Supplementary information

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)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.3897

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing