Identification of sequence variants influencing immunoglobulin levels

Nat Genet. 2017 Aug;49(8):1182-1191. doi: 10.1038/ng.3897. Epub 2017 Jun 19.


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.

MeSH terms

  • Cohort Studies
  • Female
  • Genetic Predisposition to Disease
  • Genetic Variation*
  • Genome-Wide Association Study
  • Hematopoiesis / genetics
  • Humans
  • Iceland
  • Immunity, Humoral / genetics
  • Immunoglobulin Class Switching / genetics
  • Immunoglobulin Isotypes / genetics
  • Immunoglobulins / genetics*
  • Male
  • Polymorphism, Single Nucleotide
  • Sweden


  • Immunoglobulin Isotypes
  • Immunoglobulins