Population-scale immunoglobulin genetics resolves the human B-cell system

Immunoglobulins (Ig) mediate adaptive humoral immunity, yet the regulation of B-cell responses in vivo in humans remains inaccessible to direct experimentation. Here we use population-scale Ig genetics to resolve molecular regulation of the human B-cell system. Analysis of circulating IgA, IgG, IgM, and six composite Ig traits in 114,697 individuals identifies 504 genetic associations. Integration with regulatory genomics, plasma proteomics, and immunophenotyping maps these effects across the B-cell hierarchy, recovering known regulators and revealing previously unrecognized genes in humoral immunity. At key control nodes - including Fc-gamma receptors, the immunoglobulin heavy-chain locus and the TACI-APRIL signaling axis - variants form allelic series generating graded perturbations of antibody output. Ig-associated loci show extensive overlap with autoimmunity, immunodeficiency and B-cell malignancy. These findings demonstrate that Ig traits, analyzed at population scale, encode fine-grained information about the regulation of the human B-cell system and link natural variation in humoral immunity to immune-mediated disease.