Large-scale GWAS meta-analysis of serum antibody levels reveals distinct genetic architectures

Antibodies are the principal effector proteins of humoral immunity. Dysregulated antibody production is a feature of a number of heritable immune-mediated diseases, such as the antibody deficiencies and IgA nephropathy. To characterise the common-variant architecture of serum antibody levels in the general population, we conducted the largest GWAS meta-analyses to date of serum IgA, IgM, and IgG, attaining sample sizes of 55,368, 58,777, and 85,204, respectively. We identified 82 novel associations across three isotypes. We found that isotype-specific genetic architecture was largely disjointed with few signals colocalising across isotypes in spite of their overall positive genetic correlation. We identified a large number of colocalisations between antibody phenotypes and immune-mediated diseases, and 16 between antibody phenotypes and a lymphocyte count phenotype. We report a greatly expanded catalogue of serum antibody-associated variants and characterise these in terms of their pathway context and relation to immune pathology.