Background Genomewide association studies of autoimmune diseases have mapped
hundreds of susceptibility regions in the genome. However, only for a few association
signals has the causal gene been identified, and for even fewer have the causal variant and
underlying mechanism been defined. Coincident associations of DNA variants affecting both
the risk of autoimmune disease and quantitative immune variables provide an informative
route to explore disease mechanisms and drug-targetable pathways. Methods Using case …

initially discovered an association with multiple sclerosis and systemic lupus erythematosus
in TNFSF13, a gene encoding the cytokine BAFF. By means of multiple GWASs in Sardinian
general population individuals, we then found that the same disease-risk-increasing allele at
TNFSF13B was associated with upregulated humoral immunity through increased levels of
soluble (s) BAFF, B lymphocytes, and immunoglobulins. Using fine mapping, transcriptomic
and functional studies we ultimately identified and characterized the causal variant: an …