Genetics

This blog post critically examines the study by Pukaj et al., which reframes intrathecal immunoglobulin G (IgG) synthesis—quantified via the IgG index—as a genetically informative endophenotype in multiple sclerosis (MS). Using a large multicenter European cohort and genome-wide association analyses complemented by conditional modeling, Bayesian fine-mapping, and classical HLA imputation, the article delineates a substantial heritable component to intrathecal IgG production and identifies both established MHC-driven effects and a novel association at the SAMD5 locus. It further refines signals in the immunoglobulin heavy chain constant region (including a candidate missense variant in IGHA1) and demonstrates that polygenic risk for MS susceptibility correlates with the presence and magnitude of intrathecal IgG synthesis, supporting a mechanistic link between inherited MS risk and compartmentalized CNS humoral immunity.