Engelbrecht, E.; Rodriguez, O. L.; Lees, W.; Vanwinkle, Z.; Shields, K.; Schultze, S.; Gibson, W. S.; Smith, D. R.; Jana, U.; Saha, S.; Peres, A.; Yaari, G.; Smith, M. L.; Watson, C. T.

Variation in antibody (Ab) responses contributes to disease outcomes and therapeutic responsiveness, the determinants of which remain incompletely understood. This study demonstrates that polymorphisms in immunoglobulin kappa (IGK) and lambda (IGL) loci influence baseline differences in the Ab repertoire that preclude antigen-driven responses. We pair IGK/IGL genomic sequencing with Ab repertoire profiling to comprehensively resolve coding and non-coding single nucleotide and structural variants that explain gene usage variation at >70% of light chain genes, with direct impacts on the amino acid composition of complementarity determining regions. The identification of both intergenic and coding repertoire-associated variants indicates genetic modulation of gene usage via diverse mechanisms. Relative to IGL, IGK is characterized by extensive linkage disequilibrium and genetic co-regulation of gene usage, highlighting differential regulatory and evolutionary features. These results establish the contribution of IG polymorphism in the formation of the Ab repertoire, shedding light on our understanding of Ab-mediated immunity.