The genetic regulation of the immune system in health and disease

The immune system is a complex biological network of specialized cells and molecules that evolved to defend against pathogens and, in healthy condition, distinguishes between self and non-self antigens. Despite its relevance for human health, only a few studies have systematically evaluated the genetic influence on immune cells1,2,3. Some years ago, we completed the first GWAS assessing the genetic control of 95 leukocytes subsets in 2,870 general population individuals from the SardiNIA cohort. We identified multiple variant-trait associations at 13 loci, four of which overlapping with disease risk variants, revealing parameters potentially involved in disease pathogenesis1. The efficacy of this approach was demonstrated by our group that identified and clarified the mechanism of action of a complex variant, in the 3'UTR of the BAFF gene, associated with 18 immune endo-phenotypes and predisposing for multiple sclerosis and systemic lupus erythematosus4. Here we extended the previous characterization of immune cells to about 2,500 traits, related to the levels of 300 immune cell subtypes assessed in up to 4,000 volunteers from the SardiNIA cohort. We performed a GWAS, interrogating >26M variants, identifying 135 independent associations in 69 genetic loci (p-value<6.9x10-11). Among these, 30 association signals are shared between immune traits and diseases. These data will help to understand the biological mechanisms underlying the links between pathologies and immune cells and to identify new therapeutic targets for personalized medicine. 1.Orrù V. et al, Cell 2013; 2.Roederer M. et al, Cell 2015; 3.Patin E. et al, Nat Immunol 2018; 4.Steri M. et al, NEJM 2017