Systemic lupus erythematosus (SLE) is a generalised autoimmune disease that can affect virtually any organ/tissue. It exhibits marked sexual dimorphism, being ten times more prevalent in females; it is also more common in non-European populations. Genome-wide association studies have mapped approximately 80 risk loci that implicate a range of cells in both the innate and adaptive immune systems. The disease heterogeneity remains to be explained, however, our preliminary analyses suggest that genetic risk operates in a quantitative rather than qualitative manner. I will finally take one example of an SLE risk locus (TNFSF4) that encodes the lymphocyte costimulatory molecule OX40L. I will outline, how transancestral analysis, gene expression studies and the use of mouse models support a cellular mechanism through which the genetic risk alleles predispose to SLE.