Figure 1: Architecture of singlegene disorders versus a model of autoimmune diseases caused by complex traits.

a, In simple mendelian traits, the relationship between the causal genetic variant (genotype) and the disease state is deterministic. b, In complex traits, the clinically recognized disease state results from interactions between multiple genotypes and the environment. Individual genotypes can affect one or more components of the adaptive or innate immune systems; together these lead to an altered immune response to self antigens. On the basis of current findings, the influence of any individual causal allele is modest, and therefore the relationship between the causal variant and the disease state is probabilistic. Although still providing an incomplete picture, the genetic discoveries in mendelian and common diseases are beginning to help build a model of autoimmune disease. The ultimate goal is to build a specific model for each individual disease whereby the effect of individual risk factors (genetic and non-genetic), their interactions, and their impact on disease susceptibility, disease progression and clinical management, are understood.