Addressing genetic heterogeneity in complex disease: finding seizure genes in systemic lupus erythematosus.

Complex genetic disease is inherently difficult to study due to an imperfect relationship between genotype and phenotype. One important reason for this imperfect relationship is genetic heterogeneity, the occurrence of different genetic factors underlying the same clinical syndrome. One method of addressing genetic heterogeneity is covariate-based linkage analysis, which allows the use of additional phenotypic features to define genetically distinct subsets of patients. Systemic lupus erythematosus (SLE) is one example of a complex genetic disease affecting multiple organ systems including the central nervous system. We report here the use of covariate-based linkage analysis to detect a potential genetic locus on chromosome 15 influencing the development of seizures in individuals with SLE. The use of covariates increases the power to detect linkage in the presence of genetic heterogeneity.