This study integrates multiple recent concepts and technologies to address a major aim in medical genetics: identifying susceptibility loci for complex diseases, including Trisomy 21. In particular, we establish a category of quantitative cellular phenotypes that are closely linked to clinical manifestations and perform genome-wide linkage and association studies to detect regulatory loci Chapter I describes the set-up of an experimental protocol to measure a cellular phenotype in large population sizes. We choose to investigate reactive oxygen species (ROS) production as a fundamental cellular signaling phenotype related to the innate immune system that may be involved in clinical manifestations of Down syndrome patients. Chapter II and III investigate the gentics and the biological significance of phenotypic natural variation, both in cellular phenotypes and in gene expression levels. Both studies aim at identifying loci that regulate the correlations between genetic and natural phenotypic variation in human cell lines of several cohorts.