This main focus of this dissertation is the mapping of intermediate endophenotypes in order to characterize the molecular basis of inter-individual variation in immune disease susceptibility. In the context of a complex autoimmune disease, systemic lupus erythematosus (SLE), chapter 2 describes the mapping of serum interferon-alpha (IFN-α) activity, a stable heritable molecular endophenotype, in SLE cases. This approach enabled identification of loci that could exert their effects on SLE susceptibility through dysregulation of the IFN-α pathway. The loci identified in this chapter have not been identified in previous case-control genome-wide association studies (GWAS) in SLE, highlighting the utility of the endophenotype mapping approach. In chapters 3 and 4, endophenotype analysis is used to characterize inter-individual variation in response to vitamin D, an important immunomodulator which is a modifiable environmental factor for autoimmune diseases. The patterns of transcriptional response to the active hormonal form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25D), in the presence or absence of the pro-inflammatory bacterial lipopolysaccharide (LPS), are described in chapter 3. The opposite effects of 1,25D and LPS on the transcriptome are highlighted, as well as potential molecular mechanisms through which 1,25D exerts its immunomodulatory role, such as through induction of genes in the mTOR signaling and EIF2 signaling pathways. The genetic basis of the inter-individual variation in response to 1,25D is discussed in chapter 4, where cellular and transcriptional endophenotypes were jointly analyzed to increase the power to detect novel loci. The polymorphisms underlying variation in cellular and transcriptional response to 1,25D that were identified in this study highlighted various loci that potentially mediate the immunomodulatory activities of 1,25D. Overall, the work described in this dissertation demonstrates that it is possible to detect the genetic determinants of intermediate endophenotypes, such as IFN-α activity in SLE, and cellular and transcriptional response to vitamin D, using relatively small sample sizes. These loci may not only underlie inter-individual variation in susceptibility to immune-mediated diseases, but they may also provide potential therapeutic targets for these diseases.