Understanding the effect of genetic sequence variation on phenotype is a major challenge that lies at the heart of genetics. We developed GOLPH (GenOmic Linkage to PHenotype), a statistical method to identify genetic interactions, and used it to characterize the landscape of genetic interactions between gene expression quantitative trait loci. Our results reveal that allele-specific interactions, in which a gene only exerts an influence on the phenotype in the presence of a particular allele at the primary locus, are widespread and that genetic interactions are predominantly nonadditive. The data portray a complex picture in which interacting loci influence the expression of modules of coexpressed genes involved in coherent biological processes and pathways. We show that genetic variation at a single gene can have a major impact on the global transcriptional response, altering interactions between genes through shutdown or activation of pathways. Thus, different cellular states occur not only in response to the external environment but also result from intrinsic genetic variation.