Genetic and genome-wide association studies (GWAS) have identified a myriad of human disease-associated genomic variants. However, these studies do not reveal the mechanisms by which these variants perturb cellular networks, a necessary step to intervene and improve disease outcomes. This has been challenging because multiple variants are present in haplotype blocks, thereby confounding the identification of causal variants, and because most reside in noncoding regions. Here, we review recent advances in the identification of functional variants and gene-variant associations. In addition, we examine approaches used to study perturbations in protein–protein and protein–DNA interactions associated with disease, and discuss how these perturbations affect cellular networks.