Deciphering the Emerging Complexities of Molecular Mechanisms at GWAS Loci

Genome-wide association studies (GWASs) have identified thousands of loci associated with hundreds of complex diseases and traits, and progress is being made toward elucidating the causal variants and genes underlying these associations. Functional characterization of mechanisms at GWAS loci is a multi-faceted challenge. Challenges include linkage disequilibrium and allelic heterogeneity at each locus, the noncoding nature of most loci, and the time and cost needed for experimentally evaluating the potential mechanistic contributions of genes and variants. As GWAS sample sizes increase, more loci are identified, and the complexities of individual loci emerge. Loci can consist of multiple association signals, each of which can reflect the influence of multiple variants, inseparable by association analyses. Each signal within a locus can influence the same or different target genes. Experimental studies of genes and variants can differ on the basis of cell type, cellular environment, or other context-specific variables. In this review, we describe the complexity of mechanisms at GWAS loci—including multiple signals, multiple variants, and/or multiple genes—and the implications these complexities hold for experimental study design and interpretation of GWAS mechanisms