Deciphering the Emerging Complexities of Molecular Mechanisms at GWAS Loci

Abstract

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.

Keywords: SNP; allelic heterogeneity; complex trait; gene; genome-wide association study; human genetics; mechanism; signal; variant.

Figure 1

Process for Evaluating a GWAS Locus Many approaches exist for identifying mechanisms at GWAS loci. In this review, we address three major questions at GWAS loci: (1) How many association signals exist at a locus? (2) What are the candidate causal variant(s)? (3) What are the target gene(s)? This flowchart shows how an accumulation of evidence can address these questions.

Figure 2

Hypothetical GWAS Locus with Two Signals that Affect Two Genes (A) Plot of association for two signals within 100 kb at a single GWAS locus. The first signal is shown by red circles, and the second is shown by blue triangles. The intensity of color corresponds to the strength of LD between the lead variant and other variants in the signal. (B) Hypothetical regulatory marks overlapping the positions of candidate variants. Arrows point to variants that overlap predicted regulatory regions: four for signal 1 and four for signal 2. Signal 1 variants could target gene 1, and signal 2 variants could target gene 2 because variants are located in each respective promoter.

Figure 3

Hypotheses for Multiple Target Genes at a GWAS Locus Multiple target genes can be present at a single GWAS locus. Three examples show how multiple genes might be affected. At a locus with one GWAS signal, an enhancer containing GWAS variants could target two genes simultaneously, or different genes could be targeted depending on cell type or cellular context. At a locus with two signals, each signal could target different genes. Other mechanisms could exist.