The Post-GWAS Era: From Association to Function

Abstract

During the past 12 years, genome-wide association studies (GWASs) have uncovered thousands of genetic variants that influence risk for complex human traits and diseases. Yet functional studies aimed at delineating the causal genetic variants and biological mechanisms underlying the observed statistical associations with disease risk have lagged. In this review, we highlight key advances in the field of functional genomics that may facilitate the derivation of biological meaning post-GWAS. We highlight the evidence suggesting that causal variants underlying disease risk often function through regulatory effects on the expression of target genes and that these expression effects might be modest and cell-type specific. We moreover discuss specific studies as proof-of-principle examples for current statistical, bioinformatic, and empirical bench-based approaches to downstream elucidation of GWAS-identified disease risk loci.

Figure 1

Mechanistic Understanding of Disease Risk Loci Identified by GWASs Lags Far Behind the Discovery of New SNP-Trait Associations The EBI GWAS catalog was used to determine the number of total GWASs reported from 2005 through the end of 2016, which are shown in blue. The number of post-GWAS functional studies reported each year were also identified (orange line) by (1) reviewing the titles, and in some cases, abstracts, of all research articles published in 23 relevant biomedical research journals^∗, and (2) searching PubMed using the keywords “causal variant” or “functional variant.” Additional studies were identified through references from primary research or review articles found as described. ^∗American Journal of Human Genetics, Cancer Cell, Cell, Cell Reports, Cell Stem Cell, eLife, Genome Biology, Genome Research, Human Molecular Genetics, Molecular Cell, Nature, Nature Biotechnology, Nature Communications, Nature Genetics, Nature Medicine, Nature Neuroscience, Nature Structural & Molecular Biology, Neuron, PLOS Genetics, PNAS, Science, Science Translational Medicine, Stem Cell Reports