Laying a solid foundation for Manhattan – ‘setting the functional basis for the post-GWAS era’

• Noncoding genetic risk variants affect regulatory elements, chromatin architecture, or ncRNA.
• Integrative functional methodologies inferring the function of risk loci are emerging.
• Functional GWAS analysis can guide next-generation association studies.
• Integrative functional GWAS methods inform on how to study noncoding mutations.

Genome-wide association studies (GWAS) have identified more than 8900 genetic variants, mainly single-nucleotide polymorphisms (SNPs), associated with hundreds of human traits and diseases, which define risk-associated loci. Variants that map to coding regions can affect protein sequence, translation rate, and alternative splicing, all of which influence protein function. However, the vast majority of sequence variants map to non-coding intergenic and intronic regions, and it has been much more challenging to assess the functional nature of these variants. Recent work annotating the non-coding regions of the genome has contributed to post-GWAS studies by facilitating the identification of the functional targets of risk-associated loci. Many non-coding genetic variants within risk-associated loci alter gene expression by modulating the activity of cis-regulatory elements. We review here these recent findings, discuss their implication for the post-GWAS era, and relate their importance to the interpretation of disease-associated mutations identified through whole-genome sequencing.