Beyond GWASs: illuminating the dark road from association to function

Am J Hum Genet. 2013 Nov 7;93(5):779-97. doi: 10.1016/j.ajhg.2013.10.012.


Genome-wide association studies (GWASs) have enabled the discovery of common genetic variation contributing to normal and pathological traits and clinical drug responses, but recognizing the precise targets of these associations is now the major challenge. Here, we review recent approaches to the functional follow-up of GWAS loci, including fine mapping of GWAS signal(s), prioritization of putative functional SNPs by the integration of genetic epidemiological and bioinformatic methods, and in vitro and in vivo experimental verification of predicted molecular mechanisms for identifying the targeted genes. The majority of GWAS-identified variants fall in noncoding regions of the genome. Therefore, this review focuses on strategies for assessing likely mechanisms affected by noncoding variants; such mechanisms include transcriptional regulation, noncoding RNA function, and epigenetic regulation. These approaches have already accelerated progress from genetic studies to biological knowledge and might ultimately guide the development of prognostic, preventive, and therapeutic measures.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Chromosome Mapping*
  • Computational Biology
  • Epigenesis, Genetic
  • Genetic Loci
  • Genetic Predisposition to Disease / genetics
  • Genome-Wide Association Study*
  • Humans
  • Neoplasms / genetics
  • Neoplasms / pathology
  • Phenotype
  • Polymorphism, Single Nucleotide*
  • RNA, Untranslated / genetics
  • Risk Factors


  • RNA, Untranslated