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

Beyond GWASs: illuminating the dark road from association to function.

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  • 1Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4029, Australia; School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Queensland 4072, Australia. Electronic address:


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.

Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

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