Discovery and validation of sub-threshold genome-wide association study loci using epigenomic signatures

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Discovery and validation of sub-threshold genome-wide association study loci using epigenomic signatures

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Title: Discovery and validation of sub-threshold genome-wide association study loci using epigenomic signatures
Author: Wang, Xinchen; Tucker, Nathan R; Rizki, Gizem; Mills, Robert; Krijger, Peter HL; de Wit, Elzo; Subramanian, Vidya; Bartell, Eric; Nguyen, Xinh-Xinh; Ye, Jiangchuan; Leyton-Mange, Jordan; Dolmatova, Elena V; van der Harst, Pim; de Laat, Wouter; Ellinor, Patrick T; Newton-Cheh, Christopher; Milan, David J; Kellis, Manolis; Boyer, Laurie A

Note: Order does not necessarily reflect citation order of authors.

Citation: Wang, X., N. R. Tucker, G. Rizki, R. Mills, P. H. Krijger, E. de Wit, V. Subramanian, et al. 2016. “Discovery and validation of sub-threshold genome-wide association study loci using epigenomic signatures.” eLife 5 (1): e10557. doi:10.7554/eLife.10557. http://dx.doi.org/10.7554/eLife.10557.
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Abstract: Genetic variants identified by genome-wide association studies explain only a modest proportion of heritability, suggesting that meaningful associations lie 'hidden' below current thresholds. Here, we integrate information from association studies with epigenomic maps to demonstrate that enhancers significantly overlap known loci associated with the cardiac QT interval and QRS duration. We apply functional criteria to identify loci associated with QT interval that do not meet genome-wide significance and are missed by existing studies. We demonstrate that these 'sub-threshold' signals represent novel loci, and that epigenomic maps are effective at discriminating true biological signals from noise. We experimentally validate the molecular, gene-regulatory, cellular and organismal phenotypes of these sub-threshold loci, demonstrating that most sub-threshold loci have regulatory consequences and that genetic perturbation of nearby genes causes cardiac phenotypes in mouse. Our work provides a general approach for improving the detection of novel loci associated with complex human traits. DOI: http://dx.doi.org/10.7554/eLife.10557.001
Published Version: doi:10.7554/eLife.10557
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4862755/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:27320221
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