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

Xinchen Wang, Nathan R. Tucker, Gizem Rizki, Robert Mills, Peter Hugo Lodewijk Krijger, Elzo de Wit, Vidya Subramanian, Eric Bartell, Xinh Xinh Nguyen, Jiangchuan Ye, Jordan Leyton-Mange, Elena V. Dolmatova, Pim Van Der Harst, Wouter De Laat, Patrick T. Ellinor, Christopher Newton-Cheh, David J. Milan, Manolis Kellis, Laurie A. Boyer*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

1 Citation (Scopus)

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.

Original languageEnglish
Article numbere10557
JournaleLife
Volume2016
Issue number5
DOIs
Publication statusPublished - 10 May 2016

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