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

Xinchen Wang, Nathan R Tucker, Gizem Rizki, Robert Mills, Peter Hl 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

Research output: Contribution to journal/periodicalArticleScientificpeer-review

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
JournaleLife
Volume5
DOIs
Publication statusPublished - 2016

Fingerprint Dive into the research topics of 'Discovery and validation of sub-threshold genome-wide association study loci using epigenomic signatures'. Together they form a unique fingerprint.

  • Cite this

    Wang, X., Tucker, N. R., Rizki, G., Mills, R., Krijger, P. H., de Wit, E., Subramanian, V., Bartell, E., Nguyen, X-X., Ye, J., Leyton-Mange, J., Dolmatova, E. V., van der Harst, P., de Laat, W., Ellinor, P. T., Newton-Cheh, C., Milan, D. J., Kellis, M., & Boyer, L. A. (2016). Discovery and validation of sub-threshold genome-wide association study loci using epigenomic signatures. eLife, 5. https://doi.org/10.7554/eLife.10557