Journal Article

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

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

2016

Overview

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. Most complex traits are governed by a large number of genetic contributors, each playing only a modest effect. This makes it difficult to identify the genetic variants that increase disease risk, hindering the discovery of new drug targets and the development of new therapeutics. To overcome this limitation in discovery power, the field of human genetics has traditionally sought increasingly large groups, or cohorts, of afflicted and non-afflicted individuals. Studies of large cohorts are a powerful approach for discovering new disease genes, but such groups are often impractical and sometimes impossible to obtain. However, it has become possible to complement the genetic evidence found in disease association studies with biological evidence of the effects of disease-associated genetic variants. Wang et al. focus specifically on genetic sites, or loci, that do not affect protein sequence but instead affect the non-coding control regions. These are known as enhancer elements, as they can enhance the expression of nearby genes. These loci constitute the majority of disease regions, and thus are extremely important, but their discovery has been hindered by our relatively poor understanding of the human genome. Chemical modifications known as epigenomic marks are indicative of enhancer regions. By studying the factors that affect heart rhythm, Wang et al. show that specific combinations of epigenomic marks are enriched in known trait-associated regions. This knowledge was then used to prioritize the further investigation of genetic regions that genome-wide association studies had only weakly linked to heart rhythm alterations. Wang et al. directly confirmed that genetic differences in “sub-threshold” regions indeed alter the activity of these regulatory regions in human heart cells. Furthermore, mutating or perturbing the predicted target genes of the sub-threshold enhancers caused heart defects in mouse and zebrafish. Wang et al. have demonstrated that epigenome maps can help to distinguish which sub-threshold regions from genome-wide association studies are more likely to contribute to a disease. This allows for the discovery of new disease genes with much smaller cohorts than would be needed otherwise, thus speeding up the development of new therapeutics by many years.

• Publisher: eLife Science Publications, Ltd,eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: Animals / complex trait / Consortia / Disease / Electrocardiography / Embryos / enhancer / Enhancers / Epigenetic inheritance / Epigenomics / Gene loci / Gene mapping / Gene regulation / Genetic diversity / Genetic Loci / Genome-wide association studies / Genome-Wide Association Study / Genomes / Genomics and Evolutionary Biology / Heart / Heart Conduction System - physiology / Heart diseases / Heritability / Human Biology and Medicine / Humans / Information processing / Laboratory animals / Mice / Observations / Quantitative trait loci