title: Discovery and validation of sub-threshold genome-wide association study loci using epigenomic signatures.
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.
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, United States.|Broad Institute of MIT and Harvard, Cambridge, United States.|Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, United States.
authors.forename: Xinchen
authors.identifier: 0000-0002-5198-6581
authors.initials: X
authors.lastname: Wang
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Boston, United States.
authors.forename: Nathan R
authors.initials: NR
authors.lastname: Tucker
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, United States.
authors.forename: Gizem
authors.initials: G
authors.lastname: Rizki
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Boston, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: Mills
authors.affiliation: Hubrecht Institute-KNAW, University Medical Center Utrecht, Utrecht, Netherlands.|University Medical Center Utrecht, Utrecht, Netherlands.
authors.forename: Peter Hl
authors.initials: PH
authors.lastname: Krijger
authors.affiliation: Hubrecht Institute-KNAW, University Medical Center Utrecht, Utrecht, Netherlands.|University Medical Center Utrecht, Utrecht, Netherlands.
authors.forename: Elzo
authors.initials: E
authors.lastname: de Wit
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, United States.
authors.forename: Vidya
authors.initials: V
authors.lastname: Subramanian
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, United States.
authors.forename: Eric
authors.initials: E
authors.lastname: Bartell
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Boston, United States.
authors.forename: Xinh-Xinh
authors.initials: XX
authors.lastname: Nguyen
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Boston, United States.
authors.forename: Jiangchuan
authors.initials: J
authors.lastname: Ye
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Boston, United States.
authors.forename: Jordan
authors.initials: J
authors.lastname: Leyton-Mange
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Boston, United States.
authors.forename: Elena V
authors.initials: EV
authors.lastname: Dolmatova
authors.affiliation: Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.|Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
authors.forename: Pim
authors.initials: P
authors.lastname: van der Harst
authors.affiliation: Hubrecht Institute-KNAW, University Medical Center Utrecht, Utrecht, Netherlands.|University Medical Center Utrecht, Utrecht, Netherlands.
authors.forename: Wouter
authors.initials: W
authors.lastname: de Laat
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, United States.|Cardiovascular Research Center, Massachusetts General Hospital, Boston, United States.
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Ellinor
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, United States.|Cardiovascular Research Center, Massachusetts General Hospital, Boston, United States.|Center for Human Genetic Research, Massachusetts General Hospital, Boston, United States.
authors.forename: Christopher
authors.initials: C
authors.lastname: Newton-Cheh
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Boston, United States.
authors.forename: David J
authors.initials: DJ
authors.lastname: Milan
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, United States.|Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, United States.
authors.forename: Manolis
authors.initials: M
authors.lastname: Kellis
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, United States.
authors.forename: Laurie A
authors.initials: LA
authors.lastname: Boyer
mesh_terms: D000818:Animals; D057890:Epigenomics; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D006329:Heart Conduction System / Q000502:physiology*; D006801:Humans; D051379:Mice
keywords: complex traits; enhancers; epigenomics; evolutionary biology; genome-wide association study; genomics; heritability; human; human biology; medicine; mouse; zebrafish