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

doi:10.7554/eLife.10557

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

Hubrecht Institute

Onderzoeksoutput: Bijdrage aan wetenschappelijk tijdschrift/periodieke uitgave › Artikel › Wetenschappelijk › peer review

79 Citaten (Scopus)

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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.

Originele taal-2	Engels
Tijdschrift	eLife
Volume	5
DOI's	https://doi.org/10.7554/eLife.10557
Status	Gepubliceerd - 2016

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10.7554/eLife.10557

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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

@article{d4d7e330786d433a8ea9fcc6ce6ed88b,

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.",

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

year = "2016",

doi = "10.7554/eLife.10557",

language = "English",

volume = "5",

journal = "eLife",

issn = "2050-084X",

publisher = "eLife Sciences Publications",

}

Wang, X, Tucker, NR, Rizki, G, Mills, R, Krijger, PH, de Wit, E, Subramanian, V, Bartell, E, Nguyen, X-X, Ye, J, Leyton-Mange, J, Dolmatova, EV, van der Harst, P, de Laat, W, Ellinor, PT, Newton-Cheh, C, Milan, DJ, Kellis, M & Boyer, LA 2016, 'Discovery and validation of sub-threshold genome-wide association study loci using epigenomic signatures', eLife, vol. 5. https://doi.org/10.7554/eLife.10557

TY - JOUR

T1 - Discovery and validation of sub-threshold genome-wide association study loci using epigenomic signatures

AU - Wang, Xinchen

AU - Tucker, Nathan R

AU - Rizki, Gizem

AU - Mills, Robert

AU - Krijger, Peter Hl

AU - de Wit, Elzo

AU - Subramanian, Vidya

AU - Bartell, Eric

AU - Nguyen, Xinh-Xinh

AU - Ye, Jiangchuan

AU - Leyton-Mange, Jordan

AU - Dolmatova, Elena V

AU - van der Harst, Pim

AU - de Laat, Wouter

AU - Ellinor, Patrick T

AU - Newton-Cheh, Christopher

AU - Milan, David J

AU - Kellis, Manolis

AU - Boyer, Laurie A

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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.

U2 - 10.7554/eLife.10557

DO - 10.7554/eLife.10557

M3 - Article

C2 - 27162171

SN - 2050-084X

VL - 5

JO - eLife

JF - eLife

ER -

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

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