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

Wang X, Tucker NR, Rizki G, Mills R, Krijger PH, de Wit E, Subramanian V, Bartell E, Nguyen XX, 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 - Elife (2016)

Bottom Line: 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 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, United States.

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.

No MeSH data available.


Related in: MedlinePlus

4C-seq interactions with 10 enhancers in 8 sub-threshold loci.Height of blue bars represents interaction strength with 4C viewpoint. Red curves indicate enhancer-promoter interactions called within an annotated GENCODE promoter (up to 2.5 kb upstream of TSS) at a threshold of 5.0.DOI:http://dx.doi.org/10.7554/eLife.10557.016
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fig4s3: 4C-seq interactions with 10 enhancers in 8 sub-threshold loci.Height of blue bars represents interaction strength with 4C viewpoint. Red curves indicate enhancer-promoter interactions called within an annotated GENCODE promoter (up to 2.5 kb upstream of TSS) at a threshold of 5.0.DOI:http://dx.doi.org/10.7554/eLife.10557.016

Mentions: (a) Model detailing how sub-threshold SNPs overlapping enhancers can affect QT interval. Green text: methods used to test mechanistic step in model. (b) Summary of luciferase enhancer reporter experiments. Left, luciferase enhancer reporter construct. Right, number of loci tested in panel d that exhibits significant allelic activity (p<0.05 between two haplotypes). (c), Left, schematic of a 3-D enhancer-promoter chromatin interaction detectable by 4C-seq. Right, number of loci tested in panel d where an enhancer-promoter interaction is observed in human iPS-derived cardiomyocytes by 4C-seq. (d) Experimental evidence that sub-threshold SNPs alter enhancer activity and that sub-threshold enhancers interact with gene promoters. Fold below GWS column represents degree to which sub-threshold locus is below genome-wide significance (5x10-8); Luciferase reporter column colored green if significant allelic difference in activity (p<0.05, Figure 4—figure supplement 1); Enhancer-promoter interactions column colored green if there is a detectable enhancer-promoter interaction by 4C-seq (Figure 4—figure supplement 3).


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

Wang X, Tucker NR, Rizki G, Mills R, Krijger PH, de Wit E, Subramanian V, Bartell E, Nguyen XX, 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 - Elife (2016)

4C-seq interactions with 10 enhancers in 8 sub-threshold loci.Height of blue bars represents interaction strength with 4C viewpoint. Red curves indicate enhancer-promoter interactions called within an annotated GENCODE promoter (up to 2.5 kb upstream of TSS) at a threshold of 5.0.DOI:http://dx.doi.org/10.7554/eLife.10557.016
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4862755&req=5

fig4s3: 4C-seq interactions with 10 enhancers in 8 sub-threshold loci.Height of blue bars represents interaction strength with 4C viewpoint. Red curves indicate enhancer-promoter interactions called within an annotated GENCODE promoter (up to 2.5 kb upstream of TSS) at a threshold of 5.0.DOI:http://dx.doi.org/10.7554/eLife.10557.016
Mentions: (a) Model detailing how sub-threshold SNPs overlapping enhancers can affect QT interval. Green text: methods used to test mechanistic step in model. (b) Summary of luciferase enhancer reporter experiments. Left, luciferase enhancer reporter construct. Right, number of loci tested in panel d that exhibits significant allelic activity (p<0.05 between two haplotypes). (c), Left, schematic of a 3-D enhancer-promoter chromatin interaction detectable by 4C-seq. Right, number of loci tested in panel d where an enhancer-promoter interaction is observed in human iPS-derived cardiomyocytes by 4C-seq. (d) Experimental evidence that sub-threshold SNPs alter enhancer activity and that sub-threshold enhancers interact with gene promoters. Fold below GWS column represents degree to which sub-threshold locus is below genome-wide significance (5x10-8); Luciferase reporter column colored green if significant allelic difference in activity (p<0.05, Figure 4—figure supplement 1); Enhancer-promoter interactions column colored green if there is a detectable enhancer-promoter interaction by 4C-seq (Figure 4—figure supplement 3).

Bottom Line: 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 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, United States.

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.

No MeSH data available.


Related in: MedlinePlus