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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

Sub-threshold loci associated with QT interval length are enriched in H3K4me1-defined left ventricle enhancers.Enrichment was calculated by comparing the number of loci that overlap an enhancer against 100,000 sets of randomly sampled control loci matched for genetic properties (LD block size, MAF, distance to nearest gene, number of nearest genes and presence on genotyping array).DOI:http://dx.doi.org/10.7554/eLife.10557.011
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fig3s3: Sub-threshold loci associated with QT interval length are enriched in H3K4me1-defined left ventricle enhancers.Enrichment was calculated by comparing the number of loci that overlap an enhancer against 100,000 sets of randomly sampled control loci matched for genetic properties (LD block size, MAF, distance to nearest gene, number of nearest genes and presence on genotyping array).DOI:http://dx.doi.org/10.7554/eLife.10557.011

Mentions: Whether the enrichment of SNPs in the sub-threshold significance range represents linkage disequilibrium with existing above-threshold GWAS SNPs or novel biologically relevant loci remains an unresolved question (Maurano et al., 2012). In fact, an enrichment analysis using only SNPs nearby above-threshold GWAS loci produced a strong enrichment signature in the sub-threshold significance range (Figure 3—figure supplement 2). To distinguish between the two possibilities, we took a conservative approach and removed all SNPs within 1Mb of the initial 112 QT/QRS loci. Remarkably, the enrichment for LV enhancers persists and increases in the sub-threshold range (i.e. p=1x10-4 to 5x10-8, Figure 3b), likely due to removal of nominally significant SNPs that are in LD with above-threshold QT/QRS loci and do not represent true association signals. The enrichment for active LV enhancers in sub-threshold loci is not driven by biases in MAF, LD block size, distance to nearest gene, number of nearby genes, or presence on a SNP genotyping array (Figure 3—figure supplement 3). In total, we identified 2075 SNPs with p<1x10-4 that are independent of the 112 published QT/QRS loci, of which 208 SNPs overlap LV enhancers (Supplementary file 2).


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)

Sub-threshold loci associated with QT interval length are enriched in H3K4me1-defined left ventricle enhancers.Enrichment was calculated by comparing the number of loci that overlap an enhancer against 100,000 sets of randomly sampled control loci matched for genetic properties (LD block size, MAF, distance to nearest gene, number of nearest genes and presence on genotyping array).DOI:http://dx.doi.org/10.7554/eLife.10557.011
© Copyright Policy
Related In: Results  -  Collection

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

fig3s3: Sub-threshold loci associated with QT interval length are enriched in H3K4me1-defined left ventricle enhancers.Enrichment was calculated by comparing the number of loci that overlap an enhancer against 100,000 sets of randomly sampled control loci matched for genetic properties (LD block size, MAF, distance to nearest gene, number of nearest genes and presence on genotyping array).DOI:http://dx.doi.org/10.7554/eLife.10557.011
Mentions: Whether the enrichment of SNPs in the sub-threshold significance range represents linkage disequilibrium with existing above-threshold GWAS SNPs or novel biologically relevant loci remains an unresolved question (Maurano et al., 2012). In fact, an enrichment analysis using only SNPs nearby above-threshold GWAS loci produced a strong enrichment signature in the sub-threshold significance range (Figure 3—figure supplement 2). To distinguish between the two possibilities, we took a conservative approach and removed all SNPs within 1Mb of the initial 112 QT/QRS loci. Remarkably, the enrichment for LV enhancers persists and increases in the sub-threshold range (i.e. p=1x10-4 to 5x10-8, Figure 3b), likely due to removal of nominally significant SNPs that are in LD with above-threshold QT/QRS loci and do not represent true association signals. The enrichment for active LV enhancers in sub-threshold loci is not driven by biases in MAF, LD block size, distance to nearest gene, number of nearby genes, or presence on a SNP genotyping array (Figure 3—figure supplement 3). In total, we identified 2075 SNPs with p<1x10-4 that are independent of the 112 published QT/QRS loci, of which 208 SNPs overlap LV enhancers (Supplementary file 2).

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