META-GSA: Combining Findings from Gene-Set Analyses across Several Genome-Wide Association Studies.
<h4>Introduction</h4>Gene-set analysis (GSA) methods are used as complementary approaches to genome-wide association studies (GWASs). The single marker association estimates of a predefined set of genes are either contrasted with those of all remaining genes or with a null non-associated...
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Public Library of Science (PLoS)
2015-01-01
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| Online Access: | https://doi.org/10.1371/journal.pone.0140179 |
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| author | Albert Rosenberger Stefanie Friedrichs Christopher I Amos Paul Brennan Gordon Fehringer Joachim Heinrich Rayjean J Hung Thomas Muley Martina Müller-Nurasyid Angela Risch Heike Bickeböller |
| author_facet | Albert Rosenberger Stefanie Friedrichs Christopher I Amos Paul Brennan Gordon Fehringer Joachim Heinrich Rayjean J Hung Thomas Muley Martina Müller-Nurasyid Angela Risch Heike Bickeböller |
| author_sort | Albert Rosenberger |
| collection | DOAJ |
| description | <h4>Introduction</h4>Gene-set analysis (GSA) methods are used as complementary approaches to genome-wide association studies (GWASs). The single marker association estimates of a predefined set of genes are either contrasted with those of all remaining genes or with a null non-associated background. To pool the p-values from several GSAs, it is important to take into account the concordance of the observed patterns resulting from single marker association point estimates across any given gene set. Here we propose an enhanced version of Fisher's inverse χ2-method META-GSA, however weighting each study to account for imperfect correlation between association patterns.<h4>Simulation and power</h4>We investigated the performance of META-GSA by simulating GWASs with 500 cases and 500 controls at 100 diallelic markers in 20 different scenarios, simulating different relative risks between 1 and 1.5 in gene sets of 10 genes. Wilcoxon's rank sum test was applied as GSA for each study. We found that META-GSA has greater power to discover truly associated gene sets than simple pooling of the p-values, by e.g. 59% versus 37%, when the true relative risk for 5 of 10 genes was assume to be 1.5. Under the null hypothesis of no difference in the true association pattern between the gene set of interest and the set of remaining genes, the results of both approaches are almost uncorrelated. We recommend not relying on p-values alone when combining the results of independent GSAs.<h4>Application</h4>We applied META-GSA to pool the results of four case-control GWASs of lung cancer risk (Central European Study and Toronto/Lunenfeld-Tanenbaum Research Institute Study; German Lung Cancer Study and MD Anderson Cancer Center Study), which had already been analyzed separately with four different GSA methods (EASE; SLAT, mSUMSTAT and GenGen). This application revealed the pathway GO0015291 "transmembrane transporter activity" as significantly enriched with associated genes (GSA-method: EASE, p = 0.0315 corrected for multiple testing). Similar results were found for GO0015464 "acetylcholine receptor activity" but only when not corrected for multiple testing (all GSA-methods applied; p ≈ 0.02). |
| format | Article |
| id | doaj-art-7394ce57ca4f4906addd8991627c3321 |
| institution | DOAJ |
| issn | 1932-6203 |
| language | English |
| publishDate | 2015-01-01 |
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| spelling | doaj-art-7394ce57ca4f4906addd8991627c33212025-08-20T03:10:02ZengPublic Library of Science (PLoS)PLoS ONE1932-62032015-01-011010e014017910.1371/journal.pone.0140179META-GSA: Combining Findings from Gene-Set Analyses across Several Genome-Wide Association Studies.Albert RosenbergerStefanie FriedrichsChristopher I AmosPaul BrennanGordon FehringerJoachim HeinrichRayjean J HungThomas MuleyMartina Müller-NurasyidAngela RischHeike Bickeböller<h4>Introduction</h4>Gene-set analysis (GSA) methods are used as complementary approaches to genome-wide association studies (GWASs). The single marker association estimates of a predefined set of genes are either contrasted with those of all remaining genes or with a null non-associated background. To pool the p-values from several GSAs, it is important to take into account the concordance of the observed patterns resulting from single marker association point estimates across any given gene set. Here we propose an enhanced version of Fisher's inverse χ2-method META-GSA, however weighting each study to account for imperfect correlation between association patterns.<h4>Simulation and power</h4>We investigated the performance of META-GSA by simulating GWASs with 500 cases and 500 controls at 100 diallelic markers in 20 different scenarios, simulating different relative risks between 1 and 1.5 in gene sets of 10 genes. Wilcoxon's rank sum test was applied as GSA for each study. We found that META-GSA has greater power to discover truly associated gene sets than simple pooling of the p-values, by e.g. 59% versus 37%, when the true relative risk for 5 of 10 genes was assume to be 1.5. Under the null hypothesis of no difference in the true association pattern between the gene set of interest and the set of remaining genes, the results of both approaches are almost uncorrelated. We recommend not relying on p-values alone when combining the results of independent GSAs.<h4>Application</h4>We applied META-GSA to pool the results of four case-control GWASs of lung cancer risk (Central European Study and Toronto/Lunenfeld-Tanenbaum Research Institute Study; German Lung Cancer Study and MD Anderson Cancer Center Study), which had already been analyzed separately with four different GSA methods (EASE; SLAT, mSUMSTAT and GenGen). This application revealed the pathway GO0015291 "transmembrane transporter activity" as significantly enriched with associated genes (GSA-method: EASE, p = 0.0315 corrected for multiple testing). Similar results were found for GO0015464 "acetylcholine receptor activity" but only when not corrected for multiple testing (all GSA-methods applied; p ≈ 0.02).https://doi.org/10.1371/journal.pone.0140179 |
| spellingShingle | Albert Rosenberger Stefanie Friedrichs Christopher I Amos Paul Brennan Gordon Fehringer Joachim Heinrich Rayjean J Hung Thomas Muley Martina Müller-Nurasyid Angela Risch Heike Bickeböller META-GSA: Combining Findings from Gene-Set Analyses across Several Genome-Wide Association Studies. PLoS ONE |
| title | META-GSA: Combining Findings from Gene-Set Analyses across Several Genome-Wide Association Studies. |
| title_full | META-GSA: Combining Findings from Gene-Set Analyses across Several Genome-Wide Association Studies. |
| title_fullStr | META-GSA: Combining Findings from Gene-Set Analyses across Several Genome-Wide Association Studies. |
| title_full_unstemmed | META-GSA: Combining Findings from Gene-Set Analyses across Several Genome-Wide Association Studies. |
| title_short | META-GSA: Combining Findings from Gene-Set Analyses across Several Genome-Wide Association Studies. |
| title_sort | meta gsa combining findings from gene set analyses across several genome wide association studies |
| url | https://doi.org/10.1371/journal.pone.0140179 |
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