title: Pathway-based variant enrichment analysis on the example of dilated cardiomyopathy.
abstract: Genome-wide association (GWA) studies have significantly contributed to the understanding of human genetic variation and its impact on clinical traits. Frequently only a limited number of highly significant associations were considered as biologically relevant. Increasingly, network analysis of affected genes is used to explore the potential role of the genetic background on disease mechanisms. Instead of first determining affected genes or calculating scores for genes and performing pathway analysis on the gene level, we integrated both steps and directly calculated enrichment on the genetic variant level. The respective approach has been tested on dilated cardiomyopathy (DCM) GWA data as showcase. To compute significance values, 5000 permutation tests were carried out and p values were adjusted for multiple testing. For 282 KEGG pathways, we computed variant enrichment scores and significance values. Of these, 65 were significant. Surprisingly, we discovered the "nucleotide excision repair" and "tuberculosis" pathways to be most significantly associated with DCM (p = 10(-9)). The latter pathway is driven by genes of the HLA-D antigen group, a finding that closely resembles previous discoveries made by expression quantitative trait locus analysis in the context of DCM-GWA. Next, we implemented a sub-network-based analysis, which searches for affected parts of KEGG, however, independent on the pre-defined pathways. Here, proteins of the contractile apparatus of cardiac cells as well as the FAS sub-network were found to be affected by common polymorphisms in DCM. In this work, we performed enrichment analysis directly on variants, leveraging the potential to discover biological information in thousands of published GWA studies. The applied approach is cutoff free and considers a ranked list of genetic variants as input.
authors.affiliation: Chair for Clinical Bioinformatics, Saarland University, Building E2.1, 66123, Saarbrücken, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Backes
authors.affiliation: Department of Internal Medicine III, University Hospital Heidelberg, Heidelberg, Germany.|German Center for Cardiovascular Research (DZHK), Heidelberg, Germany.|Klaus Tschira Institute for Integrative Computational Cardiology, Heidelberg, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Meder
authors.affiliation: Department of Internal Medicine III, University Hospital Heidelberg, Heidelberg, Germany.|German Center for Cardiovascular Research (DZHK), Heidelberg, Germany.
authors.forename: Alan
authors.initials: A
authors.lastname: Lai
authors.affiliation: Department of Genetic Epidemiology, Institute of Human Genetics, University of Münster, Münster, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Stoll
authors.affiliation: Department of Genetic Epidemiology, Institute of Human Genetics, University of Münster, Münster, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Rühle
authors.affiliation: Department of Internal Medicine III, University Hospital Heidelberg, Heidelberg, Germany.|German Center for Cardiovascular Research (DZHK), Heidelberg, Germany.|Klaus Tschira Institute for Integrative Computational Cardiology, Heidelberg, Germany.
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.affiliation: Chair for Clinical Bioinformatics, Saarland University, Building E2.1, 66123, Saarbrücken, Germany. andreas.keller@ccb.uni-saarland.de.
authors.forename: Andreas
authors.identifier: http://orcid.org/0000-0002-5361-0895
authors.initials: A
authors.lastname: Keller
mesh_terms: D002311:Cardiomyopathy, Dilated / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans