title: Pathway analysis for genetic association studies: to do, or not to do? That is the question.
abstract: In Genetic Analysis Workshop 18 data, we used a 3-stage approach to explore the benefits of pathway analysis in improving a model to predict 2 diastolic blood pressure phenotypes as a function of genetic variation. At stage 1, gene-based tests of association in family data of approximately 800 individuals found over 600 genes associated at p<0.05 for each phenotype. At stage 2, networks and enriched pathways were estimated with Cytoscape for genes from stage 1, separately for the 2 phenotypes, then examining network overlap. This overlap identified 4 enriched pathways, and 3 of these pathways appear to interact, and are likely candidates for playing a role in hypertension. At stage 3, using 157 maximally unrelated individuals, partial least squares regression was used to find associations between diastolic blood pressure and single-nucleotide polymorphisms in genes highlighted by the pathway analyses. However, we saw no improvement in the adjusted cross-validated R (2). Although our pathway-motivated regressions did not improve prediction of diastolic blood pressure, merging gene networks did identify several plausible pathways for hypertension.
authors.affiliation: Department of Epidemiology, Biostatistics and Occupational Health, McGill University, 1020 Pine Avenue West, Montreal, Quebec, H3A 1A2, Canada.
authors.forename: Line
authors.initials: L
authors.lastname: Dufresne
authors.affiliation: Département de Mathématiques, Université du Québec à Montréal, PK-5151, 201 avenue du Président-Kennedy, Montréal, QC H2X 3Y7, Canada.
authors.forename: Karim
authors.initials: K
authors.lastname: Oualkacha
authors.affiliation: Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Côte Ste. Catherine, Montreal, QC, H3T 1E2, Canada.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Forgetta
authors.affiliation: Department of Epidemiology, Biostatistics and Occupational Health, McGill University, 1020 Pine Avenue West, Montreal, Quebec, H3A 1A2, Canada ; Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Côte Ste. Catherine, Montreal, QC, H3T 1E2, Canada ; Department of Oncology, McGill University, Montreal, QC, Canada.
authors.forename: Celia Mt
authors.initials: CM
authors.lastname: Greenwood