title: Pedigree-based random effect tests to screen gene pathways.
abstract: The new generation of sequencing platforms opens new horizons in the genetics field. It is possible to exhaustively assay all genetic variants in an individual and search for phenotypic associations. The whole genome sequencing approach, when applied to a large human sample like the San Antonio Family Study, detects a very large number (>25 million) of single nucleotide variants along with other more complex variants. The analytical challenges imposed by this number of variants are formidable, suggesting that methods are needed to reduce the overall number of statistical tests. In this study, we develop a single degree-of-freedom test of variants in a gene pathway employing a random effect model that uses an empirical pathway-specific genetic relationship matrix as the focal covariance kernel. The empirical pathway-specific genetic relationship uses all variants (or a chosen subset) from gene members of a given biological pathway. Using SOLAR's pedigree-based variance components modeling, which also allows for arbitrary fixed effects, such as principal components, to deal with latent population structure, we employ a likelihood ratio test of the pathway-specific genetic relationship matrix model. We examine all gene pathways in KEGG database gene pathways using our method in the first replicate of the Genetic Analysis Workshop 18 simulation of systolic blood pressure. Our random effect approach was able to detect true association signals in causal gene pathways. Those pathways could be easily be further dissected by the independent analysis of all markers.
authors.affiliation: Department of Genetics, Texas Biomedical Research Institute. 7620 NW Loop 410, San Antonio, TX 78245, USA.
authors.forename: Marcio
authors.initials: M
authors.lastname: Almeida
authors.affiliation: Department of Genetics, Texas Biomedical Research Institute. 7620 NW Loop 410, San Antonio, TX 78245, USA.|Centre for Genetic Epidemiology and Biostatistics, University of Western Australia, WA, Australia.
authors.forename: Juan M
authors.initials: JM
authors.lastname: Peralta
authors.affiliation: Department of Genetics, Texas Biomedical Research Institute. 7620 NW Loop 410, San Antonio, TX 78245, USA.
authors.forename: Vidya
authors.initials: V
authors.lastname: Farook
authors.affiliation: Department of Genetics, Texas Biomedical Research Institute. 7620 NW Loop 410, San Antonio, TX 78245, USA.
authors.forename: Sobha
authors.initials: S
authors.lastname: Puppala
authors.affiliation: Department of Genetics, Texas Biomedical Research Institute. 7620 NW Loop 410, San Antonio, TX 78245, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Kent
authors.affiliation: Department of Genetics, Texas Biomedical Research Institute. 7620 NW Loop 410, San Antonio, TX 78245, USA.
authors.forename: Ravindranath
authors.initials: R
authors.lastname: Duggirala
authors.affiliation: Department of Genetics, Texas Biomedical Research Institute. 7620 NW Loop 410, San Antonio, TX 78245, USA.
authors.forename: John
authors.initials: J
authors.lastname: Blangero