title: Pathway-based factor analysis of gene expression data produces highly heritable phenotypes that associate with age.
abstract: Statistical factor analysis methods have previously been used to remove noise components from high-dimensional data prior to genetic association mapping and, in a guided fashion, to summarize biologically relevant sources of variation. Here, we show how the derived factors summarizing pathway expression can be used to analyze the relationships between expression, heritability, and aging. We used skin gene expression data from 647 twins from the MuTHER Consortium and applied factor analysis to concisely summarize patterns of gene expression to remove broad confounding influences and to produce concise pathway-level phenotypes. We derived 930 "pathway phenotypes" that summarized patterns of variation across 186 KEGG pathways (five phenotypes per pathway). We identified 69 significant associations of age with phenotype from 57 distinct KEGG pathways at a stringent Bonferroni threshold ([Formula: see text]). These phenotypes are more heritable ([Formula: see text]) than gene expression levels. On average, expression levels of 16% of genes within these pathways are associated with age. Several significant pathways relate to metabolizing sugars and fatty acids; others relate to insulin signaling. We have demonstrated that factor analysis methods combined with biological knowledge can produce more reliable phenotypes with less stochastic noise than the individual gene expression levels, which increases our power to discover biologically relevant associations. These phenotypes could also be applied to discover associations with other environmental factors.
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, United Kingdom NORMENT, KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
authors.forename: Andrew
authors.initials: A
authors.lastname: Anand Brown
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, United Kingdom.
authors.forename: Zhihao
authors.initials: Z
authors.lastname: Ding
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, St. Thomas' Campus, Westminster Bridge Road, London SE1 7EH, United Kingdom.
authors.forename: Ana
authors.initials: A
authors.lastname: Viñuela
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, St. Thomas' Campus, Westminster Bridge Road, London SE1 7EH, United Kingdom.
authors.forename: Dan
authors.initials: D
authors.lastname: Glass
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, United Kingdom.
authors.forename: Leopold
authors.initials: L
authors.lastname: Parts
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, St. Thomas' Campus, Westminster Bridge Road, London SE1 7EH, United Kingdom.
authors.forename: Tim
authors.initials: T
authors.lastname: Spector
authors.affiliation: Microsoft Research, Cambridge CB1 2FB, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Winn
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, United Kingdom rd@sanger.ac.uk.
authors.forename: Richard
authors.initials: R
authors.lastname: Durbin
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics* / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D008875:Middle Aged; D008954:Models, Biological; D010641:Phenotype; D015398:Signal Transduction
keywords: aging; factor analysis; gene expression; heritability; linear mixed models