title: Mining the human phenome using allelic scores that index biological intermediates.
abstract: It is common practice in genome-wide association studies (GWAS) to focus on the relationship between disease risk and genetic variants one marker at a time. When relevant genes are identified it is often possible to implicate biological intermediates and pathways likely to be involved in disease aetiology. However, single genetic variants typically explain small amounts of disease risk. Our idea is to construct allelic scores that explain greater proportions of the variance in biological intermediates, and subsequently use these scores to data mine GWAS. To investigate the approach's properties, we indexed three biological intermediates where the results of large GWAS meta-analyses were available: body mass index, C-reactive protein and low density lipoprotein levels. We generated allelic scores in the Avon Longitudinal Study of Parents and Children, and in publicly available data from the first Wellcome Trust Case Control Consortium. We compared the explanatory ability of allelic scores in terms of their capacity to proxy for the intermediate of interest, and the extent to which they associated with disease. We found that allelic scores derived from known variants and allelic scores derived from hundreds of thousands of genetic markers explained significant portions of the variance in biological intermediates of interest, and many of these scores showed expected correlations with disease. Genome-wide allelic scores however tended to lack specificity suggesting that they should be used with caution and perhaps only to proxy biological intermediates for which there are no known individual variants. Power calculations confirm the feasibility of extending our strategy to the analysis of tens of thousands of molecular phenotypes in large genome-wide meta-analyses. We conclude that our method represents a simple way in which potentially tens of thousands of molecular phenotypes could be screened for causal relationships with disease without having to expensively measure these variables in individual disease collections.
authors.affiliation: MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom ; School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom ; University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: David M
authors.initials: DM
authors.lastname: Evans
authors.forename: Marie Jo A
authors.initials: MJ
authors.lastname: Brion
authors.forename: Lavinia
authors.initials: L
authors.lastname: Paternoster
authors.forename: John P
authors.initials: JP
authors.lastname: Kemp
authors.forename: George
authors.initials: G
authors.lastname: McMahon
authors.forename: Marcus
authors.initials: M
authors.lastname: Munafò
authors.forename: John B
authors.initials: JB
authors.lastname: Whitfield
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Medland
authors.forename: Grant W
authors.initials: GW
authors.lastname: Montgomery
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Timpson
authors.forename: Beate
authors.initials: B
authors.lastname: St Pourcain
authors.forename: Debbie A
authors.initials: DA
authors.lastname: Lawlor
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Martin
authors.forename: Abbas
authors.initials: A
authors.lastname: Dehghan
authors.forename: Joel
authors.initials: J
authors.lastname: Hirschhorn
authors.forename: George Davey
authors.initials: GD
authors.lastname: Smith
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics; D000483:Alleles; D002097:C-Reactive Protein / Q000235:genetics; D030342:Genetic Diseases, Inborn / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008137:Longitudinal Studies; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; C090202:COG2 protein, human; D002097:C-Reactive Protein