title: Simultaneous analysis of all SNPs in genome-wide and re-sequencing association studies.
abstract: Testing one SNP at a time does not fully realise the potential of genome-wide association studies to identify multiple causal variants, which is a plausible scenario for many complex diseases. We show that simultaneous analysis of the entire set of SNPs from a genome-wide study to identify the subset that best predicts disease outcome is now feasible, thanks to developments in stochastic search methods. We used a Bayesian-inspired penalised maximum likelihood approach in which every SNP can be considered for additive, dominant, and recessive contributions to disease risk. Posterior mode estimates were obtained for regression coefficients that were each assigned a prior with a sharp mode at zero. A non-zero coefficient estimate was interpreted as corresponding to a significant SNP. We investigated two prior distributions and show that the normal-exponential-gamma prior leads to improved SNP selection in comparison with single-SNP tests. We also derived an explicit approximation for type-I error that avoids the need to use permutation procedures. As well as genome-wide analyses, our method is well-suited to fine mapping with very dense SNP sets obtained from re-sequencing and/or imputation. It can accommodate quantitative as well as case-control phenotypes, covariate adjustment, and can be extended to search for interactions. Here, we demonstrate the power and empirical type-I error of our approach using simulated case-control data sets of up to 500 K SNPs, a real genome-wide data set of 300 K SNPs, and a sequence-based dataset, each of which can be analysed in a few hours on a desktop workstation.
authors.affiliation: Department of Epidemiology and Public Health, Imperial College, London, United Kingdom. c.hoggart@ic.ac.uk
authors.forename: Clive J
authors.initials: CJ
authors.lastname: Hoggart
authors.forename: John C
authors.initials: JC
authors.lastname: Whittaker
authors.forename: Maria
authors.initials: M
authors.lastname: De Iorio
authors.forename: David J
authors.initials: DJ
authors.lastname: Balding
mesh_terms: D000465:Algorithms; D001499:Bayes Theorem; D016022:Case-Control Studies; D002877:Chromosomes, Human; D003198:Computer Simulation; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005240:Feasibility Studies; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D016013:Likelihood Functions; D015810:Linkage Disequilibrium; D020161:Physical Chromosome Mapping; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D012984:Software