title: Reprioritizing genetic associations in hit regions using LASSO-based resample model averaging.
abstract: Significance testing one SNP at a time has proven useful for identifying genomic regions that harbor variants affecting human disease. But after an initial genome scan has identified a "hit region" of association, single-locus approaches can falter. Local linkage disequilibrium (LD) can make both the number of underlying true signals and their identities ambiguous. Simultaneous modeling of multiple loci should help. However, it is typically applied ad hoc: conditioning on the top SNPs, with limited exploration of the model space and no assessment of how sensitive model choice was to sampling variability. Formal alternatives exist but are seldom used. Bayesian variable selection is coherent but requires specifying a full joint model, including priors on parameters and the model space. Penalized regression methods (e.g., LASSO) appear promising but require calibration, and, once calibrated, lead to a choice of SNPs that can be misleadingly decisive. We present a general method for characterizing uncertainty in model choice that is tailored to reprioritizing SNPs within a hit region under strong LD. Our method, LASSO local automatic regularization resample model averaging (LLARRMA), combines LASSO shrinkage with resample model averaging and multiple imputation, estimating for each SNP the probability that it would be included in a multi-SNP model in alternative realizations of the data. We apply LLARRMA to simulations based on case-control genome-wide association studies data, and find that when there are several causal loci and strong LD, LLARRMA identifies a set of candidates that is enriched for true signals relative to single locus analysis and to the recently proposed method of Stability Selection.
authors.affiliation: Department of Genetics, and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7265, USA. william.valdar@unc.edu
authors.forename: William
authors.initials: W
authors.lastname: Valdar
authors.forename: Jeremy
authors.initials: J
authors.lastname: Sabourin
authors.forename: Andrew
authors.initials: A
authors.lastname: Nobel
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Holmes
mesh_terms: D000465:Algorithms; D001499:Bayes Theorem; D002138:Calibration; D016022:Case-Control Studies; D002874:Chromosome Mapping; D003198:Computer Simulation; D055106:Genome-Wide Association Study / Q000379:methods*; D005838:Genotype; D006801:Humans; D008957:Models, Genetic; D015233:Models, Statistical; D008962:Models, Theoretical; D017720:Molecular Epidemiology / Q000379:methods; D012372:ROC Curve; D012044:Regression Analysis