Genome-Wide Association Analyses Based on Broadly Different Specifications for Prior Distributions, Genomic Windows, and Estimation Methods

摘要

A currently popular strategy (EMMAX) for genome-wide association (GWA) analysis infers association for the specific marker of interest by treating its effect as fixed while treating all other marker effects as classical Gaussian random effects. It may be more statistically coherent to specify all markers as sharing the same prior distribution, whether that distribution is Gaussian, heavy-tailed (BayesA), or has variable selection specifications based on a mixture of, say, two Gaussian distributions [stochastic search and variable selection (SSVS)]. Furthermore, all such GWA inference should be formally based on posterior probabilities or test statistics as we present here, rather than merely being based on point estimates. We compared these three broad categories of priors within a simulation study to investigate the effects of different degrees of skewness for quantitative trait loci (QTL) effects and numbers of QTL using 43,266 SNP marker genotypes from 922 Duroc–Pietrain F2-cross pigs. Genomic regions were based either on single SNP associations, on nonoverlapping windows of various fixed sizes (0.5–3 Mb), or on adaptively determined windows that cluster the genome into blocks based on linkage disequilibrium. We found that SSVS and BayesA lead to the best receiver operating curve properties in almost all cases. We also evaluated approximate maximum a posteriori (MAP) approaches to BayesA and SSVS as potential computationally feasible alternatives; however, MAP inferences were not promising, particularly due to their sensitivity to starting values. We determined that it is advantageous to use variable selection specifications based on adaptively constructed genomic window lengths for GWA studies.