Journal de biométrie et biostatistique

The Effect of Linkage Disequilibrium on Bayesian Genome-wide Association Methods

Abstract

Stephan Weinwurm, Johann Sölkner and Patrik Waldmann

The goal of genome-wide association studies (GWAS) is to identify the best subset of single-nucleotide polymorphisms (SNPs) that strongly influence a certain trait. State of the art GWAS comprise several thousand or even millions of SNPs, scored on a substantially lower number of individuals. Hence, the number of variables greatly exceeds the number of observations, which also is known as the p�¢���«n problem.
This problem has been tackled by using Bayesian variable selection methods, for example stochastic search variable selection (SSVS) and Bayesian penalized regression methods (Bayesian lasso; BLA and Bayesian ridge regression; BRR). Even though the above mentioned approaches are capable of dealing with situations where p�¢���«n, it is also known that these methods experience problems when the predictor variables are correlated. The potential problem that linkage disequilibrium (LD) between SNPs can introduce is often ignored.
The main contribution of this study is to assess the performance of SSVS, BLA, BRR and a recently introduced method denoted hybrid correlation based search (hCBS) with respect to their ability to identify quantitative trait loci, where SNPs are partially highly correlated. Furthermore, each method’s capability to predict phenotypes based on the selected SNPs and their computational demands are studied. Comparison is based upon three simulated datasets where the simulated phenotypes are assumed to be normally distributed.
Results indicate that all methods perform reasonably well with respect to true positive detections but often detect too many false positives on all datasets. As the heritability decreases, the Bayesian penalized regression methods are no longer able to detect any predictors because of shrinkage. Overall, BLA slightly outperformed the other methods and provided superior results in terms of highest true positive/ false positive ratio, but SSVS achieved the best properties on the real LD data.