An Efficient Score Test Integrated with Empirical Bayes for Genome-Wide Association Studies

Abstract

Many methods used in multi-locus genome-wide association studies (GWAS) have been developed to improve statistical power. However, most existing multi-locus methods are not quicker than single-locus methods. To address this concern, we proposed a fast score test integrated with Empirical Bayes (ScoreEB) for multi-locus GWAS. Firstly, a score test was conducted for each single nucleotide polymorphism (SNP) under a linear mixed model (LMM) framework, taking into account the genetic relatedness and population structure. Then, all of the potentially associated SNPs were selected with a less stringent criterion. Finally, Empirical Bayes in a multi-locus model was performed for all of the selected SNPs to identify the true quantitative trait nucleotide (QTN). Our new method ScoreEB adopts the similar strategy of multi-locus random-SNP-effect mixed linear model (mrMLM) and fast multi-locus random-SNP-effect EMMA (FASTmrEMMA), and the only difference is that we use the score test to select all the potentially associated markers. Monte Carlo simulation studies demonstrate that ScoreEB significantly improved the computational efficiency compared with the popular methods mrMLM, FASTmrEMMA, iterative modified-sure independence screening EM-Bayesian lasso (ISIS EM-BLASSO), hybrid of restricted and penalized maximum likelihood (HRePML) and genome-wide efficient mixed model association (GEMMA). In addition, ScoreEB remained accurate in QTN effect estimation and effectively controlled false positive rate. Subsequently, ScoreEB was applied to re-analyze quantitative traits in plants and animals. The results show that ScoreEB not only can detect previously reported genes, but also can mine new genes.

Keywords: computational efficiency; empirical bayes; genome-wide association studies; linear mixed model; multi-locus; score test.