Multilocus association testing of quantitative traits based on partial least-squares analysis

Abstract

Because of combining the genetic information of multiple loci, multilocus association studies (MLAS) are expected to be more powerful than single locus association studies (SLAS) in disease genes mapping. However, some researchers found that MLAS had similar or reduced power relative to SLAS, which was partly attributed to the increased degrees of freedom (dfs) in MLAS. Based on partial least-squares (PLS) analysis, we develop a MLAS approach, while avoiding large dfs in MLAS. In this approach, genotypes are first decomposed into the PLS components that not only capture majority of the genetic information of multiple loci, but also are relevant for target traits. The extracted PLS components are then regressed on target traits to detect association under multilinear regression. Simulation study based on real data from the HapMap project were used to assess the performance of our PLS-based MLAS as well as other popular multilinear regression-based MLAS approaches under various scenarios, considering genetic effects and linkage disequilibrium structure of candidate genetic regions. Using PLS-based MLAS approach, we conducted a genome-wide MLAS of lean body mass, and compared it with our previous genome-wide SLAS of lean body mass. Simulations and real data analyses results support the improved power of our PLS-based MLAS in disease genes mapping relative to other three MLAS approaches investigated in this study. We aim to provide an effective and powerful MLAS approach, which may help to overcome the limitations of SLAS in disease genes mapping.

Figure 1. Power comparing results of PLS-based MLAS (PLS_MLAS), PCA-based MLAS (PCA_MLAS), tagSNPs-based MLAS (tagSNPs_MLAS), TSM-based MLAS using F test (FTSM) and TSM-based MLAS using Wald test (WTSM) under the epistatic model.

Figure 2. Power comparing results of PLS-based MLAS (PLS_MLAS), PCA-based MLAS (PCA_MLAS), tagSNPs-based MLAS (tagSNPs_MLAS), TSM-based MLAS using F test (FTSM) and TSM-based MLAS using Wald test (WTSM) under the additive model.

Figure 3. Plot of genome-wide MLAS results of lean body mass implemented by PLS-based MLAS.

Significant genes are highlighted in red.