Clustering and principal-components approach based on heritability for mapping multiple gene expressions

When the number of phenotypes in a genetic study is on the scale of thousands, such as in studies concerning thousands of gene expression levels, the single-trait analysis is computationally intensive, and heavy adjustment of multiple comparisons is required. Traditional multivariate genetic linkage analysis for quantitative traits focuses on mapping only a few phenotypes and is not feasible for a large number of traits. To cope with high-dimensional phenotype data, clustering analysis and principal-component analysis (PCA) are proposed to reduce the data dimensionality and to map shared genetic contributions for multiple traits. However, standard clustering analysis and PCA are applicable for independent observations. In most genetic studies, where family data are collected, these standard analyses can only be applied to founders and can lead to the loss of information. Here, we proposed a clustering method that can exploit family structure information and applied the method to 29 gene expression levels mapped to a reported hot spot on chromosome 14. We then used a PCA approach based on heritability applicable to small number of traits to combine phenotypes in the clusters. Lastly, we used a penalized PCA approach based on heritability applicable to arbitrary number of traits to combine 150 gene expression levels with the highest heritability. Genome-wide multipoint linkage analysis was carried out on the individual traits and on the combined traits. Two previously reported peaks on chromosomes 14 and 20 were identified. Linkage evidence was stronger for traits derived from methods that incorporate family structure information.