A systematic review of analytical methods used in genetic association analysis of the X-chromosome

Abstract

Genetic association studies have been very successful at elucidating the genetic background of many complex diseases/traits. However, the X-chromosome is often neglected in these studies because of technical difficulties and the fact that most tools only utilize genetic data from autosomes. In this review, we aim to provide an overview of different practical approaches that are followed to incorporate the X-chromosome in association analysis, such as Genome-Wide Association Studies and Expression Quantitative Trait Loci Analysis. In general, the choice of which test statistics is most appropriate will depend on three main criteria: (1) the underlying X-inactivation model, (2) if Hardy-Weinberg equilibrium holds and sex-specific allele frequencies are expected and (3) whether adjustment for confounding variables is required. All in all, it is recommended that a combination of different association tests should be used for the analysis of X-chromosome.

Keywords: GWAS; X-chromosome; X-inactivation; association analysis; eQTL; linear regression.

Figure 1

Flowchart of the criteria for selecting the most appropriate test statistics for X-chromosome analysis. The green boxes present tools that can be used to help make a selection regarding XCI (XCI inference), and the blue and pink colored boxes correspond to test statistics and regression-based approaches, respectively.