X-Chromosome Multilocus Association Studies for Common and Rare Variants

X-chromosome association studies have specific model uncertainty challenges, such as unknown X-chromosome inactivation status and baseline allele, and whether to consider nonadditive and variant–sex interaction effects in the analysis. Although these challenges have been answered for single-locus X-chromosome variants, it remains unclear how to properly perform multilocus association studies when the above uncertainties are present. We first carefully investigate the inferential consequences of these uncertainties on existing multilocus association analysis methods and then propose a theoretically justified framework to analyze multilocus X-chromosome variants while addressing all the uncertainty issues. We provide separate solutions for common and rare variants, and simulation results show that our solutions are overall more powerful than existing multilocus methods that were proposed to analyze autosomal variants. We finally provide supporting evidence for our approach by revisiting some published X-chromosome association studies.