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The X-chromosome is often excluded from genome-wide association studiesbecause of analytical challenges. Some of the problems, such as the random,skewed or no X-inactivation model uncertainty, have been investigated. Otherconsiderations have received little to no attention, such as the value inconsidering non-additive and gene-sex interaction effects, and the inferentialconsequence of choosing different baseline alleles (i.e.\ the reference vs.\the alternative allele). Here we propose a unified and flexibleregression-based association test for X-chromosomal variants. We providetheoretical justifications for its robustness in the presence of various modeluncertainties, as well as for its improved power when compared with theexisting approaches under certain scenarios. For completeness, we also revisitthe autosomes and show that the proposed framework leads to a more robustapproach than the standard method. Finally, we provide supporting evidence byrevisiting several published association studies. Supplementary materials forthis article are available online.

The X Factor: A Robust and Powerful Approach to X-chromosome-Inclusive Whole-genome Association Studies