The X chromosome presents multiple analytical challenges,
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14 including (1) a male has one copy of the X chromosome while a female has two, in contrast to the autosomes; (2) the X chromosome in male germ cells only recombines with the Y chromosome in the pseudo-autosomal regions (PARs) but not in the NPR; (3) in contrast to males, the two copies in female germ cells recombine across the entire X chromosome; (4) the two female copies are also subject to X inactivation (i.e., X chromosome dosage compensation); (5) the X-inactivation status at the population level can be random, skewed, or absent (i.e., X-inactivation escape); and (6) the true X-inactivation status at the individual level cannot be derived from GWAS data alone.