How does the new PLINK handle the X chromosome in association tests run with logistic regression?

[Stephanie Schmit]

In the PLINK v1.07 FAQ, it states:

"By default, in the linear and logistic (--linear, --logistic) models, for alleles A and B, males are coded

     A   ->   0
     B   ->   1

and females are coded

     AA  ->   0
     AB  ->   1
     BB  ->   2

and additionally sex (0=male,1=female) is also automatically included as a covariate. It is therefore important not to include sex as a separate covariate in a covariate file ever, but rather to use the special --sex command that tells PLINK to add sex as coded in the PED/FAM file as the covariate (in this way, it is not double entered for X chromosome markers). If the sample is all female or all male, PLINK will know not to add sex as an additional covariate for X chromosome markers. The basic association tests that are allelic (--assoc, --mh, etc) do not need any special changes for X chromosome markers: the above only applies to the linear and logistic models where the individual, not the allele, is the unit of analysis. Similarly, the TDT remains unchanged. For the --model test and Hardy-Weinberg calculations, male X chromosome genotypes are excluded. Not all analyses currently handle X chromosomes markers (for example, LD pruning, epistasis, IBS calculations) but support will be added in future."

In PLINK 1.9, I see that: "By default, when at least one male and one female is present, sex (male = 1, female = 0) is automatically added as a covariate on X chromosome SNPs, and nowhere else. The 'sex' modifier causes it to be added everywhere, while 'no-x-sex' excludes it." 

However, as in PLINK v1.07, are male X chromosome genotypes also coded as 0/1 by default? How is the 'sex' option implemented with imputed/dosage data? 

Thank you!

[Christopher Chang]

* Yes, for backward compatibility with v1.07, v1.9 uses 0/1 male X coding unless you specified an alternative with --xchr-model.

* 'sex' should behave the same way with dosage data as it does with hardcalls.

[Sarah Nelson]

Following up to get a clearer understanding of the TDT test on chromosome X (non-PAR regions). According to this paper, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1288152/, it sounded like the TDT is different for X (non-PAR) markers, so I'm confused why the PLINK documentation says the "TDT remains unchanged" on the X. http://zzz.bwh.harvard.edu/plink/faq.shtml#faq9

Thanks for helping me understand this!

~Sarah 

[Christopher Chang]

PLINK 1.x TDT assigns equal weight to male and female children on chrX.  It may be better to assign twice as much weight to males than females (see https://genomemedicine.biomedcentral.com/articles/10.1186/gm110 ), but it shouldn't make that much of a difference.