  Mendelian randomization (MR) is an epidemiological method that can be used to
strengthen causal inference regarding the relationship between a modifiable
environmental exposure and a medically relevant trait and to estimate the
magnitude of this relationship1. Recently, there has been considerable interest
in using MR to examine potential causal relationships between parental
phenotypes and outcomes amongst their offspring. In a recent issue of BMC
Research Notes, Woolf et al (2023) present a new method, GWAS by subtraction,
to derive genome-wide summary statistics for paternal smoking and other
paternal phenotypes with the goal that these estimates can then be used in
downstream (including two sample) MR studies. Whilst a potentially useful goal,
Woolf et al. (2023) focus on the wrong parameter of interest for useful
genome-wide association studies (GWAS) and downstream cross-generational MR
studies, and the estimator that they derive is neither efficient nor
appropriate for such use.
