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Mendelian randomization (MR) is an epidemiological method that can be used tostrengthen causal inference regarding the relationship between a modifiableenvironmental exposure and a medically relevant trait and to estimate themagnitude of this relationship1. Recently, there has been considerable interestin using MR to examine potential causal relationships between parentalphenotypes and outcomes amongst their offspring. In a recent issue of BMCResearch Notes, Woolf et al (2023) present a new method, GWAS by subtraction,to derive genome-wide summary statistics for paternal smoking and otherpaternal phenotypes with the goal that these estimates can then be used indownstream (including two sample) MR studies. Whilst a potentially useful goal,Woolf et al. (2023) focus on the wrong parameter of interest for usefulgenome-wide association studies (GWAS) and downstream cross-generational MRstudies, and the estimator that they derive is neither efficient norappropriate for such use.

Woolf et als GWAS by subtraction is not useful for cross-generational Mendelian randomization studies