The so-called "smoking gene" (rs16969968) is a genetic variant that predisposes individuals with the variant to smoking and lung cancer. This genetic variant is also known as "Mr. Big," and "The Big One." In VanderWeele's study referenced in the book, the interaction impact between the smoking gene and smoking was overlooked so the mediation analysis was inaccurate.

"Smoking Gene"

 Also known as the "smoking gene," hypothesis, R.A. Fisher claimed:

1.  Specific genes, whichever they may be, negatively influence an individual's risk for lung cancer.  
2.  Some of such genes also negatively influence whether people become smokers.

University of Michigan - Ann Arbor

Cornfield's inequality was the first formal method for sensitivity analysis in observational studies. It provides a way to prevent causal relationships from being immediately refuted with the assertion that a new factor is the true cause. 

Cornfield's Inequality

Pearl, J., & Mackenzie, D. (2018). $\mathit{The \ Book \ of \ Why: \ The \ New \ Science \ of \ Cause \ and \ Effect.}$ Basic Books.

The Book of Why

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2755131/

The Book of why gives the example of Cornfield's refutation of R. A. Fisher's claim that a "Smoking Gene" could be the true cause of lung cancer deaths.

Given that studies showed that smokers were nine times more likely to develop lung cancer than non smokers, it would follow that if 11 percent of non-smokers have the “smoking gene,” then 99 percent of the
smokers would have to have the smoking gene to hold the relationship. Further, if 12% of non-smokers had the gene, it would be mathematically impossible for the smoking gene to account for the association. 

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