Read on Twitter
Below is the start of a thread by a geneticist on discovering that the most extreme single genetic variant he can find in @GWASCatalog actually tells you about the huge importance of the environment in causing disease https://twitter.com/Eric_Fauman/status/1275175100153769985
ALDH2 variation strongly influences alcohol consumption, and can be used in Mendelian Randomization (MR) studies to demonstrate that alcohol drinking has a large unfavourable effect on blood pressure https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.0050052
In East Asian populations where traditionally women drink very little, the effect of the allele on blood pressure is only seen in men (among whom many drink). The lack of an effect in women and the (statistically extremely) interaction with sex provides a "negative control"..
validation of the MR result. ALDH2 is a common variant in East Asia and (among men) has by far the largest influence on blood pressure of any common SNP; this was not seen in early East Asian GWAS 'cos they used SNP arrays suitable for European-origin populations .. no rs671
So the largest germline genetic influence on blood pressure is entirely mediated by the environment. Whilst many spurious gene by environment interactions were lauded (the sad story of gullibility is told here https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3222234/) the fact that robust ones demonstrate ..
the importance of the environment is little acknowledged. Similar interactions demonstrate that far from being beneficial for overall cardiovascular disease mortality, alcohol increases risk across the entire range of consumption https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)31772-0/fulltext
and the same approach can be used to show that (1) alcohol intake increases risk of oesophageal cancer; (2) the mechanism through this is through the downstream metabolite of alcohol, acetaldehyde https://cebp.aacrjournals.org/content/cebp/14/8/1967.full.pdf
