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
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 journals.plos.org/plosmedicine/a…
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 ncbi.nlm.nih.gov/pmc/articles/P…) 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 thelancet.com/journals/lance…
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 cebp.aacrjournals.org/content/cebp/1…
Why is this story not better known? Well, the alcohol industry don't like it, that's for sure. Here's a rather bizarre critique of MR studies showing detrimental effects of alcohol link.springer.com/content/pdf/10…
Here's our reply link.springer.com/content/pdf/10… Yes: the critique's 1st author was centrally involved in a supposed "randomized trial" funded by the alcohol industry that was designed to show that alcohol was good for you. They wanted to call the trial "Cheers" nytimes.com/2018/06/18/hea…
To his great credit @NIHDirector had this shoddy enterprise reviewed and the NIH shut it down. Here's the 165 page NIH report on the "trial", do read it, it's grimly hilarious. Emails from the "scientists" showed how far they were willing to go to ... acd.od.nih.gov/documents/pres…
get the answer the alcohol industry wanted. As alcohol unequivocally increases risk of breast cancer, the "scientists" would exclude women with a first degree relative with breast cancer. The "Wine information council" promoted Mukamal's "review" of MR ... wineinformationcouncil.eu/index.php?opti…
More on the alcohol industry supported "trial" is in pubmed.ncbi.nlm.nih.gov/31803980/ and in @drdavidmichaels excellent book, "The triumph of doubt: dark money and the science of deception"
Here are data by one of Mukamal's co-authors on the "critique" of MR; I wonder who would like these naive and obviously biased observational data suggesting you simply can't drink too much alcohol🤔For why some "researchers" don't like MR, see / finis link.springer.com/content/pdf/10… 
