Brillaint breakdown of why MR is hitting a wall here. The fact that these genetc variants explain barely 0.2% of drinking behavior is kinda wild when they're being used to overturn decades of epidemiological findings. I've seen similar issues with biomarker-based stratification in clinical trials where the proxy measure ends up capturing comorbidities rather than the exposure itself. When the smoking adjustment flips the lung cancer association, that's not confounding control, that's just proof the instrument is broken.
This whole discussion overlooks a fundamental fact... it's not the same thing to drink a shot of whiskey as it is to drink a shot of young (unaged) red wine rich in polyphenols and resveratrol.
Another very important point... it's one thing to drink a shot of alcohol in the company of friends, and another to drink alcohol due to stress or simply depression. It's very difficult to draw conclusions because it would be necessary to analyze not only the amount of alcohol consumed but also the context in which the drinker finds himself. There's certainly one factor not to be forgotten... alcohol is a diluent. It's been shown that alcoholics have reduced brain mass due to the direct action of alcohol on the brain mass rich in soluble fats, over the long period of chronic alcohol consumption.
Finally..., within our circulatory system there is a thin sheath called the endocalyx. This sheath protects small and large blood vessels and allows for greater blood flow. If this sheath is damaged, blood as it passes causes intravascular damage because a damaged or missing endocalyx sheath causes small cracks to form that are filled with calcium, fibrin, cholesterol, and other compounds that stiffen the blood vessel. Alcoholic substances not only burn glutadione (the liver burns its glutadione reserves to avoid damage). When glutadione is depleted due to excessive alcohol consumption, the liver inevitably suffers damage. Unfortunately, alcohol literally thins and then dissolves the endocalyx sheath. For this reason, drinking alcohol over a long period of time leads to an increase in blood pressure. This leads to a chain of events that leads to heart attack or stroke.
I personally drink a glass of young red wine (the best because it contains more polyphenols) a day. Even two. My theory is that we should grow old happily. Simple, right?
Really thoughtful (and refreshingly transparent) critique of how Mendelian randomization gets used as a rhetorical “causality stamp” in alcohol research. When the instrument explains ~0.2% of variance in drinking behavior, and the signal meaningfully shifts with smoking adjustment, it highlights the two MR pain points you’re underscoring: weak instruments and pleiotropy/behavioral clustering (risk-taking traits, social context, smoking propensity) that can masquerade as “alcohol effects.” This is exactly where triangulation matters: observational data can be biased (e.g., “sick quitter” effects, socioeconomic confounding), but MR isn’t a magic eraser, especially for complex, nonlinear exposures like alcohol where “dose” and “pattern” (binge vs steady) and beverage context are not genetically encoded. The practical takeaway I’d love to see more often in public health messaging: we can hold two truths at once; alcohol is plausibly carcinogenic for several sites, and yet the evidence base for “no safe level” as a universal individual-level claim is more nuanced than many headlines imply. The science (and patient counseling) is better served by clearer uncertainty statements, better instruments, and humility about what each method can and can’t conclude.
It is remarkable how many critics of observational studies have swallowed the Kool-Aid on MR.
Peter Attia has recently written that new MR studies prove that mild to moderate alcohol is not protective against CV disease.
The Eric Rimm study you have cited previously, "Genetic instrumental variable analysis: time to call mendelian randomization what it is. The example of alcohol and cardiovascular disease" was particularly helpful for me in understanding the limitations of MR in this particular area.
Brillaint breakdown of why MR is hitting a wall here. The fact that these genetc variants explain barely 0.2% of drinking behavior is kinda wild when they're being used to overturn decades of epidemiological findings. I've seen similar issues with biomarker-based stratification in clinical trials where the proxy measure ends up capturing comorbidities rather than the exposure itself. When the smoking adjustment flips the lung cancer association, that's not confounding control, that's just proof the instrument is broken.
This whole discussion overlooks a fundamental fact... it's not the same thing to drink a shot of whiskey as it is to drink a shot of young (unaged) red wine rich in polyphenols and resveratrol.
Another very important point... it's one thing to drink a shot of alcohol in the company of friends, and another to drink alcohol due to stress or simply depression. It's very difficult to draw conclusions because it would be necessary to analyze not only the amount of alcohol consumed but also the context in which the drinker finds himself. There's certainly one factor not to be forgotten... alcohol is a diluent. It's been shown that alcoholics have reduced brain mass due to the direct action of alcohol on the brain mass rich in soluble fats, over the long period of chronic alcohol consumption.
Finally..., within our circulatory system there is a thin sheath called the endocalyx. This sheath protects small and large blood vessels and allows for greater blood flow. If this sheath is damaged, blood as it passes causes intravascular damage because a damaged or missing endocalyx sheath causes small cracks to form that are filled with calcium, fibrin, cholesterol, and other compounds that stiffen the blood vessel. Alcoholic substances not only burn glutadione (the liver burns its glutadione reserves to avoid damage). When glutadione is depleted due to excessive alcohol consumption, the liver inevitably suffers damage. Unfortunately, alcohol literally thins and then dissolves the endocalyx sheath. For this reason, drinking alcohol over a long period of time leads to an increase in blood pressure. This leads to a chain of events that leads to heart attack or stroke.
I personally drink a glass of young red wine (the best because it contains more polyphenols) a day. Even two. My theory is that we should grow old happily. Simple, right?
Andrew,
Greetings from Spain
Really thoughtful (and refreshingly transparent) critique of how Mendelian randomization gets used as a rhetorical “causality stamp” in alcohol research. When the instrument explains ~0.2% of variance in drinking behavior, and the signal meaningfully shifts with smoking adjustment, it highlights the two MR pain points you’re underscoring: weak instruments and pleiotropy/behavioral clustering (risk-taking traits, social context, smoking propensity) that can masquerade as “alcohol effects.” This is exactly where triangulation matters: observational data can be biased (e.g., “sick quitter” effects, socioeconomic confounding), but MR isn’t a magic eraser, especially for complex, nonlinear exposures like alcohol where “dose” and “pattern” (binge vs steady) and beverage context are not genetically encoded. The practical takeaway I’d love to see more often in public health messaging: we can hold two truths at once; alcohol is plausibly carcinogenic for several sites, and yet the evidence base for “no safe level” as a universal individual-level claim is more nuanced than many headlines imply. The science (and patient counseling) is better served by clearer uncertainty statements, better instruments, and humility about what each method can and can’t conclude.
A scientist who cannot design a study that will support her hypothesis is no scientist.
It is remarkable how many critics of observational studies have swallowed the Kool-Aid on MR.
Peter Attia has recently written that new MR studies prove that mild to moderate alcohol is not protective against CV disease.
The Eric Rimm study you have cited previously, "Genetic instrumental variable analysis: time to call mendelian randomization what it is. The example of alcohol and cardiovascular disease" was particularly helpful for me in understanding the limitations of MR in this particular area.