A Mendelian randomisation (MR) study is a type of genetic study used by scientists to understand if a specific factor like a nutrient level, a habit or a biological process actually causes a certain health outcome. It’s named after Gregor Mendel, the scientist who discovered how genetic inheritance works, because it uses principles of genetic inheritance to mimic randomisation in a way similar to a controlled experiment.
In general, it can be difficult to determine cause-and-effect relationships in human health because many things (like diet, environment, and lifestyle) affect health and are often related to each other. Observational studies, like cohort and case-control studies, can show associations but can’t definitively say if one factor causes another because these relationships could be influenced by confounding factors (other variables that may influence the result). Mendelian randomisation is powerful because it avoids many of these issues by focusing on genetic variants, which are less likely to be influenced by outside factors.
As ever, please talk to your doctor or medical practitioner most familiar with your medical history before implementing any changes in diet, exercise or lifestyle; especially if you are under treatment. We provide links to relevant studies at bottom of page.
How Does Mendelian Randomisation Work?
Mendelian randomisation uses genetic variations, slight differences in DNA, as a type of “proxy” to study whether a factor causes a health outcome. To understand this, it helps to think of genetic variants as tiny “natural experiments” because they are randomly assigned at conception, just like how a randomised controlled trial (RCT) assigns people randomly to a treatment or control group.
For instance, some people naturally have gene variants that affect how their bodies handle cholesterol levels. By looking at people with and without these gene variants, researchers can study the effect of higher cholesterol levels on heart disease risk without needing to manipulate the cholesterol levels directly.
Since these genetic variations are inherited randomly and are fixed from birth, they provide a kind of “randomisation” that reduces the risk of confounding. This setup allows scientists to better isolate the effect of the factor they are studying.
Mendelian Randomisation in Action, Case Studies on Alzheimer's Disease
Let’s say scientists want to study whether high cholesterol truly increases the risk of developing Alzheimer’s disease. Measuring cholesterol levels and observing their link to Alzheimer’s can provide useful information, but separating cause and effect is challenging because many lifestyle and health factors like diet, exercise and genetics can influence both cholesterol levels and brain health.
In a Mendelian randomisation study, scientists would look for genetic variants that naturally lead to higher cholesterol levels. People who inherit these variants would likely have higher cholesterol than those without these genetic markers, even if they don’t have other lifestyle risk factors. If individuals with these high-cholesterol gene variants also have a higher risk of Alzheimer’s, it strongly suggests that elevated cholesterol itself may contribute to the development of Alzheimer’s disease.
These and similar studies studies actually exist, some examples as follows:
Park JK, Petrazzini BO, Bafna S, Duffy Á, Forrest IS, Vy HM, Marquez-Luna C, Verbanck M, Narula J, Rosenson RS, Jordan DM, Rocheleau G, Do R. Muesli Intake May Protect Against Coronary Artery Disease: Mendelian Randomization on 13 Dietary Traits. JACC Adv. 2024 Apr;3(4):100888. doi: 10.1016/j.jacadv.2024.100888. Epub 2024 Mar 6. PMID: 38737007; PMCID: PMC11087059.
"Conclusions: Muesli, a mixture of oats, seeds, nuts, dried fruit, and milk, may causally reduce coronary artery disease (CAD risk. Circulating levels of acetate, a gut microbiota-derived short-chain fatty acid, could be mediating its cardioprotective effects. These findings highlight the role of gut flora in cardiovascular health and help prioritize randomized trials on dietary interventions for CAD."
Zhu Y, Lan Y, Lv J, et al. Association between dietary fat intake and the risk of Alzheimer’s disease: Mendelian randomisation study. The British Journal of Psychiatry. Published online 2024:1-7. doi:10.1192/bjp.2024.163
"Conclusions: This study indicated that total dietary fat intake, especially saturated fat, contributed to the risk of Alzheimer's disease, and the effects were independent of other nutrients. These findings informed prevention strategies and management for Alzheimer's disease directly towards reducing dietary saturated fat intake."
Cai J, Sun X, Li M, Luo R, Wang W, Wang Z, Akkaif MA, Liu H. Dietary factors in relation to hypertension: a mendelian randomization study. J Health Popul Nutr. 2024 Jun 21;43(1):91. doi: 10.1186/s41043-024-00575-7. PMID: 38907314; PMCID: PMC11193250.
"Conclusions: This study uncovered causal relationships between various dietary factors and hypertension risk. Specifically, alcohol consumption in terms of drinks per week and intake frequency, as well as poultry and beef intake, were causally associated with an elevated risk of hypertension. In contrast, consuming salad/raw vegetables, dried fruits, cheese, and cereals demonstrated an inverse causal association with hypertension, suggesting a potential protective effect."
Martin L, Boutwell BB, Messerlian C, Adams CD. Mendelian randomization reveals apolipoprotein B shortens healthspan and possibly increases risk for Alzheimer's disease. Commun Biol. 2024 Feb 24;7(1):230. doi: 10.1038/s42003-024-05887-2. PMID: 38402277; PMCID: PMC10894226.
"With Mendelian randomization, we show that higher levels of APOB and LDL shorten healthspan in humans. Multivariable Mendelian randomization of APOB and LDL on healthspan suggests that the predominant trait accounting for the relationship is APOB. In addition, we provide preliminary evidence that APOB increases risk for Alzheimer's disease, a condition that ends healthspan."
European Alzheimer’s & Dementia Biobank Mendelian Randomization (EADB-MR) Collaboration. Genetic Associations Between Modifiable Risk Factors and Alzheimer Disease. JAMA Netw Open. 2023;6(5):e2313734. doi:10.1001/jamanetworkopen.2023.13734
"Conclusions and relevance: This genetic association study found novel genetic associations between high HDL cholesterol concentrations and high systolic blood pressure with higher risk of AD. These findings may inspire new drug targeting and improved prevention implementation."
Now, having digested the above, here is the short (2 minute) version that summarises the key issues...
Why Mendelian Randomisation Matters
With the rise of large-scale genetic databases, Mendelian randomisation has become more popular and more powerful. The method allows scientists to answer critical questions about whether certain lifestyle factors, like smoking, blood pressure or nutrition truly influence the risk of diseases like Alzheimer's, cancer, diabetes or heart disease.
MR studies are not without their limitations or challenges, however, they can to clarify if there’s a cause-and-effect relationship between a factor and a health outcome. By mimicking the design of a controlled experiment without direct intervention, MR studies help reduce bias from confounding factors and offer reliable insights in cases where controlled trials might be impractical or unethical. They provide valuable insights for public health recommendations, drug development, personalised medicine and lifestyle choices.
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Related Studies
Skrivankova VW, Richmond RC, Woolf BAR, et al. Strengthening the Reporting of Observational Studies in Epidemiology Using Mendelian Randomization: The STROBE-MR Statement. JAMA. 2021;326(16):1614–1621. doi:10.1001/jama.2021.18236
Bowden J, Holmes MV. Meta-analysis and Mendelian randomization: A review. Res Synth Methods. 2019 Dec;10(4):486-496. doi: 10.1002/jrsm.1346. Epub 2019 Apr 23. PMID: 30861319; PMCID: PMC6973275.
Davies NM, Holmes MV, Davey Smith G. Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians. BMJ. 2018 Jul 12;362:k601. doi: 10.1136/bmj.k601. PMID: 30002074; PMCID: PMC6041728.
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