International Journal of Epidemiology, Volume 33, Number 1, pp. 30-42
IJE vol.33 no.1 © International Epidemiological Association 2004; all rights reserved.
Reprints and Reflections |
Mendelian randomization: prospects, potentials, and limitations
Department of Social Medicine, Canynge Hall, Whiteladies Road, Bristol BS8 2PR E-mail: zetkin@bristol.ac.uk
| The first 150 words of the full text of this article appear below. |
In this issue of the International Journal of Epidemiology we reprint a letter to the Lancet by Martijn Katan1 and several commentaries2–7 concerning what has become known as ‘Mendelian randomization’8–12—the use of genotype–disease associations to make inferences about environmentally modifiable causes of disease. Here we will reflect on the prospects, potentials, and limitations of Mendelian randomization.
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Where can Mendelian randomization help observational epidemiology? |
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Mendelian randomization is the term applied to the random assortment of alleles at the time of gamete formation. This results in population distributions of genetic variants that are generally independent of behavioural and environmental factors that typically confound epidemiological associations between putative risk factors and disease. In some circumstances this can provide a study design akin to randomized comparisons.
The principles of Mendelian randomization can serve to limit several potential problems in observational epidemiology (Table 1). The avoidance of confounding is clearly a key advantage, and in view of this, Martin
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Categories of inference from Mendelian randomization |
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Mendelian randomization in action |
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Exposure propensity
Lactose intolerance and the health effects of drinking milk
Intermediate phenotypes
Familial hypercholesterolaemia: estimating the cholesterol–CHD association
Indicating the category of exposure causing disease risk
Vitamin D, sunlight, tuberculosis, and multiple sclerosis
Aspirin and colon cancer
Modifiers of environmental exposures
Alcohol intake, aldehyde dehydrogenase genotype, and coronary heart disease
Characterizing environmental exposures
Bile salts and colorectal cancer
Intergenerational influences
Methyl-tetrahydrofolate reductase (MTHFR) polymorphisms and neural tube defects
Glucokinase polymorphisms and birthweight of offspring
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Mendelian randomization—proving a negative? |
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Limitations of Mendelian Randomization
Population attributable risk and non-removable genetic factors
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Conclusions |
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