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Education And Debate

What can mendelian randomisation tell us about modifiable behavioural and environmental exposures?

BMJ 2005; 330 doi: (Published 05 May 2005) Cite this as: BMJ 2005;330:1076
  1. George Davey Smith, professor (,
  2. Shah Ebrahim, head of department1
  1. 1 Department of Social Medicine, University of Bristol, Bristol BS8 2PR
  1. Correspondence to: G Davey Smith
  • Accepted 4 February 2005

Using genetic variants as a proxy for modifiable environmental factors that are associated with disease can circumvent some of the problems of observational studies


Epidemiologists look for modifiable causes of common diseases to improve population health. However, epidemiological studies may identify spurious “causes.” For example, the epidemiological findings that hormone replacement therapy protects against coronary heart disease,w1β carotene prevents lung cancer,w2and vitamin E and vitamin C reduce risk of cardiovascular diseasew3have all been refuted by randomised controlled trials and have raised concerns about the value of epidemiological studies.1 The misleading findings were probably due to confounding by behavioural, physiological, and socioeconomic factors related both to exposures and to disease end points.2 3 One solution to these problems is mendelian randomisation.4 5

What is mendelian randomisation?

Mendelian randomisation is a recent development in genetic epidemiology6 7 based on Mendel's second law that inheritance of one trait is independent of inheritance of other traits. It uses common genetic polymorphisms that are known to influence exposure patterns (such as propensity to drink alcohol) or have effects equivalent to those produced by modifiable exposures (such as raised blood cholesterol concentration). Associations between genetic variants and outcome are not generally confounded by behavioural or environmental exposures. This means that observational studies of genetic variants have similar properties to intention to treat analyses in randomised controlled trials (fig 1).

Comparison of design of mendelian randomisation studies and randomised controlled trials

Scope of mendelian randomisation

The simplest way of appreciating the potential of mendelian randomisation is to consider applications of the underlying principles. The inferences that can be drawn from mendelian randomisation studies depend on the different ways in which genetic variants can proxy for environmentally modifiable exposures.

Understanding effects of health related behaviours

In observational studies, alcohol consumption is related to many known and unknown confounding factors; ill health …

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