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Addiction. 2018 Apr;113(4):764-774. doi: 10.1111/add.14038. Epub 2017 Nov 3.

Assessing causal relationships using genetic proxies for exposures: an introduction to Mendelian randomization.

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MRC/CSO Social and Public Health Sciences Unit, University of Glasgow, Glasgow, UK.
MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
UK Centre for Tobacco and Alcohol Studies, School of Experimental Psychology, University of Bristol, Bristol, UK.



Studying the consequences of addictive behaviours is challenging, with understanding causal relationships from observational data being particularly difficult. For example, people who smoke or drink excessively are often systematically different from those who do not, are less likely to participate in research and may misreport their behaviours when they do. Furthermore, the direction of causation between an addictive behaviour and outcome may be unclear. Mendelian randomization (MR) offers potential solutions to these problems.


We describe MR's principles and the criteria under which it is valid. We identify challenges and potential solutions in its application (illustrated using two applied examples) and describe methodological extensions in its application.


MR is subject to certain assumptions, and requires the availability of appropriate genetic data, large sample sizes and careful design and conduct. However, it has already been applied successfully to the addiction literature. The relationship between alcohol consumption (proxied by a variant in the ADH1B gene) and cardiovascular risk has been investigated, finding that alcohol consumption increases risk, with no evidence of a cardioprotective effect at moderate consumption levels. In addition, heaviness of smoking (proxied by a variant in the CHRNA5-A3-B4 gene cluster) and risk of depression and schizophrenia have been investigated, with no evidence of a causal effect of smoking on depression but some evidence of a causal effect on schizophrenia.


Mendelian randomization analyses are already producing robust evidence for addiction-related practice and policy. As genetic variants associated with addictive behaviours are identified, the potential for Mendelian randomization analyses will grow. Methodological developments are also increasing its applicability.


Addictive behaviour; Mendelian randomization analysis; causality; econometric models; epidemiological methods; genetic epidemiology

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