IJE Advance Access originally published online on September 22, 2007
International Journal of Epidemiology 2008 37(2):416-417; doi:10.1093/ije/dym187
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Letters to the Editor |
Reply
1 Department of Social Medicine, University of Bristol, Bristol BS8 2PR, UK.
2 Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK.
*Corresponding author. E-mail: george.davey-smith{at}bristol.ac.uk
We thank Murielle Bochud and colleagues1 for their letter regarding our two review articles on Mendelian randomization.2,3 We agree with them that caution needs to be applied to the interpretation of the findings from Mendelian randomization studies. They raise two new issues that we would like to comment on. First, they suggest that transmission ratio distortion (TRD) could generate spurious interpretations. As we discussed in our first paper,1 true Mendelian randomization would occur in studies relating to genetic variant transmission from both parents to their offspring and how this relates to offspring outcomes. TRD could indeed lead to erroneous conclusions in this setting. However, in practice, Mendelian randomization studies have relied on the generally well-supported notion that at a population level, genetic variants are unrelated to socioeconomic, behavioural and physiological confounding factors that would distort the interpretation of conventional epidemiological studies.4–10 In this case, TRD would only lead to spurious conclusions if the distortion was influenced by a maternal characteristic (such as folate intake) that was socially patterned or demonstrated intergenerational behavioural or environmental continuity in such a way that this leads to genotype, at a population level, becoming associated with potential confounding factors. While claims have been made in this regard, we are not aware of robust evidence that such selective TRD occurs at a level that has led to associations between genetic variants and potential confounders at the population level.10 However, we acknowledge that this is a possibility.
Second, Bochud et al. raised the issue of parent-of-origin effects. Again, in population level studies, this will only lead to erroneous conclusions if the process is influenced by maternal or paternal characteristics in such a way that it leads to alleles that are or are not imprinted (or are imprinted to different degrees) becoming associated with confounding factors at a population level. Again we know of no clearly established case of this.
Thus, while it is salutary for utilizers of the Mendelian randomization approach to recognize the issues raised by Bochud et al., more empirical data are required before it can be known whether these are of importance in practice.
Conflict of interest: None declared.
References
1 Bochud M, Chiolero A, Elston RC, Paccaud F. A cautionary note on the use of Mendelian randomization to infer causation in observational epidemiology. Int J Epidemiol (2007) 37:414–16.
2 Davey Smith G, Ebrahim S. ‘Mendelian randomization’: can genetic epidemiology contribute to understanding environmental determinants of disease? Int J Epidemiol (2003) 32:1–22.
3 Davey Smith G, Ebrahim S. Mendelian randomization: prospects, potentials, and limitations. Int J Epidemiol (2004) 33:30–42.
4 Davey Smith G, Lawlor D, Harbord R, et al. Association of C-reactive protein with blood pressure and hypertension: lifecourse confounding and Mendelian randomisation tests of causality. Arterioscler Thromb Vasc Biol (2005) 25:1051–56.
5 Davey Smith G, Harbord R, Milton J, Ebrahim S, Sterne JAC. Does elevated plasma fibrinogen increase the risk of coronary heart disease?: evidence from a meta-analysis of genetic association studies. Arterioscler Thromb Vasc Biol (2005) 25:2228–33.
6 Timpson NJ, Lawlor DA, Harbord RM, et al. C-reactive protein and its role in metabolic syndrome: Mendelian randomisation study. Lancet (2005) 366:1954–59.[CrossRef][Web of Science][Medline]
7 Lewis S, Davey Smith G. Alcohol, ALDH2 and esophageal cancer: a meta-analysis which illustrates the potentials and limitations of a Mendelian randomization approach. Cancer Epidemiol Biomarkers Prev (2005) 14:1967–71.
8 Casas JP, Shah T, Cooper J, et al. Insight into the nature of the CRP-coronary event association using Mendelian randomization. Int J Epidemiol (2006) 35:922–31.
9 Keavney B, Danesh J, Parish S, et al. Fibrinogen and coronary heart disease: test of causality by ‘Mendelian randomization’. Int J Epidemiol (2006) 35:935–43.
10 Davey Smith G, Lawlor DA, Harbord R, Timpson NJ, Day I, Ebrahim S. Clustered environments and randomized genes: a fundamental distinction between conventional and genetic epidemiology. PLOS-Medicine 2007. in press.
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