Copyright © 2004 by the Johns Hopkins Bloomberg School of Public Health
ORIGINAL CONTRIBUTIONS |
An Integrated Approach to the Meta-Analysis of Genetic Association Studies using Mendelian Randomization
From the Centre for Biostatistics and Genetic Epidemiology, Department of Health Sciences, Leicester Medical School, University of Leicester, Leicester, United Kingdom.
A natural randomization process, sometimes called Mendelian randomization, occurs at conception to determine a person’s genotype. By combining information from genotype-disease and genotype-phenotype studies, it is possible to use this Mendelian randomization to derive an estimate of the association between phenotype (risk factor) and disease that is free of the confounding and reverse causation typical of classical epidemiology. When one is synthesizing evidence, studies evaluating genotype-phenotype associations, studies evaluating genotype-disease associations, and studies evaluating both are encountered, and methods should be used that allow for this structure. Plotting the log odds ratio of genotype-disease against the mean genotype-phenotype difference may help investigators detect departures from the assumptions underlying Mendelian randomization. Testing for differences between studies reporting on only the genotype-phenotype or genotype-disease association and those reporting on both associations may help in detecting reporting bias. This integrated approach to the meta-analysis of genotype-phenotype and genotype-disease studies is illustrated here using the example of the methylenetetrahydrofolate reductase (MTHFR) gene, homocysteine level, and coronary heart disease. An integrated meta-analytical approach may increase the precision of this estimate and provide information on the assumptions underlying Mendelian randomization. Serious biases may arise if the assumptions behind the analysis based on Mendelian randomization are not met.
epidemiologic methods; genetic epidemiology; genetics; genotype; meta-analysis; phenotype
Abbreviations: Abbreviations: CI, confidence interval; MTHFR, methylenetetrahydrofolate reductase.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  V. Didelez and N. Sheehan Mendelian randomization as an instrumental variable approach to causal inference Statistical Methods in Medical Research, August 1, 2007; 16(4): 309 - 330. [Abstract] [PDF]
|
|
|
|
 |
|
 H. Refsum, E. Nurk, A. D. Smith, P. M. Ueland, C. G. Gjesdal, I. Bjelland, A. Tverdal, G. S. Tell, O. Nygard, and S. E. Vollset The Hordaland Homocysteine Study: A Community-Based Study of Homocysteine, Its Determinants, and Associations with Disease J. Nutr., June 1, 2006; 136(6): 1731S - 1740S. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Nitsch, M. Molokhia, L. Smeeth, B. L. DeStavola, J. C. Whittaker, and D. A. Leon Limits to Causal Inference based on Mendelian Randomization: A Comparison with Randomized Controlled Trials Am. J. Epidemiol., March 1, 2006; 163(5): 397 - 403. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. J Lewis, S. Ebrahim, and G. Davey Smith Meta-analysis of MTHFR 677C->T polymorphism and coronary heart disease: does totality of evidence support causal role for homocysteine and preventive potential of folate? BMJ, November 5, 2005; 331(7524): 1053. [Abstract] [Full Text] [PDF]
|
|