Introduction
I’ve seen the term Mendelian randomization in a few articles and their related papers that I’ve read recently ,and not knowing what it was I’ve written this overview to teach myself and tell anyone else who doesn’t know.
Genetic Epidemiology
Geneticepidemiology is concerned with understanding the heritable aspectsof disease risk, individual susceptibility to disease, and ultimatelywith contributing to a comprehensive molecular understandingof pathogenesis.(2) Epidemiologists look for modifiable causes of common diseasesto improve population health. However, epidemiological studiesmay identify spurious “causes.” For example, the epidemiologicalfindings that hormone replacement therapy protects against coronaryheart disease and that carotene prevents lung cancer have been refuted by randomized controlled trials,raising concerns about the value of epidemiological studies. The misleadingfindings were thought to be due to confounding by behavioral, physiological,and socioeconomic factors related both to exposures and to diseaseend points. One solution to these problems is mendelian randomization. (3)
What is Mendelian Randomization?
Mendelian randomization is a recent development in the field of genetic epidemiology which uses non-experimental studies to examine the causal effect of a modifiable phenotype or exposure on disease by making use of measured variation in genes of known function.It is based on Mendel’s second law that inheritance of one trait is independent of inheritance of other traits.If we know of a gene closely linked to the phenotype without direct effect on the disease, it can be reasonably assumed that the gene is not itself associated with any confounding factors.(2,3)
Mendelian Randomization Approach
In the Mendelian randomization approach, investigators first identify genetic polymorphisms that affect levels of the risk factor whose causal significance is queried . The relationships between polymorphisms and risk factor, risk factor and disease, and polymorphisms and disease are then quantified. If the hypothesised risk factor causes disease, it is anticipated that the association between the polymorphisms and disease risk will be at least commensurate with what would be “expected,” given the association between the polymorphisms and the risk factor, and the association between the risk factor and disease.Mendelian randomization provides a potential method to assess the causality of associations described in epidemiological studies where suitably specific drugs to undertake randomised controlled trials are not yet available.(1)
Limitations
Some limitations include a lack of suitable genetic variants, unreliable associations, population stratification, linkage disequilibrium (LD), pleiotropy, developmental canalization, the need for large sample sizes and some potential problems with binary outcomes. Given an inheritance of gene expression from parents, Mendelian randomization studies not only need to assume a random distribution of alleles in the offspring, but also a random distribution of epigenetic changes (non-Mendelian, heritable changes in gene expression not accompanied by alterations in DNA sequence) at conception, in order for the core assumptions of the Mendelian randomization methodology to remain valid .(4)
Further Reading
References:
2. Davey Smith,George and Ebrahim,Shah ‘Mendelian randomization’: can genetic epidemiology contribute to understanding environmental determinants of disease? ‘Int. J. Epidemiol. 32: 1-22.
3.Davey Smith,George and Ebrahim,Shah ,What can mendelian randomisation tell us about modifiable behavioural and environmental exposures? BMJ 2005;330:1076-1079 (7 May), doi:10.1136/bmj.330.7499.1076
4. Ikechukwu U Ogbuanu, Hongmei Zhang and Wilfried Karmau (2009) ‘Can we apply the Mendelian randomization methodology without considering epigenetic effects? doi:10.1186/1742-7622-6-3
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