Mendelian randomization
Encyclopedia
In epidemiology
, Mendelian randomization is a method of using measured variation in genes of known function to examine the causal effect of a modifiable exposure on disease in non-experimental studies. The design was first described by Gray and Wheatley (1991) as a method for obtaining unbiased estimates of the effects of a putative casual variable without conducting a traditional randomised trial . These authors also coined the term Mendelian randomization.
interest. In order to have firm evidence that a recommended public health intervention will have the desired beneficial effect, the observed association between the particular risk factor and disease must imply that the risk factor actually causes the disease.
Well-known successes include the identified causal links between smoking and lung cancer, and between blood pressure and stroke. However, there have also been notable failures when identified exposures were later shown by randomised controlled trials (RCTs) to be non-causal. For instance, it has now been shown that hormone replacement therapy
will not prevent cardiovascular disease
, as was previously thought, and may have other adverse health effects (Rossouw et al. 2002). The reason for such spurious findings in observational epidemiology is most likely to be confounding
by social, behavioural or physiological factors which are difficult to control for and particularly difficult to measure accurately. Moreover, many findings cannot be replicated by RCTs for ethical reasons.
must only affect the disease status indirectly via its effect on the exposure of interest. Because genotypes are assigned randomly when passed from parents to offspring during meiosis
, if we assume that choice of mate is not associated with genotype (panmixia
), then the population genotype distribution should be unrelated to the confounders that typically plague observational epidemiology studies. In this regard, Mendelian randomization can be thought of as a “natural” RCT. From a statistical perspective, it is an application of the technique of instrumental variables (Thomas & Conti 2004, Didelez & Sheehan 2007), with genotype acting as an instrument for the exposure of interest.
Mendelian randomization relies on getting good estimates from genetic association studies. Misleading conclusions can also be drawn in the presence of linkage disequilibrium
, genetic heterogeneity, pleiotropy
, or population stratification
(Davey Smith & Ebrahim 2003).
Epidemiology
Epidemiology is the study of health-event, health-characteristic, or health-determinant patterns in a population. It is the cornerstone method of public health research, and helps inform policy decisions and evidence-based medicine by identifying risk factors for disease and targets for preventive...
, Mendelian randomization is a method of using measured variation in genes of known function to examine the causal effect of a modifiable exposure on disease in non-experimental studies. The design was first described by Gray and Wheatley (1991) as a method for obtaining unbiased estimates of the effects of a putative casual variable without conducting a traditional randomised trial . These authors also coined the term Mendelian randomization.
Background - spurious findings from observational epidemiology
An important focus of observational epidemiology is the identification of modifiable causes of common diseases that are of public healthPublic health
Public health is "the science and art of preventing disease, prolonging life and promoting health through the organized efforts and informed choices of society, organizations, public and private, communities and individuals" . It is concerned with threats to health based on population health...
interest. In order to have firm evidence that a recommended public health intervention will have the desired beneficial effect, the observed association between the particular risk factor and disease must imply that the risk factor actually causes the disease.
Well-known successes include the identified causal links between smoking and lung cancer, and between blood pressure and stroke. However, there have also been notable failures when identified exposures were later shown by randomised controlled trials (RCTs) to be non-causal. For instance, it has now been shown that hormone replacement therapy
Hormone replacement therapy (menopause)
Hormone replacement therapy is a system of medical treatment for surgically menopausal, perimenopausal and to a lesser extent postmenopausal women...
will not prevent cardiovascular disease
Cardiovascular disease
Heart disease or cardiovascular disease are the class of diseases that involve the heart or blood vessels . While the term technically refers to any disease that affects the cardiovascular system , it is usually used to refer to those related to atherosclerosis...
, as was previously thought, and may have other adverse health effects (Rossouw et al. 2002). The reason for such spurious findings in observational epidemiology is most likely to be confounding
Confounding
In statistics, a confounding variable is an extraneous variable in a statistical model that correlates with both the dependent variable and the independent variable...
by social, behavioural or physiological factors which are difficult to control for and particularly difficult to measure accurately. Moreover, many findings cannot be replicated by RCTs for ethical reasons.
Implementing Mendelian randomization
Mendelian randomization is a method that allows one to test for, or in certain cases to estimate, a causal effect from observational data in the presence of confounding factors. It uses common genetic polymorphisms with well-understood effects on exposure patterns (e.g., propensity to drink alcohol) or effects that mimic those produced by modifiable exposures (e.g., raised blood cholesterol (Katan 1986)). Importantly, the genotypeGenotype
The genotype is the genetic makeup of a cell, an organism, or an individual usually with reference to a specific character under consideration...
must only affect the disease status indirectly via its effect on the exposure of interest. Because genotypes are assigned randomly when passed from parents to offspring during meiosis
Meiosis
Meiosis is a special type of cell division necessary for sexual reproduction. The cells produced by meiosis are gametes or spores. The animals' gametes are called sperm and egg cells....
, if we assume that choice of mate is not associated with genotype (panmixia
Panmixia
Panmixia means random mating.A panmictic population is one where all individuals are potential partners. This assumes that there are no mating restrictions, neither genetic or behavioural, upon the population, and that therefore all recombination is possible...
), then the population genotype distribution should be unrelated to the confounders that typically plague observational epidemiology studies. In this regard, Mendelian randomization can be thought of as a “natural” RCT. From a statistical perspective, it is an application of the technique of instrumental variables (Thomas & Conti 2004, Didelez & Sheehan 2007), with genotype acting as an instrument for the exposure of interest.
Mendelian randomization relies on getting good estimates from genetic association studies. Misleading conclusions can also be drawn in the presence of linkage disequilibrium
Linkage disequilibrium
In population genetics, linkage disequilibrium is the non-random association of alleles at two or more loci, not necessarily on the same chromosome. It is also referred to as to as gametic phase disequilibrium , or simply gametic disequilibrium...
, genetic heterogeneity, pleiotropy
Pleiotropy
Pleiotropy occurs when one gene influences multiple phenotypic traits. Consequently, a mutation in a pleiotropic gene may have an effect on some or all traits simultaneously...
, or population stratification
Population stratification
Population stratification is the presence of a systematic difference in allele frequencies between subpopulations in a population possibly due to different ancestry, especially in the context of association studies...
(Davey Smith & Ebrahim 2003).
External links
- Mendelian Randomization: A Perfect Causal Epidemiologic Approach to Simulate a Randomized Trial? Epidemiologic Inquiry 2006, 1: 16
- G. Davey Smith (2006). Capitalising on Mendelian randomization to assess the effects of treatments. James Lind Library.
- PHOEBE Biostatistics Group (2007) Mendelian randomisation: Inferring causality in observational epidemiology