The second law of Mendelian inheritance is about independent assortment of alleles at the time of gamete (sperm & egg cells) formation. Therefore within the population of any given species, genetic variants are likely to be distributed at random, independent of any external factors. This insight forms the basis of Mendelian Randomization (MR) technique, typically applied in studies of epidemiology.
Studies of epidemiology try to establish the causal link (given some known association) between a particular risk factor & a disease. For e.g. smoking to cancer, blood pressure to stroke, etc. The association in many cases is found to be non-causal, or reverse causal, etc. Establishing the true effect becomes challenging due to the presence of confounding factors such as social, behavioral, environmental, physiological, etc. MR helps to tackle the confounding factors in such situations.
In MR, genetic variants (polymorphism) or genotype that have an effect similar to the risk factor/ exposure are identified. An additional constraint being that the genotype must not have any direct influence on the disease. Existence of genotype in the population is random, independent of any external influence. So presence (or absence) of disease within the population possessing the genotype, establishes (or refutes) that the risk factor/ effect is actually the cause for the disease. Several researches based on Mendelian randomization have been done successfully.
Example 1: There could be a study to establish the causal relationship (given observed association) between raised cholesterol levels & chronic heart disease (CHD). Given the presence of several confounding factors such as age, physiology, smoking/ drinking habits, reverse causation (CHD causing raised cholesterol), etc., MR approach would be beneficial.
The approach would be to identify a genotype/ gene variant that is known to be linked to an increase in total cholesterol levels (but has no direct bearing on CHD). The propensity for CHD is tested for all subjects having the particular genotype, which if/ when found much higher than the general population (not possessing the gene variant) establishes that raised cholesterol levels have a causal relationship with CHD.
Instrumental Variables
MR is an application of the statistical technique of instrumental variables (IV) estimation. IV technique is also used to establish causal relationships in the presence of confounding factors.
When applied to regression models, IV technique is particularly beneficial when the explanatory variable (covariates) are correlated with the error term & give biased results. The choice of IV is such that it only induces changes in the explanatory variables, without having any independent effect on dependent variables. The IV must not be correlated to the error term. Selecting an IV that fulfills these criterias is largely done through an analytical process supported by some observational data, & by leveraging relevant priors about the field of study.
Equating MR to IV
Studies of epidemiology try to establish the causal link (given some known association) between a particular risk factor & a disease. For e.g. smoking to cancer, blood pressure to stroke, etc. The association in many cases is found to be non-causal, or reverse causal, etc. Establishing the true effect becomes challenging due to the presence of confounding factors such as social, behavioral, environmental, physiological, etc. MR helps to tackle the confounding factors in such situations.
In MR, genetic variants (polymorphism) or genotype that have an effect similar to the risk factor/ exposure are identified. An additional constraint being that the genotype must not have any direct influence on the disease. Existence of genotype in the population is random, independent of any external influence. So presence (or absence) of disease within the population possessing the genotype, establishes (or refutes) that the risk factor/ effect is actually the cause for the disease. Several researches based on Mendelian randomization have been done successfully.
Example 1: There could be a study to establish the causal relationship (given observed association) between raised cholesterol levels & chronic heart disease (CHD). Given the presence of several confounding factors such as age, physiology, smoking/ drinking habits, reverse causation (CHD causing raised cholesterol), etc., MR approach would be beneficial.
The approach would be to identify a genotype/ gene variant that is known to be linked to an increase in total cholesterol levels (but has no direct bearing on CHD). The propensity for CHD is tested for all subjects having the particular genotype, which if/ when found much higher than the general population (not possessing the gene variant) establishes that raised cholesterol levels have a causal relationship with CHD.
Instrumental Variables
MR is an application of the statistical technique of instrumental variables (IV) estimation. IV technique is also used to establish causal relationships in the presence of confounding factors.
When applied to regression models, IV technique is particularly beneficial when the explanatory variable (covariates) are correlated with the error term & give biased results. The choice of IV is such that it only induces changes in the explanatory variables, without having any independent effect on dependent variables. The IV must not be correlated to the error term. Selecting an IV that fulfills these criterias is largely done through an analytical process supported by some observational data, & by leveraging relevant priors about the field of study.
Equating MR to IV
- Risk Factor/ Effect = Explanatory Variable,
- Disease = Dependent Variable
- Genotype = Instrument Variable
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