Mendelian randomization: can genetic epidemiology help redress the failures of observational epidemiology?

Abstract

Establishing causal relationships between environmental exposures and common diseases is beset with problems of unresolved confounding, reverse causation and selection bias that may result in spurious inferences. Mendelian randomization, in which a functional genetic variant acts as a proxy for an environmental exposure, provides a means of overcoming these problems as the inheritance of genetic variants is independent of-that is randomized with respect to-the inheritance of other traits, according to Mendel's law of independent assortment. Examples drawn from exposures and outcomes as diverse as milk and osteoporosis, alcohol and coronary heart disease, sheep dip and farm workers' compensation neurosis, folate and neural tube defects are used to illustrate the applications of Mendelian randomization approaches in assessing potential environmental causes of disease. As with all genetic epidemiology studies there are problems associated with the need for large sample sizes, the non-replication of findings, and the lack of relevant functional genetic variants. In addition to these problems, Mendelian randomization findings may be confounded by other genetic variants in linkage disequilibrium with the variant under study, or by population stratification. Furthermore, pleiotropy of effect of a genetic variant may result in null associations, as may canalisation of genetic effects. If correctly conducted and carefully interpreted, Mendelian randomization studies can provide useful evidence to support or reject causal hypotheses linking environmental exposures to common diseases.

Polymorphisms in dopamine-associated genes and cognitive decline in Parkinson's disease

“…Furthermore, common variations in genes with known biological effects have been favored as a mean to test causality of disease mechanisms in observational studies 22. The present study extends earlier observations of a relationship between frontostriatally based cognitive functions and genes associated with dopamine transmission and is, to our knowledge, the first to demonstrate the DRD2 957 T/T genotype as a risk factor for PDD.…”

Mechanisms and treatment of ischaemic stroke—insights from genetic associations

“…A technique called Mendelian randomization is increasingly being used to determine causality in such situations. 54 In this technique, one selects a functional variant that is associated with an increased level of the marker in question, and determines whether it is also associated with an increased risk of the phenotype, in this case lacunar stroke. This approach has been used successfully in many cardiovascular diseases; for example, it has shown that elevated levels of C-reactive protein in patients with cardiovascular disease are likely to be secondary to atherosclerosis rather than having a causal role in disease pathogenesis.…”

Prospects for Epigenetic Epidemiology

“…The epigenotype, in contrast, is tissue and cell-type specific and may vary over time as a function of environmental exposure, aging, and random processes (48,60,172,173). Analysis of epigenetic data, therefore, cannot rely upon the assumptions of Mendelian randomization (174,175), which is predicated on the random assortment of genes transmitted from parents to offspring during gamete formation before disease onset. Associations between genotype and disease are therefore not usually biased because of reverse causation or confounding, unless linkage disequilibrium, pleiotropy, genetic heterogeneity, or population stratification are involved (174).…”