Using Natural Genetic Variation to Assess the Causal Role of Modifiable Risk Factors in Observational Studies
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Article, see p 741
“It is not in the stars to hold our destiny but in ourselves.”—William Shakespeare1
Population-based cohort studies have established a consistent link between obesity and atrial fibrillation (AF).2–4 Whether this relationship is causal, however, remains a question. Associations observed in epidemiological studies could arise as a result of confounding by behavioral or socioeconomic factors or the common co-occurrence of obesity with hypertension, diabetes mellitus, and other established risk factors for AF. Although observational studies can adjust for known confounders using statistical techniques, the existence of unknown or unmeasured confounders and lack of precision in the measured variables can lead to residual confounding. Randomized controlled trials remain the gold standard for establishing the direct, causal effect of risk factor modification on the development of a disease related to that risk factor. However, randomized controlled trials are not always feasible because of the long follow-up time required to observe sufficient numbers of outcomes and the difficulties of maintaining complex intervention protocols. Indeed, no large-scale randomized controlled trials of weight interventions for the prevention of AF have been reported to date. In this issue of Circulation, Chatterjee et al5 use the random assignment of genetic variants, an approach called Mendelian randomization,6,7 to provide support for a causal relationship between obesity and AF.
This method is founded on the principle that an individual’s genotype is determined randomly at conception from his/her parental genotypes. Furthermore, according to the Mendel law of independent assortment, genetic variants governing variation in one trait are inherited independently of those influencing another trait. Therefore, genotype will in most cases be unrelated to behavioral, dietary, and other factors that could confound the association between obesity and AF. Unlike observational studies, in which obese individuals …