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Mendelian randomization (MR),7 a genetic epidemiological approach, has made substantial inroads into our understanding of the causes, and consequences, of disease (1, 2). Conventionally, MR takes genetic variants associated with an exposure to estimate the causal effect on risk of disease. Availability of large-scale data and hypothesis-free genome-wide analyses has led to discovery of trait-associated genetic variants that surpass stringent thresholds for multiple testing correction, making genome-wide association study (GWAS) discoveries among the most reliable (i.e., among the least prone to false positives) in the scientific literature.A naive criticism of GWAS is that the discoveries made therein have limited translational utility. Combining GWAS-identified single-nucleotide polymorphisms (SNPs) into genetic instruments under the MR approach, however, offers translational opportunities, yielding notable discoveries for public health and, in the longer-term, pharmaceutical development. More immediate translational opportunities include pharmacogenetics (3) and the emerging use of GWAS for disease prediction (4). In the case of MR, recent examples include identifying that genetic liability to diabetes causes erectile dysfunction (5) and that alcohol consumption may not protect from vascular disease (6). The elucidation of these would be seemingly unachievable under other study designs, e.g., the NIH-funded Moderate Alcohol and Cardiovascular Health trial (MACH15; NCT03169530) was abandoned because of perceived influence and bias from Big Alcohol (7). As with all scientific investigations, MR studies can be influenced by unique forms of bias, confounding, and analytical inaccuracies—what differentiates MR from conventional epidemiology is the availability of multiple sensitivity analyses (1, 8), enabling scientists to test many of the implicit assumptions.In this issue of Clinical Chemistry , Mohammadi-Shemirani and colleagues (9) have turned MR on its head. They propose taking a summary score of genetic variants robustly associated with estimated glomerular filtration rate (eGFR), a trait used to assess renal function, and relating this …

Can Mendelian Randomization Shift into Reverse Gear?