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Recalibrating Mendelian randomization
July 2018
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NEW YORK—Mendelian randomization (MR), a common method that looks at genetic variation to determine how risk factors affect disease and mortality risk, may not be as straightforward as believed, according to scientists from the Department of Genetics and Genomics Sciences at the Icahn School of Medicine at Mount Sinai, Massachusetts General Hospital and the Broad Institute. The collaborators found that in 48 percent of cases of MR, horizontal pleiotropy was present.
 
Horizontal pleiotropy is a phenomenon in which genetic variants affect disease by different pathways than those being tested, and the researchers found that its presence distorted MR results by -131 to 201 percent on average, and that widespread horizontal pleiotropy induces false-positive causal relationships in as much as 10 percent of results in some cases. These results highlight the need to evaluate all MR studies for horizontal pleiotropy, according to the authors, who have developed MR-PRESSO, open-source software to detect and correct for this phenomenon. Their work was published in Nature Genetics.

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