Contact: Jennifer Gutierrez
Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology [email protected]
Phone: 646-899-1984
A Leading Method in Human Genetics Studies May Need to Be Reconsidered, as Researchers Discover Significant Distortions
Study of Mendelian randomization results detects factor called horizontal pleiotropy in close to 50 percent of significant causal relationships, a finding of great importance for detecting biomarkers for drug development and disease management
Newswise — (New York, NY - April 24, 2018) - Many conclusions drawn from a common approach to the study of human genetics could be distorted because of a previously overlooked phenomenon, according to researchers at the Department of Genetics and Genomics Sciences at the Icahn School of Medicine at Mount Sinai and collaborators from Massachusetts General Hospital and the Broad Institute. Their conclusions and a unique method they developed to help correct for this distortion were recently published in Nature Genetics.
The common approach, called Mendelian randomization (MR), is a method that uses genetic variation to assess how risk factors such as obesity and lipid levels affect the likelihood of disease and mortality. The researchers found that a phenomenon called horizontal pleiotropy – in which genetic variants influence disease through pathways different from the risk factors being tested – was present in 48 percent of the MR studies they analyzed. The results were distorted, on average, by -131 to 201 percent, meaning certain exposures analyzed in these studies may have appeared to have more or less influence on disease than they actually do.
They also found that widespread horizontal pleiotropy induced false positive causal relationships in up to 10 percent of results in certain tests.
As technology in genomic analysis has evolved rapidly in the past decade, researchers have developed multiple MR methods to study health and disease. A study of the validity of MR methods and innovation to correct for factors such as horizontal pleiotropy comes at a crucial time.
“Mendelian randomization has significant implications for drug discovery and validation,” said Ron Do, PhD, Assistant Professor in the Department of Genetics and Genomic Sciences at the Icahn School of Medicine. “It can be used to determine whether biomarkers are causal for disease, which can determine what types of drug therapeutics may be worth exploring in clinical trials, and can potentially predict accurate dosing for drug effectiveness.”
In light of these findings, the study authors stress the importance of assessing all MR studies for the occurrence of horizontal pleiotropy, and have developed open-source software to detect and correct for it, MR-PRESSO, which is available on GitHub at https://github.com/rondolab/MR-PRESSO
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The Mount Sinai Health System is New York City’s largest integrated delivery system encompassing seven hospital campuses, a leading medical school, and a vast network of ambulatory practices throughout the greater New York region. Mount Sinai’s vision is to produce the safest care, the highest quality, the highest satisfaction, the best access and the best value of any health system in the nation. The System includes approximately 7,100 primary and specialty care physicians; 10 joint-venture ambulatory surgery centers; more than 140 ambulatory practices throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and 31 affiliated community health centers. Physicians are affiliated with the renowned Icahn School of Medicine at Mount Sinai, which is ranked No. 18 for research by U.S. News & World Report’s “Best Medical Schools” and No. 13 in the nation for National Institutes of Health funding. The Mount Sinai Hospital is ranked No. 18 on U.S. News & World Report’s “Honor Roll” of top U.S. hospitals; it is one of the nation’s top 20 hospitals in Cardiology/Heart Surgery, Diabetes/Endocrinology, Gastroenterology/GI Surgery, Geriatrics, Nephrology, and Neurology/Neurosurgery, and in the top 50 in four other specialties in the 2017-2018 “Best Hospitals” issue. Mount Sinai’s Kravis Children’s Hospital also is ranked in six out of ten pediatric specialties by U.S. News & World Report. The New York Eye and Ear Infirmary of Mount Sinai is ranked 12th nationally for Ophthalmology and 50th for Ear, Nose, and Throat, while Mount Sinai Beth Israel, Mount Sinai St. Luke’s and Mount Sinai West are ranked regionally. For more information, visit http://www.mountsinai.org/, or find Mount Sinai on Facebook, Twitter and YouTube.
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