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
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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About the Icahn School of Medicine at Mount Sinai
The Icahn School of Medicine at Mount Sinai is an international leader in medical and scientific training, biomedical research, and patient care. It is the medical school for the Mount Sinai Health System, which includes seven hospital campuses, and has more than 5,000 faculty and nearly 2,000 students, residents and fellows. The School is made up of 36 multidisciplinary research, educational, and clinical institutes and 33 academic departments. It ranks 13th among U.S. medical schools for NIH funding and 2nd in research dollars per principal investigator among U.S. medical schools by the Association of American Medical Colleges (AAMC). The School was named 4th among “World’s Most Innovative Companies in Data Science” by Fast Company magazine in 2016. For more information, visit http://icahn.mssm.edu
About the Mount Sinai Health System
The Mount Sinai Health System is New York City's largest academic medical system, encompassing eight hospitals, a leading medical school, and a vast network of ambulatory practices throughout the greater New York region. Mount Sinai is a national and international source of unrivaled education, translational research and discovery, and collaborative clinical leadership ensuring that we deliver the highest quality care—from prevention to treatment of the most serious and complex human diseases. The Health System includes more than 7,200 physicians and features a robust and continually expanding network of multispecialty services, including more than 400 ambulatory practice locations throughout the five boroughs of New York City, Westchester, and Long Island. The Mount Sinai Hospital is ranked No. 14 on U.S. News & World Report's "Honor Roll" of the Top 20 Best Hospitals in the country and the Icahn School of Medicine as one of the Top 20 Best Medical Schools in country. Mount Sinai Health System hospitals are consistently ranked regionally by specialty and our physicians in the top 1% of all physicians nationally by U.S. News & World Report.