New York, NY — [May 27, 2026] — Researchers at the Icahn School of Medicine at Mount Sinai have found evidence that people who fall at the extreme high or low ends of certain traits, such as cholesterol, blood glucose, height, and age at menopause, are more likely to have a simple genetic explanation than previously thought.
Their findings, reported in the May 27 issue of Nature [https://doi.org/10.1038/s41586-026-10516-5], may lead to new insights into the causes of common diseases.
Many traits linked to human health are considered “polygenic,” meaning they are shaped by the combined influence of many common genetic variants, each contributing only a small effect. But the new study explored whether individuals with extreme trait values may instead be influenced by rarer genetic variants that have a much larger impact.
The researchers say this possibility could help explain why some individuals develop unusually high or low levels of traits associated with conditions such as diabetes, heart disease, and stroke.
“We typically think of these traits as being shaped by thousands of genetic changes, each having a very small effect,” says senior corresponding author Paul O'Reilly, PhD , Professor of Statistical Genetics in the Department of Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai in New York. “But our findings suggest that some people are at the ends of the trait spectrum because of a much smaller number of rare genetic variants with far stronger effects. If we can identify who these people are, clinicians may be able to offer them preventive care or treatments better suited to their genetic risk profile.”
The team’s hypothesis was based in part on evolutionary biology. Because extremely high or low trait values can sometimes be disadvantageous, natural selection may reduce the frequency of genetic variants that strongly drive those extremes. As a result, such variants are expected to be relatively rare in the population.
“Our goal was to better understand whether extreme trait values might sometimes arise from a different kind of genetic architecture,” says Dr. O’Reilly. “If so, that could eventually help researchers pinpoint biological pathways that are especially important in disease.”
To conduct the study, the researchers analyzed genetic patterns linked to a range of biomarkers and physical measurements, including hemoglobin, heart rate, and body weight. The team first developed two complementary statistical approaches to test whether people with extremely high or low trait values have a different genetic architecture from the broader population. One method relied on population-level genetic data, while the other compared trait levels among siblings.
Using these approaches, the team analyzed 74 quantitative traits from large-scale health and genetic datasets, including the UK Biobank and the All of Us Research Program in the United States. Together, these databases include health and genetic information from hundreds of thousands of volunteer participants representing a wide range of geographic backgrounds and ancestries.
The researchers then looked for evidence that people at the extreme ends of the traits were more likely to carry rare genetic variants with larger biological effects.
“By focusing on individuals at the extremes, we may be able to uncover clearer biological signals that are harder to detect in the general population,” says Dr. O’Reilly.
The authors note that additional studies will be needed to determine how broadly these findings apply across populations and traits. They also acknowledged that their analysis focused on the genetic causes of these traits and did not fully capture the potential influence of environmental and lifestyle factors, which are also major causes of extreme trait values.
Future research will aim to further characterize the rare variants involved and better understand how they influence disease risk.
The paper is titled “Distinct genetic architecture in the tails of complex traits.”
The study’s authors, as listed in the journal, are T. Souaiaia, H.M. Wu, A.P.S. Ori, S.W. Choi, C.J. Hoggart, and P.F. O’Reilly.
For details on funding, see the paper at https://doi.org/10.1038/s41586-026-10516-5.
About the Icahn School of Medicine at Mount Sinai
The Icahn School of Medicine at Mount Sinai is internationally renowned for its outstanding research, educational, and clinical care programs. It is the sole academic partner for the seven member hospitals* of the Mount Sinai Health System, one of the largest academic health systems in the United States, providing care to New York City’s large and diverse patient population.
The Icahn School of Medicine at Mount Sinai offers highly competitive MD, PhD, MD-PhD, and master’s degree programs, with enrollment of more than 1,200 students. It has the largest graduate medical education program in the country, with more than 2,700 clinical residents and fellows training throughout the Health System. The Graduate School of Biomedical Sciences offers 13 degree-granting programs, conducts innovative basic and translational research, and trains more than 4705 postdoctoral research fellows.
Ranked 11th nationwide in National Institutes of Health (NIH) funding, the Icahn School of Medicine at Mount Sinai is among the 90th percentile of U.S. private medical schools in Sponsored Programs Direct Expenditures per Principal Investigator, according to the Association of American Medical Colleges. More than 6,900 scientists, educators, and clinicians work within and across dozens of academic departments and multidisciplinary institutes with an emphasis on translational research and therapeutics. Through Mount Sinai Innovation Partners (MSIP), the Health System facilitates the real-world application and commercialization of medical breakthroughs made at Mount Sinai.
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* Mount Sinai Health System member hospitals: The Mount Sinai Hospital; Mount Sinai Brooklyn; Mount Sinai Morningside; Mount Sinai Queens; Mount Sinai South Nassau; Mount Sinai West; and New York Eye and Ear Infirmary of Mount Sinai.
Nature
Data/statistical analysis
People
Distinct genetic architecture in the tails of complex traits
27-May-2026