Researchers at the Icahn School of Medicine at Mount Sinai have found evidence that people who fall at the extreme upper or lower end of certain traits, such as cholesterol, blood sugar levels, height, or age at menopause, are more likely to have a simpler genetic explanation than previously thought.
Their findings were reported in the May 27 issue of the journal. nature (https://doi.org/10.1038/s41586-026-10516-5), which could lead to new insights into the causes of common diseases.
Many traits associated with human health are considered “polygenic.” This means that they are formed by the combined effects of many common genetic variations, each contributing only a small amount of influence. However, a new study investigated whether individuals with extreme trait values may be affected by rare genetic variations that have a greater impact.
Researchers say this possibility could help explain why some people develop abnormally high or low levels of traits associated with conditions such as diabetes, heart disease, and stroke.
We typically think that these traits are formed by thousands of genetic changes, each of which has a very small effect. However, our findings suggest that some people are at the far end of the trait spectrum because there are far fewer rare genetic variants that have much stronger effects. By identifying who these people are, clinicians may be able to provide them with preventive care and treatments that are better suited to their genetic risk profile. ”
Dr. Paul O’Reilly, Senior Corresponding Author, Professor of Statistical Genetics, Department of Genetic and Genomic Sciences, Icahn School of Medicine, Mount Sinai, New York
The researchers’ hypothesis was based in part on evolutionary biology. Because extremely high or low trait values can be disadvantageous, natural selection may reduce the frequency of genetic variation that strongly causes such extreme values. As a result, such variants are expected to be relatively rare within the population.
“Our goal was to better understand whether extreme trait values sometimes arise from different types of genetic makeup,” says Dr. O’Reilly. “If so, this could ultimately help researchers pinpoint biological pathways that are particularly important in disease.”
To conduct this study, the researchers analyzed genetic patterns associated with various biomarkers and physical measurements such as hemoglobin, heart rate, and weight. The researchers first developed two complementary statistical approaches to test whether people with extremely high or low trait values have a different genetic makeup than the broader population. One method relied on population-level genetic data, and the other compared trait levels between siblings.
Using these approaches, the team analyzed 74 quantitative traits from large health and genetic datasets, including the UK Biobank and the US All of Us Research Program. These databases contain health and genetic information from hundreds of thousands of volunteer participants representing a wide range of geographic backgrounds and ancestry.
The researchers then looked for evidence that people at either end of the trait were more likely to carry rare genetic variations with greater biological consequences.
“By focusing on individuals in extreme conditions, we may be able to uncover clearer biological signals that are difficult to detect in the general population,” Dr. O’Reilly said.
The authors note that additional research is needed to determine how broadly these findings apply across populations and traits. They also acknowledged that the 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 the main causes of extreme trait values.
Future studies will aim to further characterize the rare mutations involved and better understand how they influence disease risk.
sauce:
Mount Sinai Health System
Reference magazines:
Suaia, T. others. (2026) Unique genetic architecture in the tail of complex traits. nature. DOI: 10.1038/s41586-026-10516-5. https://www.nature.com/articles/s41586-026-10516-5
