A study of dozens of human traits suggests that genetic architecture may shift at the extremes.
People with unusually high or low cholesterol, blood glucose, body size, and other measurable traits may sometimes have a simpler genetic explanation than scientists have assumed. A new study suggests that rare genetic variants with relatively large effects could play an outsized role in pushing some individuals toward the extremes of the human range.
The finding challenges the usual model for many common traits, which are considered polygenic. In that model, thousands of common genetic variants each contribute a small effect. Researchers at the Icahn School of Medicine at Mount Sinai found evidence that this explanation may not apply equally to everyone, particularly people whose measurements sit at the far ends of a trait distribution.
A Different Genetic Route to Extreme Traits
“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 study, published in Nature, examined 74 quantitative traits, including cholesterol, blood glucose, hemoglobin, heart rate, body weight, height, and age at menopause. The analysis drew on large genetic and health datasets from the UK Biobank and the All of Us Research Program in the United States.
The researchers focused on whether the genetic architecture itself changed at the extremes. They tested whether people with exceptionally high or low measurements were more likely than the broader population to carry rare variants capable of producing much larger biological effects.
Why Rare Variants Might Cluster at the Extremes
The hypothesis also fits a basic prediction from evolutionary biology. Genetic variants that strongly push a biological trait toward an extreme can sometimes reduce survival or reproductive success. Over many generations, natural selection can keep such variants uncommon in the population.
That means common variants with small effects may explain much of the variation seen across most people, while rarer variants with stronger effects could be disproportionately represented among individuals at the tails of a distribution.
“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.”
Two Ways to Test the Same Idea
To investigate that possibility, the team developed two complementary statistical approaches. One examined genetic patterns at the population level, while the other compared trait values among siblings.
Using both approaches gave the researchers different ways to test whether people at the extremes showed genetic patterns distinct from those in the wider population. Across the 74 traits, the analyses produced evidence consistent with a greater contribution from rare, large effect variants among some individuals with unusually high or low measurements.
“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.
Potential Links to Common Diseases
Many of the traits examined are closely tied to common diseases. Very high blood glucose can be associated with diabetes, while abnormal cholesterol levels can contribute to cardiovascular disease and stroke risk. Identifying rare variants that strongly alter these traits could therefore help researchers isolate genes and biological pathways that have particularly large effects on disease-related processes.
Environmental and lifestyle factors remain another major part of the picture. Diet, physical activity, medications, illness, socioeconomic conditions, and other exposures can all influence measurable health traits, and the study was designed primarily to investigate genetic contributions rather than fully account for those effects.
What Researchers Still Need to Learn
The authors caution that more work is needed to determine how consistently the pattern appears across different populations and different traits. Large genetic databases do not represent every ancestry equally, and the contribution of rare variants can vary substantially between populations.
Future studies will also need to identify the specific rare variants responsible for the strongest effects and determine how they alter biological pathways connected to disease.
Reference: “Distinct genetic architecture in the tails of complex traits” by T. Souaiaia, H. M. Wu, A. P. S. Ori, S. W. Choi, C. J. Hoggart and P. F. O’Reilly, 27 May 2026, Nature.
DOI: 10.1038/s41586-026-10516-5
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