Mount Sinai Study Reveals Genetic Clues Explaining Why Obesity Affects People Differently
An international team of researchers led by Icahn School of Medicine at Mount Sinai and the University of Copenhagen in Denmark has pinpointed some of the reasons why obesity does not affect everyone in the same way. Their study, published today in Nature Medicine, identifies genetic differences that help explain why some people with obesity remain relatively healthy while others develop serious conditions like diabetes and heart disease.
The team analyzed genetic data from 452,768 people and discovered variants in 205 regions of the genome linked to higher body fat but better metabolic health. Using these discoveries, they developed a genetic risk score that adds up the impact of these variants. Individuals with higher scores were more likely to develop obesity—but were less likely to suffer from complications such as high blood pressure, high cholesterol, diabetes, or heart disease. This is due, in part, to the way fat cells behave in different people.
Importantly, these protective genetic effects were already visible in children. Kids carrying the protective variants were more likely to develop obesity but did not show the expected warning signs of metabolic disease.
“Our study shows that obesity is not a single condition—it is made up of different subtypes, each with its own risks,” said Nathalie Chami, PhD, first author on this paper and Instructor of Environmental Medicine, and Artificial Intelligence and Human Health, at the Icahn School of Medicine. “By uncovering these genetic differences, we can start to understand why obesity leads to different health outcomes in different individuals. This could eventually change how we predict, prevent, and treat obesity and its complications.”
The research also identified eight distinct obesity subtypes, each linked to unique health risks. “These insights could eventually help doctors predict which patients are most vulnerable to complications and inform new treatments that mimic the protective genetic effects found in some people,” said Dr. Chami.
The research team cautions that the findings do not mean obesity is harmless. “Most people with obesity still face health challenges, and lifestyle factors such as diet and exercise remain critical for overall health” said Zhe Wang, PhD, co-first author on this paper, and Adjunct Assistant Professor of Artificial Intelligence and Human Health, at the Icahn School of Medicine; and Assistant Professor at the University of Alabama at Birmingham.
The study was conducted in individuals from the UK Biobank, comprising people of European ancestry, and future work will extend to more diverse populations. It leveraged this data to perform a comprehensive multi-trait genome-wide screen. The team wanted to find new genes that affect body fat without being linked to cardiometabolic comorbidities by analyzing three adiposity and eight cardiometabolic traits, including lipid, glycemic, and blood pressure traits.
“By revealing new biological pathways that separate obesity from related diseases, the findings may pave the way for more personalized care, better-targeted therapies, and earlier prevention strategies—even from childhood,” said Ruth Loos, PhD, corresponding author, and Professor of Environmental Medicine at Icahn School of Medicine, and Professor at the University of Copenhagen in Denmark.
The DOI number for this paper is 10.1038/s41591-025-03931-0.
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 2,600 clinical residents and fellows training throughout the Health System. Its Graduate School of Biomedical Sciences offers 13 degree-granting programs, conducts innovative basic and translational research, and trains more than 560 postdoctoral research fellows.
Ranked 11th nationwide in National Institutes of Health (NIH) funding, the Icahn School of Medicine at Mount Sinai is among the 99th percentile in research dollars per investigator according to the Association of American Medical Colleges. More than 4,500 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.
About the Mount Sinai Health System
Mount Sinai Health System is one of the largest academic medical systems in the New York metro area, with 48,000 employees working across seven hospitals, more than 400 outpatient practices, more than 600 research and clinical labs, a school of nursing, and a leading school of medicine and graduate education. Mount Sinai advances health for all people, everywhere, by taking on the most complex health care challenges of our time—discovering and applying new scientific learning and knowledge; developing safer, more effective treatments; educating the next generation of medical leaders and innovators; and supporting local communities by delivering high-quality care to all who need it.
Through the integration of its hospitals, labs, and schools, Mount Sinai offers comprehensive health care solutions from birth through geriatrics, leveraging innovative approaches such as artificial intelligence and informatics while keeping patients’ medical and emotional needs at the center of all treatment. The Health System includes approximately 9,000 primary and specialty care physicians and 10 free-standing joint-venture centers throughout the five boroughs of New York City, Westchester, Long Island, and Florida. Hospitals within the System are consistently ranked by Newsweek’s® “The World’s Best Smart Hospitals, Best in State Hospitals, World Best Hospitals and Best Specialty Hospitals” and by U.S. News & World Report's® “Best Hospitals” and “Best Children’s Hospitals.” The Mount Sinai Hospital is on the U.S. News & World Report® “Best Hospitals” Honor Roll for 2025-2026.
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