Obesity is recognised as a worldwide health crisis that affects millions of people and contributes to a wide range of serious medical and social problems. It increases the risk of Type 2 diabetes, heart disease, osteoarthritis and various forms of stigma that impact quality of life. Although lifestyle choices play a clear part in the development of obesity, genetic research has long shown that some individuals carry inherited factors that greatly heighten their risk. More than twenty genes are already known to have substantial effects on the likelihood of becoming obese. Yet, most of this knowledge comes from studies of people with predominantly European ancestry.
A new study published on 30 October in Nature Communications by researchers at Penn State reveals how much more remains to be learned when research includes diverse populations. Using genetic data from around 850,000 adults across six continental ancestries, the team identified thirteen genes associated with obesity that show consistent links across populations. Eight of these had been previously discovered, but five—YLPM1, RIF1, GIGYF1, SLC5A3, and GRM7—had never been linked to obesity. These newly identified genes are essential because their effects are as strong as those of some of the best-known obesity genes, tripling the risk of severe obesity.
Lead author Deepro Banerjee explained that most earlier research focused overwhelmingly on Europeans, meaning genes that are rarer in those populations may never have been detected. This ancestral bias has limited scientific understanding and restricted the discovery of clinically relevant genes, especially those that may only become evident in more diverse groups. The Penn State study overcame this limitation by combining data from the UK Biobank, which includes primarily European participants, and the All of Us Research Program, a U.S. National Institutes of Health initiative designed to reflect the ancestral diversity of the United States. Together, the datasets allowed researchers to study genetic effects separately and collectively across African, American, East Asian, European, Middle Eastern and South Asian populations.
The study focused on rare loss-of-function variants—genetic changes that disrupt normal gene function and often have more potent effects on health. By analysing these variants across the protein-coding regions of the genome, the researchers confirmed that the thirteen genes they detected are associated with higher body mass index (BMI), a standard indicator of obesity. These genes are expressed primarily in the brain and adipose tissue, supporting the current understanding that both the neurological regulation of appetite and fat metabolism contribute to obesity.
Beyond identifying the genes, the team also explored how they influence related diseases. Using mediation analysis, they determined whether the increased risk of conditions such as Type 2 diabetes and heart disease arises directly from the genes or indirectly through increased BMI. Some genes, including BSN, GIGYF1 and SLTM, were found to elevate disease risk through both pathways, highlighting biological mechanisms that might require treatment beyond weight reduction alone.
The researchers also analysed blood plasma proteins in a subset of participants and identified potential biomarkers and drug targets associated with obesity-related genes. These findings help guide the development of personalised treatments and improve how doctors track patient responses to future therapies. Senior author Santhosh Girirajan emphasised that cross-ancestry studies like this are crucial for developing precision medicine strategies that benefit a global population rather than a single group.
More information: Deepro Banerjee et al, Discovery of obesity genes through cross-ancestry analysis, Nature Communications. DOI: 10.1038/s41467-025-64933-7
Journal information: Nature Communications Provided by Penn State
