Scientists have pinpointed five genes never before linked to obesity by analyzing DNA from nearly 850,000 people across six continental ancestries, a discovery that challenges the field’s long-standing focus on European populations and reveals how genetic blind spots have obscured our understanding of weight gain worldwide.
The research, published today in Nature Communications by Penn State scientists, identifies genes including YLPM1, RIF1, GIGYF1, SLC5A3, and GRM7 that triple the risk of severe obesity. These genes join about 20 others known to strongly influence whether someone develops the condition, which affects millions globally and contributes to everything from heart disease to social stigma.
What makes these findings unusual is where they came from. Most obesity genetics research has relied on data from people of European descent, creating what amounts to a genetic echo chamber. By combining information from the UK Biobank, which skews heavily European, with the more diverse All of Us Research Program in the United States, the team caught patterns that would have remained invisible in either dataset alone.
“Previous studies have relied predominantly on European-ancestry populations, reflecting an ancestral bias and missing opportunities to discover additional genes whose mutations may be more prevalent in other ancestries yet still clinically relevant for Europeans.”
The numbers tell the story of this bias clearly. The UK Biobank contributed only about 20,000 non-Europeans to the study sample. All of Us added roughly 167,000 more, suddenly making it possible to measure genetic effects independently across African, American, East Asian, European, Middle Eastern, and South Asian populations.
Genes That Work Everywhere, and Genes That Don’t
Not all obesity genes behave the same way across populations. Three genes, YLPM1, MC4R, and SLTM, showed remarkably consistent effects regardless of ancestry. YLPM1, an understudied gene expressed in brain tissue with links to mental disorders, performed like MC4R, one of the most talked-about obesity genes in the field.
Other genes told a different story. GRM7 and APBA1 showed significant differences between populations, their effects appearing much stronger in Europeans. This matters for drug development: a therapy targeting a gene that only works well in one ancestry group has limited global potential.
The newly identified genes carry roughly the same obesity risk as established culprits like MC4R and BSN. They’re expressed in the brain and fat tissue, and they correlate with increased body-fat percentage. One of them, YLPM1, shows up in mouse studies too. When researchers knocked out one copy of the gene in male mice, the animals developed significantly more body fat.
Beyond Weight: A Web of Health Problems
The research team didn’t stop at obesity. They investigated how these genes contribute to related conditions like Type 2 diabetes, high blood pressure, and heart disease. Using a statistical method called mediation analysis, they traced different paths through which disease risk increases.
Some genes, including BSN, GIGYF1, and SLTM, raise diabetes risk through two routes: directly, and indirectly by first increasing body mass index. Interestingly, the direct effect proved stronger than the indirect one through weight gain, helping explain why obesity so often leads to other serious health problems.
“Our findings emphasize the power and importance of cross-ancestry studies. Some of the previously discovered obesity genes appear to only have significant association to obesity in Europeans, which could limit their potential as therapeutic targets for a global population.”
The team also found changes in circulating blood proteins linked to the obesity genes. These protein changes point to potential drug targets and biomarkers that could help track whether treatments are working.
One practical finding emerged about polygenic risk scores, the sum of many small genetic effects. These scores increased obesity rates steadily in gene carriers, from 22 percent in the lowest-risk group to 48 percent in the highest-risk group among UK Biobank participants. The pattern held across populations, suggesting these combined genetic effects work additively rather than through complex interactions.
Despite the larger, more diverse dataset, the study still lacks enough non-European participants to discover ancestry-specific genes outside European populations. No genes reached significance thresholds in any single non-European group, while ten genes crossed that bar in European samples. The field needs more data, the researchers argue, and more representation from populations that have been systematically excluded from genomic studies.
The findings provide a more complete genetic picture of obesity across human populations, potentially guiding precision medicine efforts by revealing genes that single-population studies would miss. Whether that translates into better treatments depends on what comes next: more diverse data, deeper functional studies of these genes, and drugs designed for everyone rather than just some.
Nature Communications: 10.1038/s41467-025-64933-7
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