In one of the largest and most ancestrally diverse genetic studies of its kind, an international team of researchers has identified 13 genes linked to obesity, including five that were previously unknown. The findings, derived from an analysis of approximately 850,000 individuals, demonstrate that the genetic underpinnings of obesity are largely shared across different global populations, a discovery that could pave the way for more universally effective treatments.
The research addresses a critical shortcoming of previous large-scale genetic inquiries, which have historically focused on populations of European descent. By incorporating data from individuals of African, American, East Asian, European, Middle Eastern, and South Asian ancestry, the study provides a more comprehensive and equitable understanding of the genes that influence body weight. This broader view is essential for developing precision medicine that can be applied to a global population, as some genes previously thought to be significant were found to be less relevant outside of European groups.
A New Benchmark for Genomic Research
The study, published in Nature Communications, represents a major step forward in overcoming ancestral bias in genomics. Researchers from Penn State analyzed genetic, physical, and health data from two massive biomedical databases: the UK Biobank, which contains information from just over 450,000 adults, and the U.S. National Institutes of Health’s All of Us Research Program, which contributed data from nearly 385,000 adults. The All of Us program was particularly crucial for its inclusive cohort, designed to mirror the ancestral diversity of the United States.
By combining these vast datasets, scientists were able to conduct a powerful cross-ancestry analysis. This method allows for the detection of rare genetic variants that might be missed in smaller, less diverse studies. “Even with very large cohorts, rare, damaging variants can be hard to find unless we look across diverse populations,” said Dajiang J. Banerjee, a postdoctoral researcher at Penn State and an author of the paper. This inclusive approach not all confirms known genetic associations but also uncovers new ones that hold true for people around the world.
Five Novel Genes Uncovered
The analysis successfully identified 13 genes with a strong association to body mass index (BMI). While eight of these, including the well-documented genes MC4R and BSN, had been linked to obesity in prior studies, five were entirely new to science in this context. These newly implicated genes are YLPM1, RIF1, GIGYF1, SLC5A3, and GRM7.
Remarkably, the researchers found that these novel genes carry a significant impact. Variants in these genes were associated with an approximately threefold increase in the risk of severe obesity. This level of influence is comparable to that of MC4R, one of the most significant genes in obesity biology. The consistent effect of these genes across different ancestries underscores their fundamental role in human metabolism and weight regulation. For instance, the study highlighted YLPM1, an understudied gene expressed in brain tissue, which showed a consistent effect across all populations analyzed, similar to MC4R.
The Biology of Weight Regulation
Like previously known obesity-related genes, the five newly identified ones are primarily expressed in the brain and in adipose tissue, also known as body fat. This finding reinforces the understanding that obesity is a complex condition with deep roots in the central nervous system and metabolic processes. The genes were not only linked to BMI but also to direct measures of obesity, such as increased body-fat percentage.
The study also began to unravel how these genes function. For example, YLPM1 is a transcription factor, a type of protein that controls the activity of other genes, and has been previously connected to mental health disorders, hinting at the intricate links between brain function, mood, and metabolism. By examining plasma proteomics data—a comprehensive analysis of proteins in the blood—the team could further connect the genetic findings to measurable biological processes, identifying how genes like GIGYF1 and SLTM influence cardiometabolic conditions.
Connecting Obesity to Broader Health Risks
The research also shed light on the genetic links between obesity and its related health conditions. Several of the identified genes were found to contribute to an increased risk for type 2 diabetes, hypertension, and heart disease. The analysis showed that some genes, such as GIGYF1, influence the risk for type 2 diabetes both directly and indirectly through their effect on BMI. This provides a more nuanced picture of how genetic predispositions can lead to a cascade of health problems.
This comprehensive view is critical, as obesity is a global epidemic that significantly increases the risk for a wide range of chronic diseases. Understanding the shared genetic pathways that underlie both obesity and its comorbidities is a key step toward developing interventions that can address multiple health issues simultaneously. The findings highlight specific plasma proteins, such as LECT2 and NCAN, that are influenced by these genes and in turn affect BMI, offering potential new targets for therapeutic development.
Toward More Inclusive and Precise Medicine
Perhaps the most significant contribution of this work is its powerful demonstration of the need for diversity in genetic research. Santhosh Girirajan, a professor of genomics at Penn State and an author of the paper, noted that some genes discovered in the past appear to be significantly associated with obesity only in Europeans, limiting their utility as therapeutic targets for a global population.
By contrast, the genes identified in this cross-ancestry study have effects that are consistent across diverse populations. “Our cross-ancestry approach is helping us develop a more comprehensive view of the factors involved in obesity, which will hopefully help us develop effective therapies that can be applied through precision medicine,” Girirajan stated. This research not only expands the list of known obesity-related genes but also provides a robust framework for future genetic discoveries that are relevant to all of humanity, ensuring that the medical advances of tomorrow do not leave non-European populations behind.
