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Scientists identify causative genetic variant linked to common childhood obesity
Last reviewed: 02.07.2025
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Researchers at Children's Hospital of Philadelphia (CHOP) have identified a causal genetic variant strongly associated with childhood obesity. The study highlights the importance of the brain's hypothalamus and its role in the development of childhood obesity, and the targeted gene may be a target for future therapeutic interventions. The findings are published in the journal Cell Genomics.
Environmental and genetic factors play a key role in the increasing incidence of childhood obesity. Although the exact role of genetics in childhood obesity is not yet fully understood, previous research suggests that neural pathways in the hypothalamus control food intake and are key regulators of the disease.
Previously, international genome-wide association studies (GWAS) conducted by CHOP researchers identified specific genetic markers, or loci, associated with obesity. Most of these studies identified loci associated with childhood and adult obesity equally, and most of these loci were in noncoding regions of the genome, making it difficult to study their mechanisms.
The latest study focused on the chr12q13 locus, which contains the nearby FAIM2 gene, which gave a significantly stronger signal in childhood obesity compared to adult obesity.
"By focusing specifically on this locus, we were able to identify a causal variant associated with one of the strongest genetic signals associated with childhood obesity," said first author Sheridan H. Littleton, PhD, a postdoctoral fellow who conducted the work in CHOP's Center for Spatial and Functional Genomics.
"With further research, there is potential to learn how the target of this variant could become a target for new therapies specifically designed to treat childhood obesity."
In addition to childhood obesity, this locus has been linked to a number of related health problems, including an increased susceptibility to type 2 diabetes, increased body fat percentage in children and adults, and earlier onset of menstruation. Using a variety of methods, the researchers focused on rs7132908, a single nucleotide polymorphism (SNP), or variant, at this locus.
Previously, related CHOP studies have linked the hypothalamus to appetite, which could be linked to childhood obesity. Because the hypothalamus is located deep in the brain, it is particularly difficult to study.
To further explore the effects of the rs7132908 variant, the researchers used stem cells that develop into hypothalamic neurons, a key cell type associated with eating behavior, to study alleles of the variant. The allele associated with obesity risk affected the expression of the FAIM2 gene and reduced the proportion of neurons formed when stem cells differentiate, suggesting that the variant is associated with neurodevelopment.
"Despite a number of challenges, this study demonstrates how additional efforts can uncover important information about previously uncharacterized genetic variants and their roles in a variety of childhood and adult diseases," said Struan F.A. Grant, PhD, director of the Center for Spatial and Functional Genomics and the Daniel B. Burke Chair in Diabetes Research at CHOP.
"This work once again highlights the central role of the brain in the genetics of obesity and provides us with a strategy for further study."