Scientists identify causative genetic variant linked to common childhood obesity

Researchers at the Children's Hospital of Philadelphia (CHOP) have identified a causative 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 target gene may become a target for future therapeutic interventions. The results were published in the journal Cell Genomics.

Environmental and genetic factors play a key role in the increasing incidence of childhood obesity. Although the precise 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.

Earlier 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, with most of these loci located in non-coding 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 study first author Sheridan H. Littleton, Ph.D., a postdoctoral fellow who conducted the work. At CHOP's Center for Spatial and Functional Genomics.

“With further research, there is the potential to learn how this variant is targeted could become a target for new therapies specifically designed to treat childhood obesity.”

In addition to childhood obesity, this locus is associated with a number of associated health problems, including increased susceptibility to type 2 diabetes, increased body fat 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.

Previous related CHOP studies have linked the hypothalamus to appetite, which may be linked to childhood obesity. Because the hypothalamus is located deep in the brain, it is especially difficult to study.

To further study the effects of the rs7132908 variant, the researchers used stem cells that develop into hypothalamic neurons, a key cell type associated with feeding behavior, to study alleles for this variant. The allele associated with the risk of obesity affected the expression of the FAIM2 gene and reduced the proportion of neurons generated during stem cell differentiation, indicating that the variant is associated with neurodevelopment.

“Despite a number of challenges, this study demonstrates how additional efforts can reveal important information about previously uncharacterized genetic variants and their role in a variety of childhood and adult diseases,” said Struan FA. Grant, Ph.D., is director of the Center for Spatial and Functional Genomics and holder of the Daniel B. Burke Endowed Chair in Diabetes Research at CHOP.

“This work further highlights the central role of the brain in the genetics of obesity and provides us with a strategy for further study.”