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Obesity-Related Gene Methylation Changes Connected to BMI in Healthy Adolescents

NEW YORK (GenomeWeb) – Adolescent body weight appears to coincide with DNA methylation patterns at genes previously implicated in obesity, according to new research from investigators at Pennsylvania State University and the University of North Carolina, Chapel Hill.

"If externally validated, our data would suggest that DNA methylation in obesity-related genes may relate to obesity risk in adolescents," corresponding author Duanping Liao, a public health sciences researcher at Penn State, and his colleagues wrote in a paper published online yesterday in Scientific Reports.

For that study, the team relied on targeted bisulfite sequencing to profile methylation in blood cells from more than 250 healthy members of a Penn State Child Cohort, identifying thousands of CpG sites with ties to participants' body mass index percentile. Those BMI-related DNA methylation sites were over-represented in 11 obesity-related genes, they reported, including a gene called SIM1 that housed a methylation mark significantly linked to higher-than-usual BMI.

Based on such findings, "further longitudinal studies with larger samples are warranted," the authors wrote, noting that such investigations are needed to "confirm our findings and provide deeper insight into the causal direction of the association, as well as possible origins of the variation in DNA methylation levels."

To explore potential epigenetic contributors to body mass, the researchers started with samples from 391 participants in the Penn State Child Cohort, who were enrolled between 2002 and 2006 at the ages of five- to 12-years-old and followed for an average of nearly eight years. They narrowed in on 263 samples with sufficient peripheral blood leukocyte DNA for modified reduced-representation bisulfite sequencing with Illumina instruments to profile methylation patterns across the genome.

"While a large number of obesity-related genes have been identified by genome-wide association studies, these genetic studies have only been able to explain a limited proportion of the variance in obesity," the authors explained, noting that "a more thorough understanding of the factors associated with the susceptibility to obesity is needed."

Using information at more than 165,000 CpG sites, including nearly 103,500 intragenic CpGs, the team searched for DNA methylation associations with BMI in the participants: five participants who were considered underweight, 162 normal weight individuals, 54 overweight participants, and 42 individuals classified as obese.

In the process, the researchers unearthed 5,669 within-gene CpG sites with methylation levels that corresponded to participants' BMI percentile group — a set that encompassed 28 methylation marks in 11 genes associated with obesity in prior studies. Given the genome-wide distribution of the broader collection of CpG sites considered, their analyses indicated that the obesity-related genes were enriched for the BMI-associated methylation marks.

"[W]e observed that aggregated change in methylation of DNA from peripheral blood leukocytes on obesity-related genes was associated with obesity in population-based samples of healthy adolescents," the authors reported.

They highlighted one particularly promising association: a significant uptick in BMI percentile that coincided with increased methylation at a CpG site in a chromosome 6 gene called SIM1 that has been previously implicated in energy homeostasis and neuronal differentiation in the hypothalamus.

"While validation is pending, our results provided a potential target site for future studies investigating DNA methylation and obesity," the authors wrote, though they cautioned that "discovery studies, including the current one, may overestimate the strength of the association."

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