Scientists Link Copy Number Variants with Severe Early-Onset Obesity
Findings reported in Nature suggest further study will highlight additional obesity-related deletions.!--h2>
A group of scientists have linked deletions in certain sections of chromosome 16 with severe, early-onset obesity in children. They claim that the findings represent the first time copy number variants (CNVs) have been associated with the condition.
The research also has implications for the way childhood obesity is diagnosed; the study has already led to some children who were previously thought to have been deliberately overfed by their parents being removed from a social services at-risk register.
The researchers, from University of Cambridge Metabolic Research Laboratories, the Wellcome Trust Sanger Institute, Bristol Children’s Hospital, and St. Mary’s Hospital in Manchester published their data in Nature in a paper titled “Large, rare chromosomal deletions associated with severe early-onset obesity.”
Cambridge University’s Sadaf Farooqi, Ph.D., and colleagues claim that while genome-wide association studies have identified common SNPs associated with increased body mass index, together these only account for a small percentage of the inherited variation. In the hunt for further genetic clues, they compared the genomes of 300 children with severe obesity with those of 7,000 apparently healthy controls. The severely obese study population was chosen to include 143 children who also demonstrated developmental delay, which is known in some cases to be linked with rare CNVs.
Genome analysis highlighted a significantly higher prevalence of deletions in region 16p11.2 among the study cohort compared with the controls. These deletions were associated with highly penetrant familial severe early-onset obesity and severe insulin resistance. One large de novo 16p11.2 deletion was shown to extend through a 593-kilobase region previously associated with autism and mental retardation. The severely obese children who harbored this deletion also showed signs of developmental delay.
Importantly, 16p11.2 deletions were found to span the SH2B1 gene, which is known to be involved in leptin and insulin signaling, the researchers point out. People with deletions involving the SH2B1 gene particularly exhibited excess need to eat and severe insulin resistance that was disproportionate to their degree of obesity.
“Novel CNVs unique to patients with severe early-onset obesity and the increased CNV burden (which is not fully accounted for by SH2B1 deletions) suggest a role for additional genes in the etiology of severe obesity,” the investigators conclude. “Our findings indicate the presence at the same loci of both common variants influencing susceptibility to common obesity and more highly penetrant rare variants including CNVs associated with severe early-onset forms of the disease.”