PHG Foundation | Rare copy number variant causes childhood obesity

Rare copy number variant causes childhood obesity
10 December 2009 | By Dr Caroline Wright | Research article

Despite the fact that the modern epidemic of obesity is caused primarily by social and environmental factors – particularly the increasing availability of calorie-rich foods and decreasing levels of physical activity – weight is a highly heritable but genetically heterogeneous trait. According to the World Health Organisation, there were around 1.6 billion adults and 20 million children under the age of five worldwide who were overweight in 2005, and there are expected to be more than 700 million obese adults by 2015. Given the serious health consequences of being overweight, understanding the underlying genetics that predisposes some people to obesity is important not only for developing targeted treatments and preventative strategies, but also for reducing stigmatisation and unfair discrimination.

New research has uncovered a rare chromosomal deletion associated with early-onset obesity [Bochukova EG et al. Nature (2009) doi: 10.1038/nature08689]. In order to explore the role of rare copy number variants (CNVs) in obesity, 300 obese Caucasian children (enriched for patients with developmental delay in addition to severe obesity) were compared with over 7,000 population controls using a high resolution DNA microarray. There was a two-fold enrichment of large (>500 kb) rare (<1%) deletions in patients versus controls; in particular, an overlapping deletion in chromosome 16 (at the 16p11.2 locus) was the most common recurrent deletion, occurring in five unrelated patients and a further four cases identified in previous studies (as well as two controls with unknown weight) . These patients were found to have gained weight very rapidly in the first years of life, have elevated plasma insulin levels, and exhibit excessive hunger and high food intake. The deleted region contains numerous genes, including SH2B1, which was already implicated in obesity and encodes a protein involved in energy regulation and glucose metabolism. The authors conclude that “strategies aimed at looking for rare variants near common susceptibility loci may well prove to be fruitful in other common complex diseases”.

This discovery has already had a major impact on the lives of the children in this study, several of whom were considered to be at risk of abuse and had attracted the attention of social services because they were so severely obese. Since finding that the children carry this rare 16p11.2 deletion, two cases have already been removed from the protection register and scientists are optimistic about the remaining cases (see The Times).
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PHG Foundation | Rare copy number variant causes childhood obesity