Large, rare chromosomal deletions associated with severe early-onset obesity

Elena G. Bochukova, Ni Huang, Julia Keogh, Elana Henning, Carolin Purmann, Kasia Blaszczyk, Sadia Saeed, Julian Hamilton-Shield, Jill Clayton-Smith, Stephen O’Rahilly, Matthew E. Hurles () and I. Sadaf Farooqi ()
Additional contact information
Elena G. Bochukova: University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke’s Hospital
Ni Huang: Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK
Julia Keogh: University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke’s Hospital
Elana Henning: University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke’s Hospital
Carolin Purmann: University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke’s Hospital
Kasia Blaszczyk: University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke’s Hospital
Sadia Saeed: University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke’s Hospital
Julian Hamilton-Shield: Bristol Children’s Hospital
Jill Clayton-Smith: Genetic Medicine, St Mary’s Hospital, Oxford Road, Manchester M13 9WL, UK
Stephen O’Rahilly: University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke’s Hospital
Matthew E. Hurles: Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK
I. Sadaf Farooqi: University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke’s Hospital

Nature, 2010, vol. 463, issue 7281, 666-670

Abstract: Genetic link to obesity Obesity is a highly heritable disorder but the genetic associations reported to date account for only a small percentage of the inherited variation in body mass index. Two groups report deletions on chromosome16p11.2 that may explain part of the 'missing heritability' in terms of 'high-penetrance' mutations that are rare but when present are very often associated with severe obesity. This is in contrast to more common gene defects that are less closely associated with clinical symptoms. Bochukova et al. identified rare recurrent copy number variants in 300 patients with severe early-onset obesity, caused by deletions involving several genes including SH2B1, known to be involved in leptin and insulin signalling. Many of the patients also suffered neurodevelopmental disorders. Walters et al. identified deletions of at least 593 kilobases on chromosome 16p11.2 in 31 patients with a previously unrecognized type of extreme obesity. The strategy they used to identify the lesion — using small well-phenotyped cohorts of extreme phenotypes with targeted follow-up in genome-wide association studies and population cohorts — shows promise as a means of identifying 'missing heritability' in complex metabolic diseases more generally.

Date: 2010
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DOI: 10.1038/nature08689

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