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


Obesity is a highly heritable and genetically heterogeneous disorder1. Here we investigated the contribution of copy number variation to obesity in 300 Caucasian patients with severe early-onset obesity, 143 of whom also had developmental delay. Large (>500 kilobases), rare (<1%) deletions were significantly enriched in patients compared to 7,366 controls (P < 0.001). We identified several rare copy number variants that were recurrent in patients but absent or at much lower prevalence in controls. We identified five patients with overlapping deletions on chromosome 16p11.2 that were found in 2 out of 7,366 controls (P < 5 × 10-5). In three patients the deletion co-segregated with severe obesity. Two patients harboured a larger de novo 16p11.2 deletion, extending through a 593-kilobase region previously associated with autism2,3,4 and mental retardation5; both of these patients had mild developmental delay in addition to severe obesity. In an independent sample of 1,062 patients with severe obesity alone, the smaller 16p11.2 deletion was found in an additional two patients. All 16p11.2 deletions encompass several genes but include SH2B1, which is known to be involved in leptin and insulin signalling6. Deletion carriers exhibited hyperphagia and severe insulin resistance disproportionate for the degree of obesity. We show that copy number variation contributes significantly to the genetic architecture of human obesity.

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Figure 1: Discovery of 16p11.2 CNV associated with severe early-onset obesity.
Figure 2: Metabolic phenotype of carriers of the 16p11.2 deletion.


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We thank the patients, their families and all the Physicians who have referred patients to the Genetics of Obesity Study (GOOS). E.G.B., N.H., M.E.H. (grant no. 077014/Z/05/0Z) and I.S.F. (grant no. 082390/Z/07/Z) were funded by the Wellcome Trust. I.S.F. and S.O.R. are funded by the MRC Centre for Obesity and Related Disorders and NIHR Cambridge Biomedical Research Centre. We would like to thank L. Mavrogiannis for advice on MLPA analysis and V. Trowse for help with clinical studies. This study makes use of control data provided by the Genetic Association Information Network (GAIN) and the Wellcome Trust Case Control Consortium 2 (WTCCC2), through work funded by NIH and the Wellcome Trust (under award 085475). The GAIN General Research Use data sets used for the analyses described in this manuscript were obtained from the database of Genotype and Phenotype (dbGaP;, dbGaP accession numbers phs000017 and phs000021). A full list of the investigators who contributed to the generation of the WTCCC2 data is available from

Author Contributions I.S.F., M.E.H., E.G.B. and N.H. designed the study, analysed the data and wrote the paper. All the authors contributed to data collection and/or processing, as well as the current version of the paper.

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Correspondence to Matthew E. Hurles or I. Sadaf Farooqi.

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The authors declare no competing financial interests.

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This file contains Supplementary Figures I & 3-10 with Legends, Legend for Supplementary Figure 2, Supplementary Notes and Supplementary Tables 1-5. (PDF 1670 kb)

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Bochukova, E., Huang, N., Keogh, J. et al. Large, rare chromosomal deletions associated with severe early-onset obesity. Nature 463, 666–670 (2010).

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