Large, rare chromosomal deletions associated with severe early-onset obesity
Open accessAbstract
Obesity is a highly heritable and genetically heterogeneous disorder. 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 x 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 autism and mental retardation; 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 signalling. 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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16p11.2 deletions and duplications have been found in individuals with ASD, intellectual disability, seizure disorder, obesity, macrocephaly, and schizophrenia.
“chromosome 16p11.2 deletions and duplications have been found in individuals with ASD and intellectual disability (ID) (Weiss et al., 2008), seizure disorder (Mefford et al., 2009), obesity (Bochukova et al., 2010), macrocephaly, and schizophrenia (McCarthy et al., 2009).”
From Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism (2011) · cites this paper as Bochukova et al., 2010
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- Authors
- Bochukova, E. G., Huang, N., Keogh, J., Henning, E., Purmann, C., Blaszczyk, K., Saeed, S., Hamilton-Shield, J., Clayton-Smith, J., O’Rahilly, S., Hurles, M. E., & Farooqi, I. S.
- Affiliations
- University of Cambridge (GB)
- Wellcome Sanger Institute (GB)
- Bristol Royal Hospital for Children (GB)
- Corresponding author
- Hurles, Matthew E.
- Farooqi, I. Sadaf
- ORCID
- Venue
- Nature
- Published
- 2009-12-06
- Volume
- 463
- Issue
- 7281
- Pages
- 666-670
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3108883
- OpenAlex
- W2075690247
- Cited by
- 613
- References
- 27
- Citations by year
- 2026: 13 · 2025: 21 · 2024: 19 · 2023: 23 · 2022: 21 · 2021: 21 · 2020: 24 · 2019: 32 · 2018: 24 · 2017: 27 · 2016: 19 · 2015: 51 · 2014: 39 · 2013: 50 · 2012: 62
- FWCI
- 44.65
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- Bristol Research (University of Bristol) (submittedVersion)
- Funders
- Wellcome Trust (085475, 082390/Z/07/Z, 077014/Z/05/0Z, 077014, 082390)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- copy number variation, missing heritability, SH2B1, developmental delay, neurodevelopmental disorders, de novo deletion, obesity genetics, body mass index, intellectual disability
- MeSH terms
- Child, Developmental Disabilities, Chromosome Deletion, Chromosomes, Human, Pair 16, United Kingdom, Heterozygote, Humans, Hyperphagia, Insulin Resistance, Mutation, Obesity, Cohort Studies, Age of Onset, Inheritance Patterns, White People, Adaptor Proteins, Signal Transducing, Genome-Wide Association Study, DNA Copy Number Variations
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