A new highly penetrant form of obesity due to deletions on chromosome 16p11.2
Open accessAbstract
Obesity has become a major worldwide challenge to public health, owing to an interaction between the Western 'obesogenic' environment and a strong genetic contribution. Recent extensive genome-wide association studies (GWASs) have identified numerous single nucleotide polymorphisms associated with obesity, but these loci together account for only a small fraction of the known heritable component. Thus, the 'common disease, common variant' hypothesis is increasingly coming under challenge. Here we report a highly penetrant form of obesity, initially observed in 31 subjects who were heterozygous for deletions of at least 593 kilobases at 16p11.2 and whose ascertainment included cognitive deficits. Nineteen similar deletions were identified from GWAS data in 16,053 individuals from eight European cohorts. These deletions were absent from healthy non-obese controls and accounted for 0.7% of our morbid obesity cases (body mass index (BMI) >or= 40 kg m(-2) or BMI standard deviation score >or= 4; P = 6.4 x 10(-8), odds ratio 43.0), demonstrating the potential importance in common disease of rare variants with strong effects. This highlights a promising strategy for identifying missing heritability in obesity and other complex traits: cohorts with extreme phenotypes are likely to be enriched for rare variants, thereby improving power for their discovery. Subsequent analysis of the loci so identified may well reveal additional rare variants that further contribute to the missing heritability, as recently reported for SIM1 (ref. 3). The most productive approach may therefore be to combine the 'power of the extreme' in small, well-phenotyped cohorts, with targeted follow-up in case-control and population cohorts.
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16p11.2 deletions are associated with macrocephaly and obesity, while duplications often lead to microcephaly and low body weight/BMI.
“Deletions of 16p11.2 are associated with increased head circumference (macrocephaly) [10, 12, 17, 23] and obesity [10, 12, 16, 20], whereas duplications often result in below average head size (microcephaly) [10, 17, 23, 24] and low body weight/BMI [10, 24].”
From 16p11.2 Copy Number Variations and Neurodevelopmental Disorders (2020) · cites this paper as [20]
In individuals with neurodevelopmental disorders, genetic screenings find 16p11.2 deletions at rates of 0.25-2.9% and duplications at rates of 0.15-0.78%.
“Data compiled from eight studies [13, 15–17, 20, 24, 26, 33] screening individuals with either ASD, ID, developmental delay (DD), dysmorphic features (DF), multiple congenital anomalies (MCA), obesity, or seizures find 16p11.2 deletions at rates of 0.25–2.9%, and duplications at rates between 0.15–0.78% (Table 1).”
From 16p11.2 Copy Number Variations and Neurodevelopmental Disorders (2020) · cites this paper as [20]
16p11.2 deletions are present at higher-than-expected rates in obese individuals and are more prevalent in developmental delay patients with obesity than those without obesity.
“16p11.2 deletions are present at higher-than-expected rates in obese individuals [31], and are more prevalent in developmental delay (DD) patients with obesity than those without obesity [20].”
From 16p11.2 Copy Number Variations and Neurodevelopmental Disorders (2020) · cites this paper as [20]
Recurrent ASD-associated CNVs such as 16p11.2 are linked not only to ASD but also to schizophrenia, epilepsy, ADHD, and obesity.
“Variability of phenotype is also characteristic of recurrent ASD-associated CNVs, such as 16p11.2, which has been linked not only to ASD but also to schizophrenia, epilepsy, ADHD, and obesity (Mccarthy et al., 2009; Shinawi et al., 2010; Walters et al., 2010; Weiss et al., 2008).”
From Using Whole-Exome Sequencing to Identify Inherited Causes of Autism (2013) · cites this paper as Walters et al., 2010
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Filges, I., Sparagana, S., Sargent, M., Selby, K., Schlade‐Bartusiak, K., Lueder, G. T., Robichaux‐Viehoever, A., Schlaggar, B. L., Shimony, J. S., & Shinawi, M. (2014) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.36605 · Cited by 30 · see citing works
Neurocognitive Phenotypes and Genetic Dissection of Disorders of Brain and Behavior
Congdon, E., Poldrack, R. A., & Freimer, N. B. (2010) · Neuron · doi:10.1016/j.neuron.2010.10.007 · Cited by 22 · see citing works
The erosion of phenotypic specificity in psychiatric genetics: emerging lessons from CNTNAP2
State, M. W. (2011) · Biological Psychiatry · doi:10.1016/j.biopsych.2011.03.021 · Cited by 6 · see citing works
- Authors
- Walters, R. G., Jacquemont, S., Valsesia, A., de Smith, A. J., Martinet, D., Andersson, J., Falchi, M., Chen, F., Andrieux, J., Lobbens, S., Delobel, B., Stutzmann, F., El-Sayed Moustafa, J. S., Chèvre, J.-C., Lecoeur, C., Vatin, V., Bouquillon, S., Buxton, J. L., Boute, O., Holder-Espinasse, M., Cuisset, J.-M., Lemaitre, M.-P., Ambresin, A.-E., Brioschi, A., Gaillard, M., Giusti, V., Fellmann, F., Ferrarini, A., Hadjikhani, N., Campion, D., Guilmatre, A., Goldenberg, A., Calmels, N., Mandel, J.-L., Le Caignec, C., David, A., Isidor, B., Cordier, M.-P., Dupuis-Girod, S., Labalme, A., Sanlaville, D., Béri-Dexheimer, M., Jonveaux, P., Leheup, B., Õunap, K., Bochukova, E. G., Henning, E., Keogh, J., Ellis, R. J., MacDermot, K. D., van Haelst, M. M., Vincent-Delorme, C., Plessis, G., Touraine, R., Philippe, A., Malan, V., Mathieu-Dramard, M., Chiesa, J., Blaumeiser, B., Kooy, R. F., Caiazzo, R., Pigeyre, M., Balkau, B., Sladek, R., Bergmann, S., Mooser, V., Waterworth, D., Reymond, A., Vollenweider, P., Waeber, G., Kurg, A., Palta, P., Esko, T., Metspalu, A., Nelis, M., Elliott, P., Hartikainen, A.-L., McCarthy, M. I., Peltonen, L., Carlsson, L., Jacobson, P., Sjöström, L., Huang, N., Hurles, M. E., O’Rahilly, S., Farooqi, I. S., Männik, K., Jarvelin, M.-R., Pattou, F., Meyre, D., Walley, A. J., Coin, L. J. M., Blakemore, A. I. F., Froguel, P., & Beckmann, J. S.
- Affiliations
- Imperial College London (GB)
- Centre Hospitalier Universitaire Vaudois (CH)
- SIB Swiss Institute of Bioinformatics (CH)
- École Polytechnique Fédérale de Lausanne (CH)
- Centre Hospitalier Universitaire de Lille (FR)
- Centre National de la Recherche Scientifique (FR)
- Groupe Hospitalier de l'Institut Catholique de Lille (FR)
- Harvard University (US)
- Inserm (FR)
- Centre Hospitalier Universitaire de Rouen (FR)
- Hôpital Civil, Strasbourg (FR)
- Centre Hospitalier Universitaire de Nantes (FR)
- Hospices Civils de Lyon (FR)
- Lyon 1 Université (FR)
- Centre Hospitalier Régional et Universitaire de Nancy (FR)
- Tartu University Hospital (EE)
- University of Cambridge (GB)
- Northwick Park Hospital (GB)
- Centre Hospitalier Universitaire de Caen Normandie (FR)
- Centre Hospitalier Universitaire de Saint-Étienne (FR)
- Hôpital Necker-Enfants Malades (FR)
- University of Antwerp (BE)
- McGill University and Génome Québec Innovation Centre (CA)
- GlaxoSmithKline (United States) (US)
- University of Lausanne (CH)
- University of Tartu (EE)
- Estonian Biocentre (EE)
- University of Oulu (FI)
- Centre for Human Genetics (GB)
- Broad Institute (US)
- Wellcome Sanger Institute (GB)
- Corresponding author
- Froguel, P.
- Beckmann, J. S.
- ORCID
- Walters, R. G.
- Jacquemont, S.
- Valsesia, A.
- Falchi, M.
- Chen, F.
- Chèvre, J.-C.
- Ambresin, A.-E.
- Fellmann, F.
- Ferrarini, A.
- Hadjikhani, N.
- Campion, D.
- Calmels, N.
- Mandel, J.-L.
- David, A.
- Isidor, B.
- Labalme, A.
- Sanlaville, D.
- Leheup, B.
- Õunap, K.
- Bochukova, E. G.
- Henning, E.
- Keogh, J.
- Touraine, R.
- Philippe, A.
- Malan, V.
- Blaumeiser, B.
- Kooy, R. F.
- Caiazzo, R.
- Pigeyre, M.
- Balkau, B.
- Sladek, R.
- Bergmann, S.
- Mooser, V.
- Waterworth, D.
- Reymond, A.
- Vollenweider, P.
- Waeber, G.
- Kurg, A.
- Palta, P.
- Esko, T.
- Metspalu, A.
- Nelis, M.
- Elliott, P.
- McCarthy, M. I.
- Peltonen, L.
- Carlsson, L.
- Jacobson, P.
- Huang, N.
- Hurles, M. E.
- O’Rahilly, S.
- Farooqi, I. S.
- Pattou, F.
- Meyre, D.
- Walley, A. J.
- Coin, L. J. M.
- Blakemore, A. I. F.
- Froguel, P.
- Beckmann, J. S.
- Venue
- Nature
- Published
- 2010-02
- Volume
- 463
- Issue
- 7281
- Pages
- 671-675
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2880448
- OpenAlex
- W2005710199
- Cited by
- 543
- References
- 42
- Citations by year
- 2026: 7 · 2025: 15 · 2024: 25 · 2023: 13 · 2022: 19 · 2021: 28 · 2020: 19 · 2019: 22 · 2018: 25 · 2017: 33 · 2016: 26 · 2015: 48 · 2014: 47 · 2013: 48 · 2012: 68
- FWCI
- 38.81
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- St George's Online Research Archive (St George's University of London) (acceptedVersion)
- PubMed Central (acceptedVersion)
- SERVAL (Université de Lausanne) (acceptedVersion, other-oa)
- IRIS (submittedVersion)
- Queen Mary Research Online (Queen Mary University of London) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- HAL (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Research Repository (Kingston University London) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- Minerva Access (University of Melbourne) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Spiral (Imperial College London) (submittedVersion)
- STM:n Hallinnonalan avoin julkaisuarkisto (Julkari) (submittedVersion)
- Funders
- Eli Lilly and Company
- GlaxoSmithKline
- Sanofi
- Åke Wiberg Stiftelse
- Jeanssons Stiftelser
- Genome Canada
- Ludwig Institute for Cancer Research
- Wellcome Trust (77796, 077014, 089061, 079534, 082390)
- Les Laboratories Pierre Fabre
- National Institute for Health and Care Research
- Research Councils UK
- European Commission
- Institut National de la Santé et de la Recherche Médicale
- Stiftelsen för Strategisk Forskning
- VINNOVA
- Fédération Française de Cardiologie
- Israel Science Foundation
- Novo Nordisk
- Vetenskapsrådet
- Fondation de France
- Oulun Yliopisto
- Université de Lausanne
- Association Diabète Risque Vasculaire
- National Institutes of Health (6r01hl087679-03, 5rl1mh083268-05)
- Novartis Pharma
- Medical Research Council
- Socialstyrelsen
- European Regional Development Fund
- Direction de l’hospitalisation et de l’offre de Soins
- Biocenter, University of Oulu
- National Heart, Lung, and Blood Institute (5R01 HL087679-02, R01 HL087679)
- National Institute of Mental Health (R01MH063706, RL1-MH083268, 1RL1MH083268-01, 5R01 MH63706:02)
- 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
- obesity, chromosome 16p11.2, copy number variation, missing heritability, neurodevelopmental disorders, cognitive impairment, SH2B1, leptin signaling, insulin signaling, extreme phenotypes, body mass index
- MeSH terms
- Adolescent, Adult, Aging, Child, Chromosome Deletion, Chromosomes, Human, Pair 16, Cognition Disorders, Europe, Female, Heterozygote, Humans, Male, Mutation, Obesity, Sex Characteristics, Reproducibility of Results, Cohort Studies, Body Mass Index, Case-Control Studies, Age of Onset, Penetrance, Inheritance Patterns, Genome-Wide Association Study, Young Adult
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