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A new highly penetrant form of obesity due to deletions on chromosome 16p11.2.

Walters, RG; Jacquemont, S; Valsesia, A; de Smith, AJ; Martinet, D; Andersson, J; Falchi, M; Chen, F; Andrieux, J; Lobbens, S; et al. Walters, RG; Jacquemont, S; Valsesia, A; de Smith, AJ; Martinet, D; Andersson, J; Falchi, M; Chen, F; Andrieux, J; Lobbens, S; Delobel, B; Stutzmann, F; El-Sayed Moustafa, JS; Chèvre, J-C; Lecoeur, C; Vatin, V; Bouquillon, S; Buxton, JL; 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; Ounap, K; Bochukova, EG; Henning, E; Keogh, J; Ellis, RJ; Macdermot, KD; van Haelst, MM; Vincent-Delorme, C; Plessis, G; Touraine, R; Philippe, A; Malan, V; Mathieu-Dramard, M; Chiesa, J; Blaumeiser, B; Kooy, RF; 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, MI; Peltonen, L; Carlsson, L; Jacobson, P; Sjöström, L; Huang, N; Hurles, ME; O'Rahilly, S; Farooqi, IS; Männik, K; Jarvelin, M-R; Pattou, F; Meyre, D; Walley, AJ; Coin, LJM; Blakemore, AIF; Froguel, P; Beckmann, JS (2010) A new highly penetrant form of obesity due to deletions on chromosome 16p11.2. Nature, 463 (7281). pp. 671-675. ISSN 1476-4687
SGUL Authors: Walley, Andrew John

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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.

Item Type: Article
Additional Information: This is a post-peer-review, pre-copyedit version of an article published in Nature. The final authenticated version is available online at:
Keywords: Adolescent, Adult, Age of Onset, Aging, Body Mass Index, Case-Control Studies, Child, Chromosome Deletion, Chromosomes, Human, Pair 16, Cognition Disorders, Cohort Studies, Europe, Female, Genome-Wide Association Study, Heterozygote, Humans, Inheritance Patterns, Male, Mutation, Obesity, Penetrance, Reproducibility of Results, Sex Characteristics, Young Adult, Chromosomes, Human, Pair 16, Humans, Obesity, Chromosome Deletion, Body Mass Index, Case-Control Studies, Cohort Studies, Reproducibility of Results, Cognition Disorders, Age of Onset, Aging, Sex Characteristics, Heterozygote, Inheritance Patterns, Penetrance, Mutation, Adolescent, Adult, Child, Europe, Female, Male, Genome-Wide Association Study, Young Adult, MD Multidisciplinary, General Science & Technology
SGUL Research Institute / Research Centre: Academic Structure > Institute of Medical & Biomedical Education (IMBE)
Journal or Publication Title: Nature
ISSN: 1476-4687
Language: eng
4 February 2010Published
1 December 2009Accepted
Publisher License: Publisher's own licence
Project IDFunderFunder ID
082390Wellcome Trust
G0600331Medical Research Council
079534Wellcome Trust
G0500539Medical Research Council
G0900554Medical Research Council
077014Wellcome Trust
089061Wellcome Trust
G0600331(77796)Medical Research Council
310000-112552Swiss National FoundationUNSPECIFIED
320030_122674Swiss National FundUNSPECIFIED
33CSCO-122661Swiss National FundUNSPECIFIED
SF0180142s08Estonian GovernmentUNSPECIFIED
SF0180026s09Estonian GovernmentUNSPECIFIED
201413 ENGAGESeventh Framework Programme
212111 BBMRISeventh Framework Programme
205419Seventh Framework Programme
K2008-65X-20753-01-4Swedish Research Council Formas
K2007-55X-11285-13Swedish Research Council Formas
529-2002-6671Swedish Research Council Formas
104781Academy of FinlandUNSPECIFIED
120315Academy of FinlandUNSPECIFIED
QLG1-CT-2000-01643European Commission
PubMed ID: 20130649
Web of Science ID: WOS:000274193900038
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