Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2010 Feb 4;463(7281):671-5.
doi: 10.1038/nature08727.

A New Highly Penetrant Form of Obesity Due to Deletions on Chromosome 16p11.2

Free PMC article

A New Highly Penetrant Form of Obesity Due to Deletions on Chromosome 16p11.2

R G Walters et al. Nature. .
Free PMC article


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.


Figure 1
Figure 1. Identification and validation of deletions at 16p11.2
(a) aCGH data showing the location of the 16p11.2 deletion. The data show the log2 intensity ratio for a deletion carrier compared to an undeleted control sample. Grey bars connected by a broken line denote the segmental duplication flanking the deletion region. Vertical bars indicate the positions of the probe pairs used for MLPA validation. Note that CGH and genotyping array probes targeted against segmental duplications may not accurately report copy number due to the increased number of homologous sequences in the diploid state. Genome coordinates are according to the hg18 build of the reference genome. (b) MLPA validation of 16p11.2 deletions. Representative MLPA results are shown, illustrating one instance of maternal transmission and two instances of de novo deletions. Genotyping data excluded the possibility of non-paternity. Full results for MLPA validation and inheritance analysis are shown in Supplementary Figure S1. Each panel shows the relative magnitude of the normalised, integrated signal at each probe location, in order of chromosomal position of the MLPA probe pairs as indicated in (a). Each panel corresponds to its respective position on the associated pedigree, as shown.
Figure 2
Figure 2. Dependence of BMI on age in subjects having a deletion at 16p11.2
Data are for all individuals carrying a deletion for whom phenotypic data are available. Similar data from this study only are shown in Supplementary Figures S2 and S3. Lines denote the age- and gender-corrected thresholds (solid/broken – male/female) for obesity and morbid obesity. Symbols are: Square/circle – male/female; black/grey – ascertained/not ascertained for developmental delay; filled/open – ascertained/not ascertained for obesity; diamond – first-degree relative of proband; cross – previously published data-. The 31 year old male with BMI ~20 kg.m−2 was diabetic based on fasting blood glucose >7 mmol/L.

Similar articles

  • Large, rare chromosomal deletions associated with severe early-onset obesity.
    Bochukova EG, Huang N, Keogh J, Henning E, Purmann C, Blaszczyk K, Saeed S, Hamilton-Shield J, Clayton-Smith J, O'Rahilly S, Hurles ME, Farooqi IS. Bochukova EG, et al. Nature. 2010 Feb 4;463(7281):666-70. doi: 10.1038/nature08689. Epub 2009 Dec 6. Nature. 2010. PMID: 19966786 Free PMC article.
  • Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus.
    Jacquemont S, Reymond A, Zufferey F, Harewood L, Walters RG, Kutalik Z, Martinet D, Shen Y, Valsesia A, Beckmann ND, Thorleifsson G, Belfiore M, Bouquillon S, Campion D, de Leeuw N, de Vries BB, Esko T, Fernandez BA, Fernández-Aranda F, Fernández-Real JM, Gratacòs M, Guilmatre A, Hoyer J, Jarvelin MR, Kooy RF, Kurg A, Le Caignec C, Männik K, Platt OS, Sanlaville D, Van Haelst MM, Villatoro Gomez S, Walha F, Wu BL, Yu Y, Aboura A, Addor MC, Alembik Y, Antonarakis SE, Arveiler B, Barth M, Bednarek N, Béna F, Bergmann S, Beri M, Bernardini L, Blaumeiser B, Bonneau D, Bottani A, Boute O, Brunner HG, Cailley D, Callier P, Chiesa J, Chrast J, Coin L, Coutton C, Cuisset JM, Cuvellier JC, David A, de Freminville B, Delobel B, Delrue MA, Demeer B, Descamps D, Didelot G, Dieterich K, Disciglio V, Doco-Fenzy M, Drunat S, Duban-Bedu B, Dubourg C, El-Sayed Moustafa JS, Elliott P, Faas BH, Faivre L, Faudet A, Fellmann F, Ferrarini A, Fisher R, Flori E, Forer L, Gaillard D, Gerard M, Gieger C, Gimelli S, Gimelli G, Grabe HJ, Guichet A, Guillin O, Hartikainen AL, Heron D, Hippolyte L, Holder M, Homuth G, Isidor B, Jaillard S, Jaros Z, Jiménez-Murcia S, Helas GJ, Jonveaux P, Kaksonen S, Keren B, Kloss-Brandstätter A, Knoers NV, Koolen DA, Kroisel PM, Kronenberg F, Labalme A, Landais E, Lapi E, Layet V, Legallic S, Leheup B, Leube B, Lewis S, Lucas J, MacDermot KD, Magnusson P, Marshall C, Mathieu-Dramard M, McCarthy MI, Meitinger T, Mencarelli MA, Merla G, Moerman A, Mooser V, Morice-Picard F, Mucciolo M, Nauck M, Ndiaye NC, Nordgren A, Pasquier L, Petit F, Pfundt R, Plessis G, Rajcan-Separovic E, Ramelli GP, Rauch A, Ravazzolo R, Reis A, Renieri A, Richart C, Ried JS, Rieubland C, Roberts W, Roetzer KM, Rooryck C, Rossi M, Saemundsen E, Satre V, Schurmann C, Sigurdsson E, Stavropoulos DJ, Stefansson H, Tengström C, Thorsteinsdóttir U, Tinahones FJ, Touraine R, Vallée L, van Binsbergen E, Van der Aa N, Vincent-Delorme C, Visvikis-Siest S, Vollenweider P, Völzke H, Vulto-van Silfhout AT, Waeber G, Wallgren-Pettersson C, Witwicki RM, Zwolinksi S, Andrieux J, Estivill X, Gusella JF, Gustafsson O, Metspalu A, Scherer SW, Stefansson K, Blakemore AI, Beckmann JS, Froguel P. Jacquemont S, et al. Nature. 2011 Aug 31;478(7367):97-102. doi: 10.1038/nature10406. Nature. 2011. PMID: 21881559 Free PMC article.
  • Rare genomic structural variants in complex disease: lessons from the replication of associations with obesity.
    Walters RG, Coin LJ, Ruokonen A, de Smith AJ, El-Sayed Moustafa JS, Jacquemont S, Elliott P, Esko T, Hartikainen AL, Laitinen J, Männik K, Martinet D, Meyre D, Nauck M, Schurmann C, Sladek R, Thorleifsson G, Thorsteinsdóttir U, Valsesia A, Waeber G, Zufferey F, Balkau B, Pattou F, Metspalu A, Völzke H, Vollenweider P, Stefansson K, Järvelin MR, Beckmann JS, Froguel P, Blakemore AI. Walters RG, et al. PLoS One. 2013;8(3):e58048. doi: 10.1371/journal.pone.0058048. Epub 2013 Mar 12. PLoS One. 2013. PMID: 23554873 Free PMC article. Clinical Trial.
  • Copy number variants in obesity-related syndromes: review and perspectives on novel molecular approaches.
    D'Angelo CS, Koiffmann CP. D'Angelo CS, et al. J Obes. 2012;2012:845480. doi: 10.1155/2012/845480. Epub 2012 Dec 17. J Obes. 2012. PMID: 23316347 Free PMC article. Review.
  • Chipping away the 'missing heritability': GIANT steps forward in the molecular elucidation of obesity - but still lots to go.
    Hebebrand J, Volckmar AL, Knoll N, Hinney A. Hebebrand J, et al. Obes Facts. 2010 Oct;3(5):294-303. doi: 10.1159/000321537. Epub 2010 Oct 15. Obes Facts. 2010. PMID: 20975295 Free PMC article. Review.
See all similar articles

Cited by 199 articles

See all "Cited by" articles


    1. Walley AJ, Asher JE, Froguel P. The genetic contribution to non-syndromic human obesity. Nat. Rev. Genet. 2009;10:431–442. - PubMed
    1. Manolio TA, et al. Finding the missing heritability of complex diseases. Nature. 2009;461:747–753. - PMC - PubMed
    1. Stutzmann F, et al. Loss-of-function mutations in SIM1 cause a specific form of Prader-Willi-like syndrome. Diabetologia. 2009;52:S104.
    1. Froguel P, Blakemore AIF. The Power of the Extreme in Elucidating Obesity. New Eng. J. Med. 2008;359:891–893. - PubMed
    1. Conrad DF, et al. Origins and functional impact of copy number variation in the human genome. Nature. 2009;461 doi:10.1038/nature08516. - PMC - PubMed

Publication types

MeSH terms

Associated data