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


Obesity has become a major worldwide challenge to public health, owing to an interaction between the Western ‘obesogenic’ environment and a strong genetic contribution1. 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 component1. Thus, the ‘common disease, common variant’ hypothesis is increasingly coming under challenge2. 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) ≥ 40 kg m-2 or BMI standard deviation score ≥ 4; P = 6.4 × 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’4 in small, well-phenotyped cohorts, with targeted follow-up in case-control and population cohorts.

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Figure 1: Identification and validation of deletions at 16p11.2.
Figure 2: Dependence of BMI on age in subjects having a deletion at 16p11.2.

Accession codes

Primary accessions

Gene Expression Omnibus

Data deposits

The expression microarray data for carriers of 16p11.2 deletions is deposited in Gene Expression Omnibus under accession number GSE19238.


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A.J.W., A.I.F.B. and P.F. are supported by grants from the Wellcome Trust and the Medical Research Council (MRC). J.S.B. is supported by a grant from the Swiss National Foundation (310000-112552). L.J.M.C. is supported by an RCUK Fellowship. S.J. is funded by Swiss National Fund 320030_122674 and the Synapsis Foundation, University of Lausanne. A.V. is funded by the Ludwig Institute for Cancer Research. S.B. is supported by the Swiss Institute of Bioinformatics. I.S.F. and M.E.H. are funded by the Wellcome Trust and the MRC. We thank the DHOS (Direction de l’Hospitalisation et de l’Organisation des Soins) from the French Ministry of Health for their support in the development of several array CGH platforms in France. We thank ‘le Conseil Regional Nord Pas de Calais/FEDER’ for their financial support. Part of the CoLaus computation was performed at the Vital-IT center for high-performance computing of the Swiss Institute of Bioinformatics. The CoLaus authors thank Y. Barreau, M. Firmann, V. Mayor, A.-L. Bastian, B. Ramic, M. Moranville, M. Baumer, M. Sagette, J. Ecoffey and S. Mermoud for data collection. The CoLaus study was supported by grants from GlaxoSmithKline, the Faculty of Biology and Medicine of Lausanne and by the Swiss National Foundation (33CSCO-122661). K.M., A.K., T.E., M.N. and A.M. received support from targeted financing from Estonian Government SF0180142s08, and P.P. from SF0180026s09; and from the EU through the European Regional Development Fund. T.E., M.N. and A.M. received support from FP7 grants (201413 ENGAGE, 212111 BBMRI, ECOGENE (no. 205419, EBC)). The genotyping of the Estonian Genome Project samples were performed in the Estonian Biocentre Genotyping Core Facility. The EGPUT authors thank V. Soo for technical help in genotyping. The Northwick Park authors acknowledge support from the NIHR Biomedical Research Centre Scheme and the Hammersmith Hospital Charity Trustees. Genome Canada and Genome Quebec funded the genotyping of DESIR subjects. Work on the SOS sib pair cohort was supported by grants from the Swedish Research Council (K2008-65X-20753-01-4, K2007-55X-11285-13, 529-2002-6671), the Swedish Foundation for Strategic Research to Sahlgrenska Center for Cardiovascular and Metabolic Research, the Swedish Diabetes Foundation, the Åke Wiberg Foundation, Foundations of the National Board of Health and Welfare, the Jeansson Foundations, the Magn Bergvall Foundation, the Tore Nilson Foundation, the Royal Physiographic Society (Nilsson-Ehle Foundation), VINNOVA-VINNMER, and the Swedish federal government under the LUA/ALF agreement. The DESIR study has been supported by INSERM, CNAMTS, Lilly, Novartis Pharma and Sanofi-Aventis, by INSERM (Réseaux en Santé Publique, Interactions entre les determinants de la santé), by the Association Diabète Risque Vasculaire, the Fédération Française de Cardiologie, La Fondation de France, ALFEDIAM, ONIVINS, Ardix Medical, Bayer Diagnostics, Becton Dickinson, Cardionics, Merck Santé, Novo Nordisk, Pierre Fabre, Roche and Topcon. Northern Finland Birth Cohort 1966 (NFBC1966) was supported by the Academy of Finland (project grants 104781, 120315 and Center of Excellence in Complex Disease Genetics), University Hospital Oulu, Biocenter, University of Oulu, Finland, the European Commission (EURO-BLCS, Framework 5 award QLG1-CT-2000-01643), NHLBI grant 5R01HL087679-02 through the STAMPEED program (1RL1MH083268-01), NIH/NIMH (5R01MH63706:02), the ENGAGE project and grant agreement HEALTH-F4-2007-201413, and the MRC (studentship grant G0500539). The NFBC authors thank P. Rantakallio for the launch of NFBC1966 and initial data collection, S. Vaara for data collection, T. Ylitalo for administration, M. Koiranen for data management, and O. Tornwall and M. Jussila for DNA biobanking.

Author Contributions A.I.F.B., P.F., J.S.B. and L.J.M.C. designed and supervised the study. F.C., D.M., S.J., J.A. and S.B. coordinated and managed patient databases. R.G.W., A.V., A.J.d.S., C.L., F.S., F.C., J.-C.C., J.L.B., S.L., N.H. and J.S.E.-S.M. performed data analysis. A.J.d.S. conducted the MLPA analysis. J.A., M.F. and A.J.W. analysed expression data. A.-E.A., A.B., A.D., A.F., A.G., A.G., A.L., A.P., B.B., B.D., B.I., B.L., C.V.-D., C.L.C., D.C., D.M., D.S., F.F., G.M., G.P., J.-L.M., J.-M.C., J.A., J.C., K.M., K.D.M., K.O., M.M.v.H., M.-P.C., M.-P.L., M.P., M.B.-D., M.H.-E., M.M., N.C., O.B., P.J., R.C., R.E., R.F.K., R.T., S.D.-G., S.J., V.G. and V.M. supervised patient recruitment and performed cytogenetic analysis. A.-L.H., A.K., A.M., A.R., B.B., D.M., D.W., E.G.B., E.H., F.P., G.W., I.S.F., J.A., J.K., L.C., L.P., L.S., M.E.H., M.I.M., M.N., M.-R.J., N.H., P.E., P.J., P.P., P.V., R.S., S.B., S.O’R., T.E., V.M. and V.V. supervised cohort recruitment and/or conducted genotyping. R.G.W., S.J., A.V., A.J.d.S., L.J.M.C., A.I.F.B., P.F. and J.S.B. wrote and edited the manuscript and prepared figures. P.F. and J.S.B. contributed equally. All authors commented on and approved the manuscript.

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Correspondence to P. Froguel or J. S. Beckmann.

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Walters, R., Jacquemont, S., Valsesia, A. et al. A new highly penetrant form of obesity due to deletions on chromosome 16p11.2. Nature 463, 671–675 (2010).

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