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

Abstract

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.

References

  1. 1

    Walley, A. J., Asher, J. E. & Froguel, P. The genetic contribution to non-syndromic human obesity. Nature Rev. Genet. 10, 431–442 (2009)

  2. 2

    Manolio, T. A. et al. Finding the missing heritability of complex diseases. Nature 461, 747–753 (2009)

  3. 3

    Stutzmann, F. et al. Loss-of-function mutations in SIM1 cause a specific form of Prader–Willi-like syndrome. Diabetologia 52, S104 (2009)

  4. 4

    Froguel, P. & Blakemore, A. I. F. The power of the extreme in elucidating obesity. N. Engl. J. Med. 359, 891–893 (2008)

  5. 5

    Conrad, D. F. et al. Origins and functional effect of copy number variation in the human genome. Nature advance online publication 10.1038/nature08516 (7 October 2009)

  6. 6

    Meyre, D. et al. Genome-wide association study for early-onset and morbid adult obesity identifies three new risk loci in European populations. Nature Genet. 41, 157–159 (2009)

  7. 7

    Farooqi, I. S. & O’Rahilly, S. Recent advances in the genetics of severe childhood obesity. Arch. Dis. Child. 83, 31–34 (2000)

  8. 8

    Kumar, R. A. et al. Recurrent 16p11.2 microdeletions in autism. Hum. Mol. Genet. 17, 628–638 (2008)

  9. 9

    Marshall, C. R. et al. Structural variation of chromosomes in autism spectrum disorder. Am. J. Hum. Genet. 82, 477–488 (2008)

  10. 10

    Weiss, L. A. et al. Association between microdeletion and microduplication at 16p11.2 and autism. N. Engl. J. Med. 358, 667–675 (2008)

  11. 11

    Bijlsma, E. K. et al. Extending the phenotype of recurrent rearrangements of 16p11.2: deletions in mentally retarded patients without autism and in normal individuals. Eur. J. Med. Genet. 52, 77–87 (2009)

  12. 12

    McCarthy, S. E. et al. Microduplications of 16p11.2 are associated with schizophrenia. Nature Genet. 41, 1223–1227 (2009)

  13. 13

    Ghebranious, N., Giampietro, P. F., Wesbrook, F. P. & Rezkalla, S. H. A novel microdeletion at 16p11.2 harbors candidate genes for aortic valve development, seizure disorder, and mild mental retardation. Am. J. Med. Genet. A. 143A, 1462–1471 (2007)

  14. 14

    Fernandez, B. A. et al. Phenotypic spectrum associated with de novo and inherited deletions and duplications at 16p11.2 in individuals ascertained for diagnosis of autism spectrum disorder. J. Med. Genet., 10.1136/jmg.2009.069369 (in the press)

  15. 15

    Shimojima, K., Inoue, T., Fujii, Y. & Ohno, K. Yamamoto, T. A familial 593 kb microdeletion of 16p11.2 associated with mental retardation and hemivertebrae. Eur. J. Med. Genet. 52, 433–435 (2009)

  16. 16

    Firmann, M. et al. Prevalence of obesity and abdominal obesity in the Lausanne population. BMC Cardiovasc. Disord. 8 330 10.1186/1471-2261-8-6 (2008)

  17. 17

    Sabatti, C. et al. Genome-wide association analysis of metabolic traits in a birth cohort from a founder population. Nature Genet. 41, 35–46 (2009)

  18. 18

    Nelis, M. et al. Genetic structure of Europeans: a view from the north-east. PLoS One 4 e5472 10.1371/journal.pone.0005472 (2009)

  19. 19

    Balkau, B., Eschwege, E., Tichet, J. & Marre, M. Proposed criteria for the diagnosis of diabetes: evidence from a French epidemiological study (D.E.S.I.R.). Diabetes Metab. 23, 428–434 (1997)

  20. 20

    Sladek, R. et al. A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 445, 881–885 (2007)

  21. 21

    Jernås, M. et al. Regulation of carboxylesterase 1 (CES1) in human adipose tissue. Biochem. Biophys. Res. Commun. 383, 63–67 (2009)

  22. 22

    Yeo, G. S. et al. A frameshift mutation in MC4R associated with dominantly inherited human obesity. Nature Genet. 20, 111–112 (1998)

  23. 23

    Vaisse, C., Clement, K., Guy-Grand, B. & Froguel, P. A frameshift mutation in human MC4R is associated with a dominant form of obesity. Nature Genet. 20, 113–114 (1998)

  24. 24

    Willer, C. J. et al. Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nature Genet. 41, 25–34 (2009)

  25. 25

    Chen, A. Y., Kim, S. E., Houtrow, A. J. & Newacheck, P. W. Prevalence of obesity among children with chronic conditions. Obesity (Silver Spring), 18, 210–213 (2010)

  26. 26

    Boeka, A. G. & Lokken, K. L. Neuropsychological performance of a clinical sample of extremely obese individuals. Arch. Clin. Neuropsychol. 23, 467–474 (2008)

  27. 27

    Poskitt, E. M. European Childhood Obesity Group. Defining childhood obesity: the relative body mass index (BMI). Acta Paediatr. 84, 961–963 (1995)

  28. 28

    Rolland-Cachera, M. F. et al. Body mass index variations: centiles from birth to 87 years. Eur. J. Clin. Nutr. 45, 13–21 (1991)

  29. 29

    Fisher, R. A. On the interpretation of χ2 from contingency tables, and the calculation of P . J. R. Stat. Soc. A 85, 87–94 (1922)

  30. 30

    Woolf, B. On estimating the relation between blood group and disease. Ann. Hum. Genet. 19, 251–253 (1955)

  31. 31

    Marioni, J. C. et al. Breaking the waves: improved detection of copy number variation from microarray-based comparative genomic hybridization. Genome Biol. 8 R228 10.1186/gb-2007-8-10-r228 (2007)

  32. 32

    Bengtsson, H., Simpson, K., Bullard, J. & Hansen, K. aroma.affymetrix: a generic framework in R for analyzing small to very large Affymetrix data sets in bounded memory. (Department of Statistics, University of California, Berkeley, Technical Report 745, 2008)

  33. 33

    Bengtsson, H., Irizarry, R., Carvalho, B. & Speed, T. P. Estimation and assessment of raw copy numbers at the single locus level. Bioinformatics 24, 759–767 (2008)

  34. 34

    Bengtsson, H., Ray, A., Spellman, P. & Speed, T. P. A single-sample method for normalizing and combining full-resolution copy numbers from multiple platforms, labs and analysis methods. Bioinformatics 25, 861–867 (2009)

  35. 35

    Huang, J. et al. Whole genome DNA copy number changes identified by high density oligonucleotide arrays. Hum. Genomics 1, 287–299 (2004)

  36. 36

    Olshen, A. B. & Venkatraman, E. S. Circular binary segmentation for the analysis of array-based DNA copy number data. Biostatistics 5, 557–572 (2004)

  37. 37

    Venkatraman, E. S. & Olshen, A. B. A faster circular binary segmentation algorithm for the analysis of array CGH data. Bioinformatics 23, 657–663 (2007)

  38. 38

    Collela, S. et al. QuantiSNP: an objective Bayes hidden-Markov model to detect and accurately map copy number variation using SNP genotyping data. Nucleic Acids Res. 35, 2013–2025 (2007)

  39. 39

    Wang, K. et al. PennCNV: an integrated hidden Markov model designed for high-resolution copy number variation detection in whole-genome SNP genotyping data. Genome Res. 17, 1665–1674 (2007)

  40. 40

    Korn, J. N. et al. Integrated genotype calling and association analysis of SNPs, common copy number polymorphisms and rare CNVs. Nature Genet. 40, 1253–1260 (2008)

  41. 41

    Schouten, J. P. et al. Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification. Nucleic Acids Res. 30, e57 (2002)

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Acknowledgements

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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