Common multi-allelic copy number variants (CNVs) appear enriched for phenotypic associations compared to their biallelic counterparts1,2,3,4. Here we investigated the influence of gene dosage effects on adiposity through a CNV association study of gene expression levels in adipose tissue. We identified significant association of a multi-allelic CNV encompassing the salivary amylase gene (AMY1) with body mass index (BMI) and obesity, and we replicated this finding in 6,200 subjects. Increased AMY1 copy number was positively associated with both amylase gene expression (P = 2.31 × 10−14) and serum enzyme levels (P < 2.20 × 10−16), whereas reduced AMY1 copy number was associated with increased BMI (change in BMI per estimated copy = −0.15 (0.02) kg/m2; P = 6.93 × 10−10) and obesity risk (odds ratio (OR) per estimated copy = 1.19, 95% confidence interval (CI) = 1.13–1.26; P = 1.46 × 10−10). The OR value of 1.19 per copy of AMY1 translates into about an eightfold difference in risk of obesity between subjects in the top (copy number > 9) and bottom (copy number < 4) 10% of the copy number distribution. Our study provides a first genetic link between carbohydrate metabolism and BMI and demonstrates the power of integrated genomic approaches beyond genome-wide association studies.

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The authors would like to thank the study participants in each of the studies, as well as the field investigators for the recruitment and examination of study subjects. The authors would also like to thank P. Maboudou and T. Brousseau for the measurement of serum amylase levels in the ABOS study subjects and P. Gele for the handling of ABOS samples. The authors thank the Genotyping Facility at the Wellcome Trust Sanger Institute for generating the TwinsUK SNP array data. The authors also thank E. Petretto, M. Manca, L. Coin, T. Andrew, I. Prokopenko, T. Norat and S. Richardson for helpful discussions, L. Arnalsteen, H. Verkindt, C. Eberle and M.F. Six for their contributions to the ABOS study and M. Deweider and F. Allegaert for laboratory processing of the DESIR samples, as well as S. Burbidge and M. Harvey of the Imperial College High-Performance Computing service for their assistance (http://www3.imperial.ac.uk/ict/services/hpc).

This work was supported by grants from the Wellcome Trust (grants 079534/z/06/z and 085555), the Medical Research Council (K2010-55X-11285-13), the Swedish Research Council, the Swedish Foundation for Strategic Research to the Sahlgrenska Center for Cardiovascular and Metabolic Research, the Swedish Diabetes Foundation and the Swedish federal government under the LUA/ALF agreement and by the European Community's Seventh Framework Programme (FP7/2007-2013) EUROCHIP project. M.F. is supported by the Medical Research Council (MR/K01353X/1), the British Skin Foundation (5044i), Qatar Foundation (GEQATDIAB) and the Commission of the European Communities (115005). P.F. is supported by the Medical Research Council (G1002084/1), the Imperial College Healthcare National Health Service (NHS) Trust Biomedical Research Centre (P46304 WMDI), the Commission of the European Communities (294785) and the Qatar Foundation (GEQATDIAB).

The DESIR study has been supported by INSERM contracts with CNAMTS, Lilly, Novartis Pharma and Sanofi-Aventis and by INSERM (Réseaux en Santé Publique, Interactions entre les Déterminants de la Santé), Cohortes Santé TGIR, Association Diabète Risque Vasculaire, 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.

DESIR Study Group. INSERM U780: B.B., M.A. Charles, P. Ducimetière, E. Eschwège; INSERM U367: F. Alhenc-Gelas; CHU (Centre Hospitalier Universitaire) D'Angers: Y. Gallois, A. Girault; Bichat Hospital: F. Fumeron, M. Marre, R. Roussel; CHU Rennes: F. Bonnet; CNRS UMR 8090, Lille: S. Cauchi, P.F.; Centres d'Examens de Santé: Alençon, Angers, Blois, Caen, Chartres, Chateauroux, Cholet, Le Mans, Orleans-Tours; Institute de Recherche Médecine Générale: J. Cogneau; general practitioners of the region; Institute Inter-Regional pour la Santé: C. Born, E. Caces, M. Cailleau, N. Copin, O. Lantieri, J.G. Moreau, F. Rakotozafy, J. Tichet, S. Vol.

This study makes use of data generated by the Genome Structural Variation Consortium (principal investigators N. Carter, M. Hurles, C. Lee and S. Scherer) who we thank for pre-publication access to their CNV discovery (and/or) genotyping data, made available through the websites http://www.sanger.ac.uk/research/areas/humangenetics/cnv/ and http://dgv.tcag.ca/dgv/app/home as a resource to the community. Funding for the project was provided by the Wellcome Trust (grant 077006/Z/05/Z), the Canada Foundation of Innovation and the Ontario Innovation Trust, the Canadian Institutes of Health Research, the Genome Canada/Ontario Genomics Institute, the McLaughlin Centre for Molecular Medicine, the Ontario Ministry of Research and Innovation, the Hospital for Sick Children Foundation, the Department of Pathology at Brigham and Women's Hospital and US National Institutes of Health grants HG004221 and GM081533.

TwinsUK was funded by the Wellcome Trust; the authors acknowledge funding of the GWAS with the support of the Wellcome Trust Sanger Centre and the National Eye Institute via a US National Institutes of Health/Center for Inherited Disease Research (CIDR) genotyping project grant (principal investigator T. Young); also the European Community's Seventh Framework Programme (FP7/2007-2013), ENGAGE project grant agreement HEALTH-F4-2007-201413. The study also receives support from the National Institute for Health Research (NIHR) BioResource Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London. The project also received support from a Biotechnology and Biological Sciences Research Council (BBSRC) project grant (G20234). The ABOS study was partially supported by Lille University Hospital and INSERM (Centre d'Investigation Clinique de Lille) and by grants from Conseil Regional Nord-Pas de Calais (ARCIR Obésité).

F. Pesce was supported by a fellowship from the European Renal Association–European Dialysis and Transplant Association (ERA-EDTA; ALTF 72-2010). M.N.A.-S. is supported by a PhD scholarship from the Research Division of the Qatar Foundation. R.S. is a recipient of a Chercheur Boursier award from the Fonds de la Recherche en Santé du Québec and a New Investigator Award from the Canadian Institutes of Health Research. P.D. is supported by the Wellcome Trust. T.D.S. is in receipt of an NIHR Senior Investigator award and a European Research Council Senior Researcher award.

Author information

Author notes

    • Mario Falchi
    •  & Julia Sarah El-Sayed Moustafa

    These authors contributed equally to this work.

    • Mario Falchi
    • , Timothy D Spector
    •  & Philippe Froguel

    These authors jointly directed this work.


  1. Department of Genomics of Common Disease, Imperial College London, London, UK.

    • Mario Falchi
    • , Julia Sarah El-Sayed Moustafa
    • , Petros Takousis
    • , Francesco Pesce
    • , Johanna C Andersson-Assarsson
    • , Rajkumar Dorajoo
    • , Mashael Nedham Al-Shafai
    • , Erdal Ozdemir
    • , Andrew Walley
    •  & Philippe Froguel
  2. Renal, Dialysis and Transplant Unit, Department of Emergency and Organ Transplantation (D.E.T.O.), University of Bari “Aldo Moro”, Bari, Italy.

    • Francesco Pesce
  3. CNRS UMR 8199, Lille Pasteur Institute, Lille, France.

    • Amélie Bonnefond
    • , Aurélie Dechaume
    • , Marlène Huyvaert
    • , Emmanuel Vaillant
    • , Odile Poulain-Godefroy
    •  & Philippe Froguel
  4. Lille 2 University, Lille, France.

    • Amélie Bonnefond
    • , Aurélie Dechaume
    • , Marlène Huyvaert
    • , Marie Pigeyre
    • , Robert Caiazzo
    • , Emmanuel Vaillant
    • , Odile Poulain-Godefroy
    • , Francois Pattou
    •  & Philippe Froguel
  5. Qatar Biomedical Research Institute (QBRI), Qatar Foundation, Doha, Qatar.

    • Amélie Bonnefond
    •  & Philippe Froguel
  6. European Genomic Institute for Diabetes (EGID), Lille, France.

    • Amélie Bonnefond
    • , Alexandre Patrice
    • , Aurélie Dechaume
    • , Marlène Huyvaert
    • , Marie Pigeyre
    • , Robert Caiazzo
    • , Violeta Raverdy
    • , Emmanuel Vaillant
    • , Odile Poulain-Godefroy
    • , Francois Pattou
    •  & Philippe Froguel
  7. Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

    • Johanna C Andersson-Assarsson
    • , Peter Jacobson
    • , Lars Sjostrom
    •  & Lena M S Carlsson
  8. Center for Cardiovascular and Metabolic Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

    • Johanna C Andersson-Assarsson
    • , Peter Jacobson
    • , Lars Sjostrom
    •  & Lena M S Carlsson
  9. Department of Genome Sciences, University of Washington, Seattle, Washington, USA.

    • Peter H Sudmant
    •  & Evan E Eichler
  10. Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore.

    • Rajkumar Dorajoo
  11. Research Division, Qatar Foundation, Doha, Qatar.

    • Mashael Nedham Al-Shafai
  12. Department of Mathematics, Imperial College London, London, UK.

    • Leonardo Bottolo
  13. Department of Psychiatry, University of Hong Kong, Hong Kong, China.

    • Hon-Cheong So
    •  & Pak Chung Sham
  14. Cardiovascular Research Methods Centre, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.

    • Robert W Davies
  15. INSERM UMR 859, Lille, France.

    • Alexandre Patrice
    • , Marie Pigeyre
    • , Robert Caiazzo
    • , Violeta Raverdy
    •  & Francois Pattou
  16. Centre Hospitalier Régional Universitaire (CHRU) Lille, Lille, France.

    • Alexandre Patrice
    • , Marie Pigeyre
    • , Robert Caiazzo
    • , Violeta Raverdy
    •  & Francois Pattou
  17. Bariatric Program, Ottawa Hospital, Ottawa, Ontario, Canada.

    • Robert Dent
  18. Department of Twin Research & Genetic Epidemiology, King's College London, St. Thomas' Hospital Campus, London, UK.

    • Massimo Mangino
    • , Pirro G Hysi
    • , Christopher J Hammond
    •  & Timothy D Spector
  19. Norwich Medical School, University of East Anglia, Norwich, UK.

    • Jane Skinner
  20. Wellcome Trust Sanger Institute, Hinxton, UK.

    • Sarah Field
    •  & Panos Deloukas
  21. Centre de Recherche en Epidémiologie et Santé des Populations, INSERM U1018, Epidemiology of Diabetes, Obesity and Chronic Kidney Disease over the Life Course, Villejuif, France.

    • Beverley Balkau
  22. Université Paris–Sud 11, UMRS 1018, Villejuif, France.

    • Beverley Balkau
  23. Department of Endocrinology, Diabetology and Nutrition, Bichat-Claude Bernard University Hospital, Assistance Publique–Hôpitaux de Paris (AP-HP), Paris, France.

    • Michel Marre
  24. INSERM U695, Paris 7 University, Paris, France.

    • Michel Marre
  25. INSERM UMR 1122 Interactions Géne-Environnement en Physiopathologie Cardio-Vasculaire, Université de Lorraine, Nancy, France.

    • Sophie Visvikis-Siest
  26. Paediatric Endocrine Unit, Lille Teaching Hospital, Lille, France.

    • Jacques Weill
  27. William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

    • Panos Deloukas
  28. Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia.

    • Panos Deloukas
  29. Atherogenomics Laboratory, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.

    • Ruth McPherson
  30. Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.

    • Ruth McPherson
  31. Saw Swee Hock School of Public Health, National University of Singapore, National University Hospital System, Singapore.

    • Jeannette Lee
    •  & E Shyong Tai
  32. Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, National University Hospital System, Singapore.

    • E Shyong Tai
  33. Duke–National University of Singapore Graduate Medical School, Singapore.

    • E Shyong Tai
  34. Department of Human Genetics, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.

    • Robert Sladek
  35. Department of Medicine, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.

    • Robert Sladek
  36. McGill University and Génome Québec Innovation Centre, Montreal, Quebec, Canada.

    • Robert Sladek
  37. Section of Genomic Medicine, National Heart and Lung Institute, Imperial College London, London, UK.

    • Andrew Walley
  38. Howard Hughes Medical Institute, Seattle, Washington, USA.

    • Evan E Eichler


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M.F. and P.F. conceived the study. M.F., P.F. and T.D.S. directed the project. M.F., J.S.E.-S.M. and P.F. wrote the manuscript. P.T., F. Pesce, A.B. and J.C.A.-A. contributed equally to this work. A.B., T.D.S., R.S., F. Pattou, H.-C.S., P.H.S., L.B., F. Pesce, P.T., R. Dorajoo, P.C.S. and E.E.E. edited the manuscript. J.S.E.-S.M., P.T., F. Pesce, J.C.A.-A., R. Dorajoo, M.N.A.-S., E.O., A.B., A.D. and M.H. performed the laboratory experiments. M.F., J.S.E.-S.M., J.C.A.-A., L.B., P.H.S., E.E.E., P.C.S. and H.-C.S. performed the statistical analyses. R.W.D., A.P., R. Dent, M. Mangino, P.G.H., J.S., M.P., R.C., V.R., E.V., S.F., B.B., M. Marre, S.V.-S., J.W., O.P.-G., P.J., L.S., C.J.H., P.D., R.M., J.L., E.S.T., L.M.S.C., A.W., F. Pattou, T.D.S. and P.F. provided samples, data and/or reagents. All authors commented on and approved the manuscript.

Competing interests

The authors declare no competing financial interests.

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