title: Low copy number of the salivary amylase gene predisposes to obesity.
abstract: Common multi-allelic copy number variants (CNVs) appear enriched for phenotypic associations compared to their biallelic counterparts. 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/m(2); 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.
authors.affiliation: 1] Department of Genomics of Common Disease, Imperial College London, London, UK. [2] [3] [4].
authors.forename: Mario
authors.initials: M
authors.lastname: Falchi
authors.affiliation: 1] Department of Genomics of Common Disease, Imperial College London, London, UK. [2].
authors.forename: Julia Sarah
authors.initials: JS
authors.lastname: El-Sayed Moustafa
authors.affiliation: Department of Genomics of Common Disease, Imperial College London, London, UK.
authors.forename: Petros
authors.initials: P
authors.lastname: Takousis
authors.affiliation: 1] Department of Genomics of Common Disease, Imperial College London, London, UK. [2] Renal, Dialysis and Transplant Unit, Department of Emergency and Organ Transplantation (D.E.T.O.), University of Bari "Aldo Moro", Bari, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Pesce
authors.affiliation: 1] CNRS UMR 8199, Lille Pasteur Institute, Lille, France. [2] Lille 2 University, Lille, France. [3] Qatar Biomedical Research Institute (QBRI), Qatar Foundation, Doha, Qatar. [4] European Genomic Institute for Diabetes (EGID), Lille, France.
authors.forename: Amélie
authors.initials: A
authors.lastname: Bonnefond
authors.affiliation: 1] Department of Genomics of Common Disease, Imperial College London, London, UK. [2] Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. [3] Center for Cardiovascular and Metabolic Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Johanna C
authors.initials: JC
authors.lastname: Andersson-Assarsson
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Sudmant
authors.affiliation: 1] Department of Genomics of Common Disease, Imperial College London, London, UK. [2] Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore.
authors.forename: Rajkumar
authors.initials: R
authors.lastname: Dorajoo
authors.affiliation: 1] Department of Genomics of Common Disease, Imperial College London, London, UK. [2] Research Division, Qatar Foundation, Doha, Qatar.
authors.forename: Mashael Nedham
authors.initials: MN
authors.lastname: Al-Shafai
authors.affiliation: Department of Mathematics, Imperial College London, London, UK.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Bottolo
authors.affiliation: Department of Genomics of Common Disease, Imperial College London, London, UK.
authors.forename: Erdal
authors.initials: E
authors.lastname: Ozdemir
authors.affiliation: Department of Psychiatry, University of Hong Kong, Hong Kong, China.
authors.forename: Hon-Cheong
authors.initials: HC
authors.lastname: So
authors.affiliation: Cardiovascular Research Methods Centre, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Davies
authors.affiliation: 1] European Genomic Institute for Diabetes (EGID), Lille, France. [2] INSERM UMR 859, Lille, France. [3] Centre Hospitalier Régional Universitaire (CHRU) Lille, Lille, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Patrice
authors.affiliation: Bariatric Program, Ottawa Hospital, Ottawa, Ontario, Canada.
authors.forename: Robert
authors.initials: R
authors.lastname: Dent
authors.affiliation: Department of Twin Research & Genetic Epidemiology, King's College London, St. Thomas' Hospital Campus, London, UK.
authors.forename: Massimo
authors.initials: M
authors.lastname: Mangino
authors.affiliation: Department of Twin Research & Genetic Epidemiology, King's College London, St. Thomas' Hospital Campus, London, UK.
authors.forename: Pirro G
authors.initials: PG
authors.lastname: Hysi
authors.affiliation: 1] CNRS UMR 8199, Lille Pasteur Institute, Lille, France. [2] Lille 2 University, Lille, France. [3] European Genomic Institute for Diabetes (EGID), Lille, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Dechaume
authors.affiliation: 1] CNRS UMR 8199, Lille Pasteur Institute, Lille, France. [2] Lille 2 University, Lille, France. [3] European Genomic Institute for Diabetes (EGID), Lille, France.
authors.forename: Marlène
authors.initials: M
authors.lastname: Huyvaert
authors.affiliation: Norwich Medical School, University of East Anglia, Norwich, UK.
authors.forename: Jane
authors.initials: J
authors.lastname: Skinner
authors.affiliation: 1] Lille 2 University, Lille, France. [2] European Genomic Institute for Diabetes (EGID), Lille, France. [3] INSERM UMR 859, Lille, France. [4] Centre Hospitalier Régional Universitaire (CHRU) Lille, Lille, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Pigeyre
authors.affiliation: 1] Lille 2 University, Lille, France. [2] European Genomic Institute for Diabetes (EGID), Lille, France. [3] INSERM UMR 859, Lille, France. [4] Centre Hospitalier Régional Universitaire (CHRU) Lille, Lille, France.
authors.forename: Robert
authors.initials: R
authors.lastname: Caiazzo
authors.affiliation: 1] European Genomic Institute for Diabetes (EGID), Lille, France. [2] INSERM UMR 859, Lille, France. [3] Centre Hospitalier Régional Universitaire (CHRU) Lille, Lille, France.
authors.forename: Violeta
authors.initials: V
authors.lastname: Raverdy
authors.affiliation: 1] CNRS UMR 8199, Lille Pasteur Institute, Lille, France. [2] Lille 2 University, Lille, France. [3] European Genomic Institute for Diabetes (EGID), Lille, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Vaillant
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Field
authors.affiliation: 1] 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. [2] Université Paris-Sud 11, UMRS 1018, Villejuif, France.
authors.forename: Beverley
authors.initials: B
authors.lastname: Balkau
authors.affiliation: 1] Department of Endocrinology, Diabetology and Nutrition, Bichat-Claude Bernard University Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France. [2] INSERM U695, Paris 7 University, Paris, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Marre
authors.affiliation: INSERM UMR 1122 Interactions Géne-Environnement en Physiopathologie Cardio-Vasculaire, Université de Lorraine, Nancy, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Visvikis-Siest
authors.affiliation: Paediatric Endocrine Unit, Lille Teaching Hospital, Lille, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Weill
authors.affiliation: 1] CNRS UMR 8199, Lille Pasteur Institute, Lille, France. [2] Lille 2 University, Lille, France. [3] European Genomic Institute for Diabetes (EGID), Lille, France.
authors.forename: Odile
authors.initials: O
authors.lastname: Poulain-Godefroy
authors.affiliation: 1] Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. [2] Center for Cardiovascular and Metabolic Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Jacobson
authors.affiliation: 1] Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. [2] Center for Cardiovascular and Metabolic Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Sjostrom
authors.affiliation: Department of Twin Research & Genetic Epidemiology, King's College London, St. Thomas' Hospital Campus, London, UK.
authors.forename: Christopher J
authors.identifier: 0000000232272620
authors.initials: CJ
authors.lastname: Hammond
authors.affiliation: 1] Wellcome Trust Sanger Institute, Hinxton, UK. [2] William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK. [3] Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia.
authors.forename: Panos
authors.identifier: 000000019251070X
authors.initials: P
authors.lastname: Deloukas
authors.affiliation: Department of Psychiatry, University of Hong Kong, Hong Kong, China.
authors.forename: Pak Chung
authors.initials: PC
authors.lastname: Sham
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authors.forename: Ruth
authors.initials: R
authors.lastname: McPherson
authors.affiliation: Saw Swee Hock School of Public Health, National University of Singapore, National University Hospital System, Singapore.
authors.forename: Jeannette
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authors.lastname: Lee
authors.affiliation: 1] Saw Swee Hock School of Public Health, National University of Singapore, National University Hospital System, Singapore. [2] Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, National University Hospital System, Singapore. [3] Duke-National University of Singapore Graduate Medical School, Singapore.
authors.forename: E Shyong
authors.initials: ES
authors.lastname: Tai
authors.affiliation: 1] Department of Human Genetics, Faculty of Medicine, McGill University, Montreal, Quebec, Canada. [2] Department of Medicine, Faculty of Medicine, McGill University, Montreal, Quebec, Canada. [3] McGill University and Génome Québec Innovation Centre, Montreal, Quebec, Canada.
authors.forename: Robert
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authors.lastname: Sladek
authors.affiliation: 1] Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. [2] Center for Cardiovascular and Metabolic Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Lena M S
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authors.affiliation: 1] Department of Genomics of Common Disease, Imperial College London, London, UK. [2] Section of Genomic Medicine, National Heart and Lung Institute, Imperial College London, London, UK.
authors.forename: Andrew
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authors.affiliation: 1] Department of Genome Sciences, University of Washington, Seattle, Washington, USA. [2] Howard Hughes Medical Institute, Seattle, Washington, USA.
authors.forename: Evan E
authors.initials: EE
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authors.affiliation: 1] Lille 2 University, Lille, France. [2] European Genomic Institute for Diabetes (EGID), Lille, France. [3] INSERM UMR 859, Lille, France. [4] Centre Hospitalier Régional Universitaire (CHRU) Lille, Lille, France.
authors.forename: Francois
authors.initials: F
authors.lastname: Pattou
authors.affiliation: 1] Department of Twin Research & Genetic Epidemiology, King's College London, St. Thomas' Hospital Campus, London, UK. [2].
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Spector
authors.affiliation: 1] Department of Genomics of Common Disease, Imperial College London, London, UK. [2] CNRS UMR 8199, Lille Pasteur Institute, Lille, France. [3] Lille 2 University, Lille, France. [4] Qatar Biomedical Research Institute (QBRI), Qatar Foundation, Doha, Qatar. [5] European Genomic Institute for Diabetes (EGID), Lille, France. [6] [7].
authors.forename: Philippe
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authors.lastname: Froguel
mesh_terms: D015992:Body Mass Index; D050260:Carbohydrate Metabolism / Q000235:genetics*; D018628:Gene Dosage / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D023281:Genomics / Q000379:methods; D006801:Humans; D046228:Microarray Analysis; D009765:Obesity / Q000235:genetics*; D016017:Odds Ratio; D055291:Salivary alpha-Amylases / Q000097:blood / Q000235:genetics*
chemical_list: C524788:AMY1A protein, human; D055291:Salivary alpha-Amylases