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Nat Genet. 2014 May;46(5):492-7. doi: 10.1038/ng.2939. Epub 2014 Mar 30.

Low copy number of the salivary amylase gene predisposes to obesity.

Author information

1
1] Department of Genomics of Common Disease, Imperial College London, London, UK. [2] [3] [4].
2
1] Department of Genomics of Common Disease, Imperial College London, London, UK. [2].
3
Department of Genomics of Common Disease, Imperial College London, London, UK.
4
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.
5
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.
6
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.
7
Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
8
1] Department of Genomics of Common Disease, Imperial College London, London, UK. [2] Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore.
9
1] Department of Genomics of Common Disease, Imperial College London, London, UK. [2] Research Division, Qatar Foundation, Doha, Qatar.
10
Department of Mathematics, Imperial College London, London, UK.
11
Department of Psychiatry, University of Hong Kong, Hong Kong, China.
12
Cardiovascular Research Methods Centre, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
13
1] European Genomic Institute for Diabetes (EGID), Lille, France. [2] INSERM UMR 859, Lille, France. [3] Centre Hospitalier Régional Universitaire (CHRU) Lille, Lille, France.
14
Bariatric Program, Ottawa Hospital, Ottawa, Ontario, Canada.
15
Department of Twin Research & Genetic Epidemiology, King's College London, St. Thomas' Hospital Campus, London, UK.
16
1] CNRS UMR 8199, Lille Pasteur Institute, Lille, France. [2] Lille 2 University, Lille, France. [3] European Genomic Institute for Diabetes (EGID), Lille, France.
17
Norwich Medical School, University of East Anglia, Norwich, UK.
18
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.
19
Wellcome Trust Sanger Institute, Hinxton, UK.
20
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.
21
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.
22
INSERM UMR 1122 Interactions Géne-Environnement en Physiopathologie Cardio-Vasculaire, Université de Lorraine, Nancy, France.
23
Paediatric Endocrine Unit, Lille Teaching Hospital, Lille, France.
24
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.
25
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.
26
1] Atherogenomics Laboratory, University of Ottawa Heart Institute, Ottawa, Ontario, Canada. [2] Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
27
Saw Swee Hock School of Public Health, National University of Singapore, National University Hospital System, Singapore.
28
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.
29
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.
30
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.
31
1] Department of Genome Sciences, University of Washington, Seattle, Washington, USA. [2] Howard Hughes Medical Institute, Seattle, Washington, USA.
32
1] Department of Twin Research & Genetic Epidemiology, King's College London, St. Thomas' Hospital Campus, London, UK. [2].
33
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].

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.

PMID:
24686848
DOI:
10.1038/ng.2939
[Indexed for MEDLINE]

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