Low copy number of the salivary amylase gene predisposes to obesity
Mario Falchi
(1)
,
Julie Sarah El-Sayed Moustafa
(1)
,
Petros Takousis
(1)
,
Francesco Pesce
(1, 2)
,
Amélie Bonnefond
(3, 4, 5)
,
Johanna Andersson-Assarsson
(1, 6)
,
Peter Sudmant
(7)
,
Rajkumar Dorajoo
(1, 8)
,
Mashael Nedham Al-Shafai
(1, 9)
,
Leonardo Bottolo
(10)
,
Erdal Ozdemir
(1)
,
Hon-Cheong So
(11)
,
Robert Davies
(12)
,
Alexandre Patrice
(5, 13, 14)
,
Robert Dent
(15)
,
Massimo Mangino
(16)
,
Pirro Hysi
(16)
,
Aurélie Dechaume
(3, 5)
,
Marlène Huyvaert
(3, 5)
,
Jane Skinner
(17)
,
Marie Pigeyre
(3, 5, 14)
,
Robert Caiazzo
(3, 5, 14)
,
Violeta Raverdy
(3, 5, 14)
,
Emmanuel Vaillant
(3, 5, 14)
,
Sarah Field
(18)
,
Beverley Balkau
(19, 20)
,
Michel Marre
(21, 22)
,
Sophie Visvikis-Siest
(23)
,
Jacques Weill
(24)
,
Odile Poulain-Godefroy
(3, 5)
,
Peter Jacobson
(6)
,
Lars Sjostrom
(6)
,
Christopher Hammond
(16)
,
Panos Deloukas
(18, 25, 26)
,
Pak Chung Sham
(27)
,
Ruth Mcpherson
(12)
,
Jeannette Lee
(28)
,
E Shyong Tai
(28, 29)
,
Robert Sladek
(30, 31, 32)
,
Lena Carlsson
(6)
,
Andrew Walley
(1, 33)
,
Evan Eichler
(7, 34)
,
François Pattou
(5, 14, 13)
,
Timothy D. Spector
(16)
,
Philippe Froguel
(1, 3, 5, 4)
1
Department of Genomics of Common Disease [London, UK]
2 UNIBA - Università degli studi di Bari Aldo Moro = University of Bari Aldo Moro
3 EGENODIA (GI3M) - Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283
4 QBRI - Qatar Biomedical Research Institute
5 EGID - Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508
6 Sahlgrenska Academy at University of Gothenburg [Göteborg]
7 University of Washington [Seattle]
8 GIS - Genome Institute of Singapore
9 Qatar Foundation
10 Institute for Mathematical Sciences
11 CUHK - City University of Hong Kong [Hong Kong]
12 University of Ottawa Heart Institute
13 RTD - Recherche translationnelle sur le diabète - U 1190
14 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
15 The Ottawa Hospital
16 King‘s College London
17 Norwich Medical School
18 The Wellcome Trust Sanger Institute [Cambridge]
19 Epidémiologie cardiovasculaire et métabolique
20 CESP - Centre de recherche en épidémiologie et santé des populations
21 Service d'endocrinologie, diabétologie et nutrition [CHU Bichat]
22 (U 695) - Déterminants génétiques du diabète de type 2 et de ses complications vasculaires
23 IGE-PCV - Interactions Gène-Environnement en Physiopathologie Cardio-Vasculaire
24 Service d'endocrinologie pédiatrique [CHU Lille]
25 William Harvey Research Institute, Barts and the London Medical School
26 Princess Al-Jawhara AlBrahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD)
27 CUHK - The Chinese University of Hong Kong [Hong Kong]
28 NUS - National University of Singapore
29 Duke-National University of Singapore Graduate Medical School
30 Department of Human Genetics [Montréal]
31 Department of Medecine [Montréal]
32 McGill University and Genome Quebec Innovation Centre
33 National Heart & Lung Institute
34 Howard Hughes Medical Institute [Seattle]
2 UNIBA - Università degli studi di Bari Aldo Moro = University of Bari Aldo Moro
3 EGENODIA (GI3M) - Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283
4 QBRI - Qatar Biomedical Research Institute
5 EGID - Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508
6 Sahlgrenska Academy at University of Gothenburg [Göteborg]
7 University of Washington [Seattle]
8 GIS - Genome Institute of Singapore
9 Qatar Foundation
10 Institute for Mathematical Sciences
11 CUHK - City University of Hong Kong [Hong Kong]
12 University of Ottawa Heart Institute
13 RTD - Recherche translationnelle sur le diabète - U 1190
14 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
15 The Ottawa Hospital
16 King‘s College London
17 Norwich Medical School
18 The Wellcome Trust Sanger Institute [Cambridge]
19 Epidémiologie cardiovasculaire et métabolique
20 CESP - Centre de recherche en épidémiologie et santé des populations
21 Service d'endocrinologie, diabétologie et nutrition [CHU Bichat]
22 (U 695) - Déterminants génétiques du diabète de type 2 et de ses complications vasculaires
23 IGE-PCV - Interactions Gène-Environnement en Physiopathologie Cardio-Vasculaire
24 Service d'endocrinologie pédiatrique [CHU Lille]
25 William Harvey Research Institute, Barts and the London Medical School
26 Princess Al-Jawhara AlBrahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD)
27 CUHK - The Chinese University of Hong Kong [Hong Kong]
28 NUS - National University of Singapore
29 Duke-National University of Singapore Graduate Medical School
30 Department of Human Genetics [Montréal]
31 Department of Medecine [Montréal]
32 McGill University and Genome Quebec Innovation Centre
33 National Heart & Lung Institute
34 Howard Hughes Medical Institute [Seattle]
Amélie Bonnefond
- Fonction : Auteur
- PersonId : 1305499
- IdHAL : amelie-bonnefond
- ORCID : 0000-0001-9976-3005
Rajkumar Dorajoo
- Fonction : Auteur
- PersonId : 786095
- ORCID : 0000-0001-6608-2051
Marie Pigeyre
- Fonction : Auteur
Robert Caiazzo
- Fonction : Auteur
Violeta Raverdy
- Fonction : Auteur
Emmanuel Vaillant
- Fonction : Auteur
Sophie Visvikis-Siest
- Fonction : Auteur
- PersonId : 740132
- IdHAL : sofia-siest
- ORCID : 0000-0001-8104-8425
- IdRef : 101311532
Philippe Froguel
- Fonction : Auteur
Résumé
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.