Low copy number of the salivary amylase gene predisposes to obesity
Open accessAbstract
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.
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These contained genes known to have CNVs associated with human health, including amylase (four to ten copies), β-defensin (three to seven copies, DEFB107A) and NOTCH2NLC-NOTCH2NLB (one additional copy).
“These contained genes known to have CNVs associated with human health, including amylase61 (four to ten copies), β-defensin62 (three to seven copies, DEFB107A) and NOTCH2NLC–NOTCH2NLB63 (one additional copy).”
From A draft human pangenome reference. (2023) · cites this paper as [61]
The paper’s main text (page unavailable) links AMY1 copy-number variation to obesity, supporting the amylase example. It reports an estimated range of one to eighteen copies, however, not four to ten. The β-defensin and NOTCH2NLC–NOTCH2NLB examples carry separate citations and are not judged here. (LLM, conf=0.89)
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References 50 · Cited by 254
- Authors
- Falchi, M., El-Sayed Moustafa, J. S., Takousis, P., Pesce, F., Bonnefond, A., Andersson-Assarsson, J. C., Sudmant, P. H., Dorajoo, R., Al-Shafai, M. N., Bottolo, L., Ozdemir, E., So, H.-C., Davies, R. W., Patrice, A., Dent, R., Mangino, M., Hysi, P. G., Dechaume, A., Huyvaert, M., Skinner, J., Pigeyre, M., Caiazzo, R., Raverdy, V., Vaillant, E., Field, S., Balkau, B., Marre, M., Visvikis-Siest, S., Weill, J., Poulain-Godefroy, O., Jacobson, P., Sjostrom, L., Hammond, C. J., Deloukas, P., Sham, P. C., McPherson, R., Lee, J., Tai, E. S., Sladek, R., Carlsson, L. M. S., Walley, A., Eichler, E. E., Pattou, F., Spector, T. D., & Froguel, P.
- Affiliations
- Imperial College London (GB)
- Centre National de la Recherche Scientifique (FR)
- University of Washington (US)
- Agency for Science, Technology and Research (SG)
- University of Hong Kong (HK)
- Ottawa Heart Institute (CA)
- Inserm (FR)
- Ottawa Hospital (CA)
- St Thomas' Hospital (GB)
- University of East Anglia (GB)
- Wellcome Sanger Institute (GB)
- Université Paris-Sud (FR)
- Centre Hospitalier Universitaire de Lille (FR)
- University of Gothenburg (SE)
- University of London (GB)
- National University of Singapore (SG)
- McGill University and Génome Québec Innovation Centre (CA)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Falchi, Mario
- Froguel, Philippe
- ORCID
- Falchi, Mario
- Takousis, Petros
- Pesce, Francesco
- Bonnefond, Amélie
- Sudmant, Peter H
- Dorajoo, Rajkumar
- Al-Shafai, Mashael Nedham
- Bottolo, Leonardo
- So, Hon-Cheong
- Dent, Robert
- Mangino, Massimo
- Hysi, Pirro G
- Skinner, Jane
- Pigeyre, Marie
- Caiazzo, Robert
- Raverdy, Violeta
- Balkau, Beverley
- Marre, Michel
- Jacobson, Peter
- Hammond, Christopher J
- Deloukas, Panos
- Sham, Pak Chung
- McPherson, Ruth
- Tai, E Shyong
- Sladek, Robert
- Carlsson, Lena M S
- Walley, Andrew
- Eichler, Evan E
- Froguel, Philippe
- Venue
- Nature Genetics
- Published
- 2014-03-30
- Volume
- 46
- Issue
- 5
- Pages
- 492-497
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC6485469
- OpenAlex
- W1989111033
- Cited by
- 254
- References
- 50
- Citations by year
- 2026: 6 · 2025: 12 · 2024: 13 · 2023: 17 · 2022: 16 · 2021: 33 · 2020: 23 · 2019: 20 · 2018: 23 · 2017: 26 · 2016: 24 · 2015: 25 · 2014: 16
- FWCI
- 19.92
- Type
- journal article
- Language
- en
- Open access
- green
- kclpure.kcl.ac.uk
- Licence
- other-oa
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Research Portal (King's College London) (acceptedVersion, other-oa)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- CINECA IRIS Institutional Research Information System (University of Bari Aldo Moro) (submittedVersion, other-oa)
- UEA Digital Repository (University of East Anglia) (submittedVersion)
- HAL (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Queen Mary Research Online (Queen Mary University of London) (submittedVersion)
- Funders
- Eli Lilly and Company
- Sanofi
- Brigham and Women's Hospital
- Qatar Foundation
- Ontario Innovation Trust
- Genome Canada
- Wellcome Trust (FP7/2007–2013, 085555, 079534/Z/06/Z, 079534, 077006/Z/05/Z)
- Ontario Genomics
- Les Laboratories Pierre Fabre
- Australian Government
- Ontario Genomics Institute
- National Institute for Health and Care Research (FP7/2007–2013, SRF/01/010)
- British Skin Foundation (5044i)
- Imperial College London
- Imperial College Healthcare NHS Trust
- King's College London
- Agence Nationale de la Recherche (ANR-10-EQPX-0007)
- Institut National de la Santé et de la Recherche Médicale
- Stiftelsen för Strategisk Forskning
- Fédération Française de Cardiologie
- Novo Nordisk
- Vetenskapsrådet (FP7/2007-2013, 11285, K2010-55X-11285-13)
- Fondation de France
- Centre National de la Recherche Scientifique
- Hospital for Sick Children
- Centre hospitalier régional universitaire de Lille
- European Renal Association-European Dialysis and Transplant Association
- Association Diabète Risque Vasculaire
- Centre Hospitalier Universitaire de Rennes
- National Institutes of Health (5p41hg004221-03, FP7/2007-2013)
- Directorate for Biological Sciences
- Novartis Pharma
- Canadian Institutes of Health Research
- Medical Research Council (FP7/20072013, G1002084/1, MR/K01353X/1)
- Biotechnology and Biological Sciences Research Council (G20234)
- Ontario Ministry of Research and Innovation
- National Human Genome Research Institute (HG004221, P41-HG004221)
- National Institute of General Medical Sciences (GM081533, R01GM081533)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- salivary amylase, AMY1, copy number variation, obesity, body mass index, gene dosage effect, adipose tissue gene expression, carbohydrate metabolism, obesity risk
- MeSH terms
- Humans, Obesity, Body Mass Index, Odds Ratio, Gene Dosage, Genetic Predisposition to Disease, Genomics, Microarray Analysis, Carbohydrate Metabolism, Salivary alpha-Amylases
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