. 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

Mario Falchi¹, Julia Sarah El-Sayed Moustafa², Petros Takousis³, Francesco Pesce⁴, Amélie Bonnefond⁵, Johanna C Andersson-Assarsson⁶, Peter H Sudmant⁷, Rajkumar Dorajoo⁸, Mashael Nedham Al-Shafai⁹, Leonardo Bottolo¹⁰, Erdal Ozdemir³, Hon-Cheong So¹¹, Robert W Davies¹², Alexandre Patrice¹³, Robert Dent¹⁴, Massimo Mangino¹⁵, Pirro G Hysi¹⁵, Aurélie Dechaume¹⁶, Marlène Huyvaert¹⁶, Jane Skinner¹⁷, Marie Pigeyre¹⁸, Robert Caiazzo¹⁸, Violeta Raverdy¹³, Emmanuel Vaillant¹⁶, Sarah Field¹⁹, Beverley Balkau²⁰, Michel Marre²¹, Sophie Visvikis-Siest²², Jacques Weill²³, Odile Poulain-Godefroy¹⁶, Peter Jacobson²⁴, Lars Sjostrom²⁴, Christopher J Hammond¹⁵, Panos Deloukas²⁵, Pak Chung Sham¹¹, Ruth McPherson²⁶, Jeannette Lee²⁷, E Shyong Tai²⁸, Robert Sladek²⁹, Lena M S Carlsson²⁴, Andrew Walley³⁰, Evan E Eichler³¹, Francois Pattou¹⁸, Timothy D Spector³², Philippe Froguel³³

Affiliations

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].

PMID: 24686848
PMCID: PMC6485469
DOI: 10.1038/ng.2939

Low copy number of the salivary amylase gene predisposes to obesity

Mario Falchi et al. Nat Genet. 2014 May.

. 2014 May;46(5):492-7.

doi: 10.1038/ng.2939. Epub 2014 Mar 30.

Authors

Affiliations

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].

PMID: 24686848
PMCID: PMC6485469
DOI: 10.1038/ng.2939

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.

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Figures

**Figure 1. Manhattan plot of gene-centric CNV association study (GCAS) results with gene expression levels in subcutaneous adipose tissue from the Swedish sib-pair dataset**
Chromosomal location for each probe is given on the horizontal axis for each of the 22 autosomes, while minus log₁₀ (P) of the association between probe signal intensity and gene expression levels is shown on the vertical axis. The probes tested against the amylase genes transcriptional levels are shown in green.

**Figure 2. The amylase region in detail**
Top to bottom: famCNV association results between signal intensity at probes within 30kb of the amylase cluster and amylase expression levels (probeset 208498_s_at) in adipose tissue (black dots) in the Swedish family discovery study, with chromosomal coordinates given on the horizontal axis and minus log₁₀(P) on the vertical axis; locations of probes showing association between signal intensity and BMI: cnvi0020639 (blue; Swedish family discovery study), cnvi0022844 (red; TwinsUK); gene content in the amylase region based on the human reference sequence (hg19; RefSeq), depicting *AMY2B, AMY2A* and the *AMY1A/B/C* genes, as well as two high sequence similarity segmental duplications in the region; LD between HapMap markers (release 23) calculated with HaploView (darker shading corresponds to higher r² value). Because of the repetitive nature of this region, which contains six paralogs (including one pseudogenized copy) in the reference genome (Supplementary Figure 13), the cnvi0020639 and the cnvi0022844 probes were found to map to two locations within the amylase gene cluster.

**Figure 3**
Effect of estimated *AMY1* copy-number on obesity and BMI. A: Scatter plots of raw qPCR signal intensity (ΔΔCt) plotted against BMI for the TwinsUK and DESIR samples. B: Boxplots of ΔΔCt in normal weight (BMI<25kg/m²) and obese (BMI≥30kg/m²) subjects in the TwinsUK, DESIR and AOB samples. For plots A and B, low ΔΔCt values correspond to high *AMY1* copy-numbers. C: relative copy-number distribution in obese cases (BMI≥30 kg/m²; black bars) versus normal weight controls (BMI<25 kg/m²; grey bars) in the TwinsUK, DESIR, and AOB studies. Estimated copy-numbers higher than 13 (showing frequency < 2.5%) were collapsed together into a single category. D and E: BMI at different estimated *AMY1* copy-numbers and *AMY1* copy-number estimates by BMI categories in the TwinsUK and DESIR population samples. WHO BMI classification: Underweight (<18.5); Normal range (18.50 – 24.99); Pre obese (25.00 – 29.99); Obese class I (30.00 – 34.99); Obese class II (35.00 – 39.99). Error bars represent the standard error of the mean. *Association between BMI and qPCR ΔΔCt intensity signal, corrected for age, sex (DESIR), family (TwinsUK) and genotyping plate. **Wilcoxon rank sum test.

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Comment in

Obesity. Copy number variants in AMY1 connected with obesity via carbohydrate metabolism.
Greenhill C. Greenhill C. Nat Rev Endocrinol. 2014 Jun;10(6):312. doi: 10.1038/nrendo.2014.54. Epub 2014 Apr 15. Nat Rev Endocrinol. 2014. PMID: 24732973 No abstract available.

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Low copy number of the salivary amylase gene predisposes to obesity

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Low copy number of the salivary amylase gene predisposes to obesity

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