Low copy number of the salivary amylase gene predisposes to obesity

Mario Falchi; Julia Sarah El-Sayed Moustafa; Petros Takousis; Francesco Pesce; Amélie Bonnefond; Johanna C. Andersson-Assarsson; Peter H Sudmant; Rajkumar Dorajoo; Mashael Nedham Al-shafai; Leonardo Bottolo; Erdal Ozdemir; Hon-cheong So; Robert W Davies; Alexandre Patrice; Robert Dent; Massimo Mangino; Pirro G. Hysi; Aurélie Dechaume; Marlène Huyvaert; Jane Skinner; Marie Pigeyre; Robert Caiazzo; Violeta Raverdy; Emmanuel Vaillant; Sarah Field; Beverley Balkau; Michel Marre; Sophie Visvikis-Siest; Jacques Weill; Odile Poulain-Godefroy; Peter Jacobson; Lars Sjostrom; Christopher J Hammond; Panos Deloukas; Pak Chung Sham; Ruth Mcpherson; Jeannette Lee; E Shyong Tai; Robert Sladek; Lena M. S. Carlsson; Andrew Walley; Evan E Eichler; Francois Pattou; Timothy D Spector; Philippe Froguel

doi:10.1038/ng.2939

Low copy number of the salivary amylase gene predisposes to obesity

Mario Falchi, Julia Sarah El-Sayed Moustafa, Petros Takousis, Francesco Pesce, Amélie Bonnefond, Johanna C. Andersson-Assarsson, Peter H Sudmant, Rajkumar Dorajoo, Mashael Nedham Al-shafai, Leonardo Bottolo, Erdal Ozdemir, Hon-cheong So, Robert W Davies, Alexandre Patrice, Robert Dent, Massimo Mangino, Pirro G. Hysi, Aurélie Dechaume, Marlène Huyvaert, Jane SkinnerMarie Pigeyre, Robert Caiazzo, Violeta Raverdy, Emmanuel Vaillant, Sarah Field, Beverley Balkau, Michel Marre, Sophie Visvikis-Siest, Jacques Weill, Odile Poulain-Godefroy, Peter Jacobson, Lars Sjostrom, Christopher J Hammond, Panos Deloukas, Pak Chung Sham, Ruth Mcpherson, Jeannette Lee, E Shyong Tai, Robert Sladek, Lena M. S. Carlsson, Andrew Walley, Evan E Eichler, Francois Pattou, Timothy D Spector, Philippe Froguel

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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.

Original language	English
Pages (from-to)	492-497
Number of pages	6
Journal	Nature Genetics
Volume	46
Issue number	5
DOIs	https://doi.org/10.1038/ng.2939
Publication status	Published - 30 Mar 2014

Keywords

Gene regulation
Genome-wide association studies
Obesity

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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Cite this

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., Davies, R. W., Patrice, A., Dent, R., Mangino, M., Hysi, P. G., Dechaume, A., Huyvaert, M., ... Froguel, P. (2014). Low copy number of the salivary amylase gene predisposes to obesity. Nature Genetics, 46(5), 492-497. https://doi.org/10.1038/ng.2939

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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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doi = "10.1038/ng.2939",

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Falchi, M, El-Sayed Moustafa, JS, Takousis, P, Pesce, F, Bonnefond, A, Andersson-Assarsson, JC, Sudmant, PH, Dorajoo, R, Al-shafai, MN, Bottolo, L, Ozdemir, E, So, H, Davies, RW, Patrice, A, Dent, R, Mangino, M, Hysi, PG, 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, CJ, Deloukas, P, Sham, PC, Mcpherson, R, Lee, J, Tai, ES, Sladek, R, Carlsson, LMS, Walley, A, Eichler, EE, Pattou, F, Spector, TD & Froguel, P 2014, 'Low copy number of the salivary amylase gene predisposes to obesity', Nature Genetics, vol. 46, no. 5, pp. 492-497. https://doi.org/10.1038/ng.2939

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T1 - Low copy number of the salivary amylase gene predisposes to obesity

AU - Falchi, Mario

AU - El-Sayed Moustafa, Julia Sarah

AU - Takousis, Petros

AU - Pesce, Francesco

AU - Bonnefond, Amélie

AU - Andersson-Assarsson, Johanna C.

AU - Sudmant, Peter H

AU - Dorajoo, Rajkumar

AU - Al-shafai, Mashael Nedham

AU - Bottolo, Leonardo

AU - Ozdemir, Erdal

AU - So, Hon-cheong

AU - Davies, Robert W

AU - Patrice, Alexandre

AU - Dent, Robert

AU - Mangino, Massimo

AU - Hysi, Pirro G.

AU - Dechaume, Aurélie

AU - Huyvaert, Marlène

AU - Skinner, Jane

AU - Pigeyre, Marie

AU - Caiazzo, Robert

AU - Raverdy, Violeta

AU - Vaillant, Emmanuel

AU - Field, Sarah

AU - Balkau, Beverley

AU - Marre, Michel

AU - Visvikis-Siest, Sophie

AU - Weill, Jacques

AU - Poulain-Godefroy, Odile

AU - Jacobson, Peter

AU - Sjostrom, Lars

AU - Hammond, Christopher J

AU - Deloukas, Panos

AU - Sham, Pak Chung

AU - Mcpherson, Ruth

AU - Lee, Jeannette

AU - Tai, E Shyong

AU - Sladek, Robert

AU - Carlsson, Lena M. S.

AU - Walley, Andrew

AU - Eichler, Evan E

AU - Pattou, Francois

AU - Spector, Timothy D

AU - Froguel, Philippe

PY - 2014/3/30

Y1 - 2014/3/30

N2 - 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.

AB - 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.

KW - Gene regulation

KW - Genome-wide association studies

KW - Obesity

U2 - 10.1038/ng.2939

DO - 10.1038/ng.2939

M3 - Article

VL - 46

SP - 492

EP - 497

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

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ER -