Portal de Periódicos da CAPES

Low copy number of the salivary amylase gene predisposes to obesity

2014; Nature Portfolio; Volume: 46; Issue: 5 Linguagem: Inglês

10.1038/ng.2939

1546-1718

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

Genetics and Neurodevelopmental Disorders

Mario Falchi, Philippe Froguel and colleagues report association of a multi-allelic copy number variant encompassing the salivary amylase gene AMY1 with body mass index and risk of obesity. 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.