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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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 languageEnglish
Pages (from-to)492-497
Number of pages6
JournalNature Genetics
Issue number5
Publication statusPublished - 30 Mar 2014


  • Gene regulation
  • Genome-wide association studies
  • Obesity

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