Nat Genet. 2014 Mar 30. doi: 10.1038/ng.2939. [Epub ahead of print]
Low copy number of the salivary amylase gene predisposes to obesity.
Falchi M1, El-Sayed Moustafa JS2, Takousis P3, Pesce F4, Bonnefond A5, Andersson-Assarsson JC6, Sudmant PH7, Dorajoo R8, Al-Shafai MN9, Bottolo L10,Ozdemir E3, So HC11, Davies RW12, Patrice A13, Dent R14, Mangino M15, Hysi PG15, Dechaume A16, Huyvaert M16, Skinner J17, Pigeyre M18, Caiazzo R18,Raverdy V13, Vaillant E16, Field S19, Balkau B20, Marre M21, Visvikis-Siest S22, Weill J23, Poulain-Godefroy O16, Jacobson P24, Sjostrom L24, Hammond CJ15,Deloukas P25, Sham PC11, McPherson R26, Lee J27, Tai ES28, Sladek R29, Carlsson LM24, Walley A30, Eichler EE31, Pattou F18, Spector TD32, Froguel P33.
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/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.
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