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. 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

Free PMC article

Low Copy Number of the Salivary Amylase Gene Predisposes to Obesity

Mario Falchi et al. Nat Genet. .
Free PMC article


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.


Figure 1
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
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
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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