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Structural forms of the human amylase locus and their relationships to SNPs, haplotypes and obesity


Hundreds of genes reside in structurally complex, poorly understood regions of the human genome1,2,3. One such region contains the three amylase genes (AMY2B, AMY2A and AMY1) responsible for digesting starch into sugar. Copy number of AMY1 is reported to be the largest genomic influence on obesity4, although genome-wide association studies for obesity have found this locus unremarkable. Using whole-genome sequence analysis3,5, droplet digital PCR6 and genome mapping7, we identified eight common structural haplotypes of the amylase locus that suggest its mutational history. We found that the AMY1 copy number in an individual's genome is generally even (rather than odd) and partially correlates with nearby SNPs, which do not associate with body mass index (BMI). We measured amylase gene copy number in 1,000 obese or lean Estonians and in 2 other cohorts totaling 3,500 individuals. We had 99% power to detect the lower bound of the reported effects on BMI4, yet found no association.

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Figure 1: Copy number distributions of the amylase genes and structural haplotypes of the amylase locus.
Figure 2: Relationship of the amylase structural haplotypes to SNPs and SNP haplotypes.
Figure 3: Association analysis of AMY1 copy number with obesity or BMI in three cohorts.


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This work was supported by a grant from the National Human Genome Research Institute (R01 HG006855) to S.A.M. to support C.L.U., R.E.H. and S.A.M. Work by T.E. and A.M. was supported through the Estonian Genome Center of the University of Tartu (EGCUT) by Targeted Financing from the Estonian Ministry of Science and Education (SF0180142s08), the Development Fund of the University of Tartu (SP1GVARENG) and the European Regional Development Fund to the Centre of Excellence in Genomics (3.2.0304.11-0312) and through Framework Programme 7 grant 313010. T.E., A.M. and J.N.H. were further supported by the US National Institutes of Health (R01 DK075787). T.M.F. is supported by European Research Council funding (Framework Programme 7, SZ-50371-GLUCOSEGENES), M.A.T. and M.N.W. are supported by the Wellcome Trust Institutional Strategic Support Award (WT097835MF), and M.B. is supported by US National Institutes of Health grant DK062370.

Author information




C.L.U., J.N.H. and S.A.M. conceived the project. C.L.U. pursued molecular (ddPCR) and statistical analyses of amylase locus structural variation. R.E.H. contributed analyses of whole-genome sequence data. T.E., A.M., C.L.U., J.E.M. and J.N.H. analyzed the Estonian cohort. M.A.T., M.N.W., T.M.F., R.E.H. and S.K. analyzed the InCHIANTI cohort. M.I.M., M.B., D.M.A., R.E.H., C.L.U. and C.F. analyzed the GoT2D cohort. C.N.P., M.T.P., C.L.U. and R.E.H. analyzed the GPC cohort. A.R.H. and H.C. performed the NanoChannel-based genome mapping. C.L.U., J.N.H. and S.A.M. wrote the manuscript, with contributions from D.M.A., T.M.F., M.B., M.I.M. and T.E.

Corresponding authors

Correspondence to Joel N Hirschhorn or Steven A McCarroll.

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Competing interests

A.R.H. and H.C. are employees at BioNano Genomics, Inc., and own company stock options.

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Usher, C., Handsaker, R., Esko, T. et al. Structural forms of the human amylase locus and their relationships to SNPs, haplotypes and obesity. Nat Genet 47, 921–925 (2015).

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