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Usher, Christina

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Usher

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Christina

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Usher, Christina

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2015 - 20162

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Author's Publications: search.filters.isAuthorOfPublication.747fca43-b621-4138-9280-7809cbaac986

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    Structural Forms of the Human Amylase Locus and Their Relationships to SNPs, Haplotypes, and Obesity
    (2015-05-18) Usher, Christina; Warman, Matthew; Capellini, Terence; Armour, John; Daly, Mark J.
    Hundreds of human genes reside in structurally complex loci that elude molecular analysis and assessment in genome-wide association studies (GWAS). One such locus contains the three different amylase genes (AMY2B, AMY2A, and AMY1) responsible for digesting starch into sugar. The copy number of AMY1 is reported to be the genome’s largest influence on obesity, yet has gone undetected in GWAS. Using droplet digital PCR (ddPCR), sequence analysis, and optical mapping, we characterized eight common structural forms of the amylase locus, their mutational histories, and their relationships to SNPs. We found that AMY1 copy number has a unique distribution undetectable to earlier methods that can be understood from an underlying set of structural forms and their allele frequencies. Despite a history of recurrent structural mutations, AMY1 copy number has maintained partial correlations to nearby SNPs; these SNPs do not associate with body mass index (BMI). To directly test for association, we measured amylase gene copy number using ddPCR in 1,000 Estonians selected for being either obese or lean and in two cohorts totaling ~3,500 individuals using sequence analysis. We had 99% power to detect even the lower bound of the reported effects on BMI and obesity, yet found no association. This study model of using multiple methods to analyze the copy number, structural haplotypes, and surrounding SNP haplotypes of multi-allelic variants will likely facilitate more robust disease association results in future studies.
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    Structural forms of the human amylase locus and their relationships to SNPs, haplotypes, and obesity
    (2016) Usher, Christina; Handsaker, Robert; Esko, Tõnu; Tuke, Marcus A; Weedon, Michael N; Hastie, Alex R; Cao, Han; Moon, Jennifer E; Kashin, Seva; Fuchsberger, Christian; Metspalu, Andres; Pato, Carlos N; Pato, Michele T; McCarthy, Mark I; Boehnke, Michael; Altshuler, David; Frayling, Timothy M; Hirschhorn, Joel; McCarroll, Steven
    Hundreds of genes reside in structurally complex, poorly understood regions of the human genome1-3. One such region contains the three amylase genes (AMY2B, AMY2A, and AMY1) responsible for digesting starch into sugar. The copy number of AMY1 is reported to be the genome’s largest influence on obesity4, though 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 AMY1 copy number in individuals’ genomes is generally even (rather than odd) and partially correlates to nearby SNPs, which do not associate with BMI. We measured amylase gene copy number in 1,000 obese or lean Estonians and in two 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.