Characterizing structural variation at the amylase locus influencing oral health

Abstract Nearly every adult in the United States will develop at least one cavity, with some individuals experiencing a significantly higher incidence. While environmental factors like diet and oral hygiene are important, heritability also plays a crucial role in determining oral health. Specifically, genetics accounts for up to 65% of the variation

between individuals in their experience with dental caries. Despite this, the identification of specific genetic variants contributing to this heritability is still in its infancy. A recent genome-wide association study (GWAS) found a genetic variant, rs72694438, that is associated with the likelihood of needing dentures. This means that

something within that genomic region is influencing tooth health. Interestingly, this variant is located near the gene(s) for salivary amylase, an enzyme that initiates starch digestion in the mouth. Salivary amylase also has the ability to bind to commensal oral bacteria like Streptococcus gordonii, potentially affecting their adhesion to teeth and their competition with cariogenic species

such as Streptococcus mutans. Some studies have suggested an association between the level of salivary amylase and the level of dental caries. However, studying this locus is challenging because an individual can have anywhere from 2 to >17 copies of the amylase gene, AMY1. This means conventional methods of counting

copies (such as qPCR) are insufficient and can lead to spurious and conflicting results. In addition, quantifying tooth health across large numbers of people can be difficult and imprecise. Here, I propose to use modern computational methods coupled with a densely phenotyped large cohort with genetic data (UK Biobank, 500k samples) to overcome these problems with statistical power. In preliminary

analyses, I could accurately genotype AMY1 copy number and found that it is strongly associated with the likelihood of requiring dentures (p = 2.31x10-19, OR for 2 to 17 copies = 1.41) and more weakly with bleeding gums (p=0.0045, OR for 2 to 17 copies = 0.89). This association has one of the largest effect sizes for a common

genetic variant in dental health discovered to date. I propose to fully characterize the structure of the amylase locus and its mechanisms for affecting tooth health. For Aim 1, I will work to improve the copy number estimation and knowledge of the haplotype structure at the amylase locus. For Aim 2, I will associate amylase copy number with dental phenotypes. For Aim 3, I will

associate AMY1 copy number with the abundance of bacterial taxa in the oral microbiome. Through these aims, I intend to elucidate the mechanistic pathway linking this genetic variant to the oral microbiome and, ultimately, to tooth health.