Abstract
The oral microbiota contains billions of microbial cells, which could contribute to diseases in many body sites. Challenged by eating, drinking, and dental hygiene on a daily basis, the oral microbiota is regarded as highly dynamic. Here, we report significant human genomic associations with the oral metagenome from more than 1915 individuals, for both the tongue dorsum (n = 2017) and saliva (n = 1915). We identified five genetic loci associated with oral microbiota at study-wide significance (p < 3.16 × 10−11). Four of the five associations were well replicated in an independent cohort of 1439 individuals: rs1196764 at APPL2 with Prevotella jejuni, Oribacterium uSGB 3339 and Solobacterium uSGB 315; rs3775944 at the serum uric acid transporter SLC2A9 with Oribacterium uSGB 1215, Oribacterium uSGB 489 and Lachnoanaerobaculum umeaense; rs4911713 near OR11H1 with species F0422 uSGB 392; and rs36186689 at LOC105371703 with Eggerthia. Further analyses confirmed 84% (386/455 for tongue dorsum) and 85% (391/466 for saliva) of host genome-microbiome associations including six genome-wide significant associations mutually validated between the two niches. As many of the oral microbiome-associated genetic variants lie near miRNA genes, we tentatively validated the potential of host miRNAs to modulate the growth of specific oral bacteria. Human genetics accounted for at least 10% of oral microbiome compositions between individuals. Machine learning models showed that polygenetic risk scores dominated over oral microbiome in predicting risk of dental diseases such as dental calculus and gingival bleeding. These findings indicate that human genetic differences are one explanation for a stable or recurrent oral microbiome in each individual.
Highlights
A healthy individual swallows 1–1.5 L of saliva every day[1], and its residing microbes could colonize the gut of susceptible individuals[2,3,4]
The microbiome composition was determined according to alignment to a total of 56,213 metagenome-assembled genomes (MAGs) that have been organized into 3589 species-level clusters (SGBs) together with existing genomes, of which 40% (1441/3589) was specific in this cohort[22]
We found four loci associated with both the salivary microbiome and metabolic traits or diseases at genome-wide significance: DPEP2/NFATC3 that associated with species Lancefieldella sp000564995 was linked to high-density lipoprotein cholesterol (HDLC); PDXDC2P-NPIPB14P associated with species Centipeda sp000468035 linked to thyroid abnormality; LARP1 associated with species Aggregatibacter kilianii linked to mean corpuscular hemoglobin; SMARCA1 associated with species Veillonella parvula linked to pharyngeal mucosal congestion (PMC) (Supplementary Fig. S8)
Summary
A healthy individual swallows 1–1.5 L of saliva every day[1], and its residing microbes could colonize the gut of susceptible individuals[2,3,4]. Oral metagenomic shotgun sequencing data has been available from the Human Microbiome Project (HMP)[5], for rheumatoid arthritis[6] and colorectal cancer[3]. The strongest signal in cohorts of European ancestry is the association between LCT1 and Bifidobacterium, explained by the metabolism of lactose by the commensal bacterium These large-scale genome-wide association studies have mainly focused on the fecal microbiome; the. The other study reported a gene copy number (CN) of the AMY1 locus correlated with the oral and gut microbiome composition and function[21]. These two studies used 16 S rRNA amplicon sequencing for a small number of samples. The influence of human genes on the composition of the oral microbiome and genetic stability between different oral niches are still poorly understood
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