Pilot GWAS of caries in African-Americans shows genetic heterogeneity

Abstract

Background Dental caries is the most common chronic disease in the US and disproportionately affects racial/ethnic minorities. Caries is heritable, and though genetic heterogeneity exists between ancestries for a substantial portion of loci associated with complex disease, a genome-wide association study (GWAS) of caries specifically in African Americans has not been performed previously. Methods We performed exploratory GWAS of dental caries in 109 African American adults (age > 18) and 96 children (age 3–12) from the Center for Oral Health Research in Appalachia (COHRA1 cohort). Caries phenotypes (DMFS, DMFT, dft, and dfs indices) assessed by dental exams were tested for association with 5 million genotyped or imputed single nucleotide polymorphisms (SNPs), separately in the two age groups. The GWAS was performed using linear regression with adjustment for age, sex, and two principal components of ancestry. A maximum of 1 million adaptive permutations were run to determine empirical significance. Results No loci met the threshold for genome-wide significance, though some of the strongest signals were near genes previously implicated in caries such as antimicrobial peptide DEFB1 (rs2515501; p = 4.54 × 10− 6) and TUFT1 (rs11805632; p = 5.15 × 10− 6). Effect estimates of lead SNPs at suggestive loci were compared between African Americans and Caucasians (adults N = 918; children N = 983). Significant (p < 5 × 10− 8) genetic heterogeneity for caries risk was found between racial groups for 50% of the suggestive loci in children, and 12–18% of the suggestive loci in adults. Conclusions The genetic heterogeneity results suggest that there may be differences in the contributions of genetic variants to caries across racial groups, and highlight the critical need for the inclusion of minorities in subsequent and larger genetic studies of caries in order to meet the goals of precision medicine and to reduce oral health disparities.

Ecological speciation promoted by divergent regulation of functional genes within African cichlid fishes

“…This also is consistent with a heritable genetic basis to these complex phenotypes upon which selection can act. In support of this prediction, we found evidence of recent selection on several genes involved in epithelial cell morphogenesis and apical constriction, including the gene iqgap2 which showed evidence of divergent regulation both through expression and splicing QTLs, and has been functionally linked to tooth development in humans 84, 85 .…”

“…Interestingly, iqgap2 has been implicated in Wnt-pathway regulation, and more specifically in tooth development in mice 84, 85 . Scrn3 is putatively involved in blood glucose regulating, and serine-type endopeptidase proteins are often functionally linked to regulation of blood coagulation 86 , both of which are common adaptive responses to hypoxia 87, 88 .…”

Replication of GWAS significant loci in a sub-Saharan African Cohort with early childhood caries: a pilot study

“…A recent pilot GWAS of caries by Orlavo et al conducted among African-Americans showed genetic heterogeneity. They concluded that there may be differences in the contributions of genetic variants to caries across racial groups [18].…”

Multi‐marker genetic association and interaction tests with interval‐censored survival outcomes

“…However, genetic studies of early childhood caries (ECC) before age 6 have not found any association variant with a genome‐wide significance. All the existing genome‐wide association studies of ECC (Ballantine et al, 2017; Orlova et al, 2019; Shaffer et al, 2011) tested the genetic association in a single‐locus manner. In this paper, we performed a genome‐wide association analysis of an ECC data set using the proposed multi‐marker association tests.…”