ABSTRACT
The importance of susceptibility genes in the risk for dental caries has been clearly established. While many candidate caries genes have been proposed, to date, few of them have been rigorously validated through observational and experimental studies. Moreover, most genetic epidemiological studies have analyzed global caries phenotypes that ignore the possibility that genes may exert differential effects across tooth surfaces of the dentition. Therefore, we performed genome-wide association studies (GWAS) of 5 novel dental caries phenotypes (developed by clustering the permanent dentition into categories of tooth surfaces based on co-occurrence of caries) to nominate new candidate caries genes. GWAS was performed in 920 self-reported white participants, aged 18 to 75 years, with genotype data on 518,997 genetic variants. We identified a significant genetic association between dental caries of the anterior mandibular teeth and LYZL2 (p value = 9e-9), which codes a bacteriolytic agent thought to be involved in host defense. We also identified a significant genetic association between caries of the mid- dentition tooth surfaces and AJAP1 (p value = 2e-8), a gene possibly involved in tooth development. Suggestive genetic associations were also observed for ABCG2, PKD2, the dentin/bone SCPP sub-family, EDNRA, TJFBR1, NKX2-3, IFT88, TWSG1, IL17D, and SMAD7 (p values < 7e-6). We nominate these novel genes for future study.
Subject(s)
Dental Caries Susceptibility/genetics , Dental Caries/genetics , ATP Binding Cassette Transporter, Subfamily G, Member 2 , ATP-Binding Cassette Transporters/genetics , Adolescent , Adult , Aged , Bicuspid/pathology , Calcium Channels/genetics , Cell Adhesion Molecules/genetics , Cuspid/pathology , DMF Index , Genetic Variation/genetics , Genome-Wide Association Study , Genotype , Homeodomain Proteins/genetics , Humans , Incisor/pathology , Interleukin-17/genetics , Mandible , Middle Aged , Muramidase/genetics , Neoplasm Proteins/genetics , Phenotype , Proteins/genetics , Smad7 Protein/genetics , TRPP Cation Channels/genetics , Transcription Factors/genetics , Tumor Suppressor Proteins/genetics , Young AdultABSTRACT
The oceanic nation of Palau has been geographically and culturally isolated over most of its 2000 year history. As part of a study of the genetic basis of schizophrenia in Palau, we genotyped five large, multigenerational schizophrenia pedigrees using markers every 10 cM (CHLC/Weber screening set 6). The number of affected/unaffected individuals genotyped per family ranged from 11/21 to 5/5. Thus the pedigrees varied in their information for linkage, but each was capable of producing a substantial LOD score. We fitted a simple dominant and recessive model to these data using multipoint linkage analysis implemented by Simwalk2. Predictably, the most informative pedigrees produced the best linkage results. After genotyping additional markers in the region, one pedigree produced a LOD = 3.4 (5q distal) under the dominant model. Seven of nine schizophrenics in the pedigree, mostly 3rd-4th degree relatives, share a 15-cM, 7-marker haplotype. For a different pedigree, another promising signal occurred on distal 3q, LOD = 2.6, for the recessive model. For two other pedigrees, the best LODs were modest, slightly better than 2.0 on 5q and 9p, while the fifth pedigree produced no noteworthy linkage signal. Similar to the results for other populations, our results suggest there are multiple genes conferring liability to schizophrenia even in the small population of Palau (roughly 21,000 individuals) in remote Oceania.
