Rs2281845

rs2281845 is a SNP located on chromosome 1q32.1, about 250 bp upstream of the first exon of the CACNA1S (voltage-dependent calcium channel, L type) gene. The linkage disequilibrium block containing rs2281845 extends 22 kb downstream and includes the TMEM9 gene (transmembrane protein 9). This SNP has been clinically associated with tooth development. The minor allele (T) has specifically been associated with reduced mature dentition between the ages of 6 and 14 in women.

In a 2011 report, a genome-wide quantitative trait association study conducted with 521,741 SNPs over 5,097 women from the Danish National Birth Cohort (DNBC) found a significant (p-value=1.31E-10) association between the rs2281845 T allele and a reduction in permanent teeth erupted (-0.105) between ages 6 and 14. To confirm this finding, an additional 3,696 individuals were also tested for this association. These subjects were drawn from three additional Danish cohorts, as well as one from the United States. The association was replicated in each of the Danish cohorts (p-values=5.43E-05, 1.09E-04, and 0.012, respectively), but the group from the United States exhibited a weak association (p-value=0.242) in the opposite direction (+0.065 teeth). This contradictory finding was attributed to small sample size and deficiencies in phenotype reporting. The original GWAS and replication datasets, when combined for a total of 8,793 subjects, showed a statistically significant (p-value=8.03E-17) negative association with number of permanent teeth (-0.103).

Within the same study, three additional SNPs were identified in the initial DNBC cohort GWAS as having a significant association with number of permanent teeth between ages 6 and 14. These SNPs &#8211; rs12424086, rs4491709, rs7924176 &#8211; were each validated to statistical significance with a replication set (p-values=2.30E-12, 2.16E-14, and 5.64E-19, respectively). No loci aside from those containing these four SNPs exhibited a p-value of less than 5.0E-6.

Each of these SNPs that were identified in the context of dental development may be confounded by associations with generalized maturation programs. The authors note that while the phenotype of mature teeth was measured here, the SNPs could in fact correlate better with measures of puberty such as &#8220;skeletal maturation, Tanner score and growth spurt,&#8221; with number of mature teeth simply as a manifestation of these other phenotypes.

Mechanistically, rs2281845&#8217;s effect on tooth development may be linked to expression of TMEM9. In a study linking SNPs to gene expression in monocytes, several variants in linkage disequilibrium with rs2281845 were found to be significantly associated with TMEM9 expression. The SNP with highest linkage to rs2281845, rs6667912 (r2=0.42) showed a significant association (p-value=6x10E-29).

Little is known regarding the function of TMEM9. It is a well-conserved, 26kDa transmembrane protein with expression throughout a wide variety of human tissues and cells. An &#8216;&#8216;in vitro&#8217;&#8217; study showed localization to the ER, late endosomes, and lysosomes along with LAMP1 coexpression, but its function within the cell is not yet well-characterized.