Genome-wide association study and meta-analysis of missing teeth and functional dentition

Retention of a functional dentition of twenty or more permanent teeth is an important World Health Organization (WHO) goal, as missing teeth adversely affects oral health quality of life, especially masticatory function and aesthetic appearance and satisfaction. Previous studies show that tooth loss is moderately heritable, and genome-wide association studies (GWAS) of periodontitis and dental caries, the two main causes of tooth loss, have successfully identified genetic variants associated with these oral diseases. Thus, this work aimed to identify genetic variants associated with missing teeth by performing genome-wide association scans in five cohorts and a subsequent meta-analyses. Genome-wide association scans using linear and logistic regression for a quantitative trait and functional dentition, respectively, were performed in five cohorts: The Center for Oral Health Research in Appalachia cohort 1 (COHRA; N = 955), Dental Registry and DNA Repository of the University of Pittsburgh School of Dental Medicine (DRDR; N = 227), and cohorts from The Pittsburgh Orofacial Clefts Studies (POFC) project recruited from the United States (POFC-USA; N = 192), Guatemala (POFC-G; N = 272), and the Patagonia region of Argentina (POFC-PA; N = 182). Three p-value based meta-analyses were performed: a white-only meta-analysis (COHRA and DRDR; N = 1182), a Hispanics-only meta-analysis (POFC-G and POFC-PA; N = 454), and a trans-ethnic meta-analysis (COHRA, DRDR, POFC-G, and POFC-PA; N = 1636). Two regions of the genome were associated with missing teeth at genome-wide significance (p < 5 x 10-8) and were located near genes relevant to dental and oral health (POSTN, a critical regulator of periodontal homeostasis, and MTRR, which functions in methionine synthesis, a process previously implicated by GWAS of dental caries.) Furthermore, many regions of the genome showed suggestive significance (p < 1 x 10-5) and were located near genes biologically relevant to tooth loss. These discoveries corroborate existing evidence for a genetic contribution to tooth loss, and supports the hypothesis that common genetic variants influence tooth loss. The public health significance of this work is that such findings may ultimately lead to the identification of individuals at risk for tooth loss and the development of novel treatments.