Periodontitis is one of the most common inflammatory human diseases with a strong genetic component. Due to the limited sample size of available periodontitis cohorts and the underlying trait heterogeneity, genome-wide association studies (GWASs) of chronic periodontitis (CP) have largely been unsuccessful in identifying common susceptibility factors. A combination of quantitative trait loci (QTL) mapping in mice with association studies in humans has the potential to discover novel risk loci. To this end, we assessed alveolar bone loss in response to experimental periodontal infection in 25 lines (286 mice) from the Collaborative Cross (CC) mouse population using micro–computed tomography (µCT) analysis. The orthologous human chromosomal regions of the significant QTL were analyzed for association using imputed genotype data (OmniExpress BeadChip arrays) derived from case-control samples of aggressive periodontitis (AgP; 896 cases, 7,104 controls) and chronic periodontitis (CP; 2,746 cases, 1,864 controls) of northwest European and European American descent, respectively. In the mouse genome, QTL mapping revealed 2 significant loci (–log P = 5.3; false discovery rate = 0.06) on chromosomes 1 (Perio3) and 14 (Perio4). The mapping resolution ranged from ~1.5 to 3 Mb. Perio3 overlaps with a previously reported QTL associated with residual bone volume in F2 cross and includes the murine gene Ccdc121. Its human orthologue showed previously a nominal significant association with CP in humans. Use of variation data from the genomes of the CC founder strains further refined the QTL and suggested 7 candidate genes (CAPN8, DUSP23, PCDH17, SNORA17, PCDH9, LECT1, and LECT2). We found no evidence of association of these candidates with the human orthologues. In conclusion, the CC populations enabled mapping of confined QTL that confer susceptibility to alveolar bone loss in mice and larger human phenotype-genotype samples and additional expression data from gingival tissues are likely required to identify true positive signals.
Bibliographical noteFunding Information:
This work was supported by the German Research Foundation DFG (Deutsche Forschungsgemeinschaft; GZ: SCHA 1582/3-1 and SCHA 1582/4-1) and by the Israel Science Foundation (grant number 429/09). The data for the European American CP cases were generated by the following research grants of the US National Institutes of Health (NIH): RO1-DE022527, UL1-TR001111, and RO1-DE021418. The Federal Ministry of Education and Research (01GR0468) supported collection of the popgen control sample. The Dortmund Health Study (DHS) is supported by the German Migraine & Headache Society (DMKG) and by unrestricted grants of equal share from Almirall, AstraZeneca, Berlin Chemie, Boehringer, Boots Health Care, Glaxo-Smith-Kline, Janssen Cilag, McNeil Pharma, MSD Sharp & Dohme, and Pfizer to the University of Münster (collection of sociodemographic and clinical data). The Institute of Epidemiology and Social Medicine, University of Münster funded blood collection in the Dortmund Health Study, and the Federal Ministry of Research and Education (BMBF, grant 01ER0816) supported genotyping. FOCUS was supported by the Federal Ministry of Education and Research BMBF (FKZ 0315540A). The Heinz Nixdorf Foundation (Germany) supported the HNR study. In addition, the Federal Ministry of Education and Science and the German Research Council (DFG; Project SI 236/8-1, SI 236/9-1, ER 155/6-1) funded it. The German Centre financed Genotyping of the Illumina HumanOmni-1 Quad BeadChips of the HNR subjects for Neurodegenerative Diseases (DZNE), Bonn. We further thank Corinna Bruckmann, Christof Dörfer, Peter Eickholz, Yvonne Jockel-Schneider, Jörg Meyle, Barbara Noack, and Ingmar Staufenbiel for the recruitment of cases of aggressive periodontitis. The authors declare no potential conflicts of interest with respect to the authorship and/or publication of this article.
© 2018, © International & American Associations for Dental Research 2018.
- Collaborative Cross
- QTL mapping
- alveolar bone loss
- animal model