TY - JOUR
T1 - Integration of Murine and Human Studies for Mapping Periodontitis Susceptibility
AU - Nashef, A.
AU - Qabaja, R.
AU - Salaymeh, Y.
AU - Botzman, M.
AU - Munz, M.
AU - Dommisch, H.
AU - Krone, B.
AU - Hoffmann, P.
AU - Wellmann, J.
AU - Laudes, M.
AU - Berger, K.
AU - Kocher, T.
AU - Loos, B.
AU - van der Velde, N.
AU - Uitterlinden, A. G.
AU - de Groot, L. C.P.G.M.
AU - Franke, A.
AU - Offenbacher, S.
AU - Lieb, W.
AU - Divaris, K.
AU - Mott, R.
AU - Gat-Viks, I.
AU - Wiess, E.
AU - Schaefer, A.
AU - Iraqi, F. A.
AU - Haddad, Y. H.
N1 - Publisher Copyright:
© 2018, © International & American Associations for Dental Research 2018.
PY - 2018/5/1
Y1 - 2018/5/1
N2 - 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.
AB - 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.
KW - Collaborative Cross
KW - GWAS
KW - QTL mapping
KW - alveolar bone loss
KW - animal model
KW - genetic
UR - http://www.scopus.com/inward/record.url?scp=85045057660&partnerID=8YFLogxK
U2 - 10.1177/0022034517744189
DO - 10.1177/0022034517744189
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C2 - 29294296
AN - SCOPUS:85045057660
SN - 0022-0345
VL - 97
SP - 537
EP - 546
JO - Journal of Dental Research
JF - Journal of Dental Research
IS - 5
ER -