title: Genome-wide association study of primary tooth eruption identifies pleiotropic loci associated with height and craniofacial distances.
abstract: Twin and family studies indicate that the timing of primary tooth eruption is highly heritable, with estimates typically exceeding 80%. To identify variants involved in primary tooth eruption, we performed a population-based genome-wide association study of 'age at first tooth' and 'number of teeth' using 5998 and 6609 individuals, respectively, from the Avon Longitudinal Study of Parents and Children (ALSPAC) and 5403 individuals from the 1966 Northern Finland Birth Cohort (NFBC1966). We tested 2 446 724 SNPs imputed in both studies. Analyses were controlled for the effect of gestational age, sex and age of measurement. Results from the two studies were combined using fixed effects inverse variance meta-analysis. We identified a total of 15 independent loci, with 10 loci reaching genome-wide significance (P < 5 × 10(-8)) for 'age at first tooth' and 11 loci for 'number of teeth'. Together, these associations explain 6.06% of the variation in 'age of first tooth' and 4.76% of the variation in 'number of teeth'. The identified loci included eight previously unidentified loci, some containing genes known to play a role in tooth and other developmental pathways, including an SNP in the protein-coding region of BMP4 (rs17563, P = 9.080 × 10(-17)). Three of these loci, containing the genes HMGA2, AJUBA and ADK, also showed evidence of association with craniofacial distances, particularly those indexing facial width. Our results suggest that the genome-wide association approach is a powerful strategy for detecting variants involved in tooth eruption, and potentially craniofacial growth and more generally organ development.
authors.affiliation: MRC Centre for Causal Analyses in Translational Epidemiology (CAiTE), School of Social and Community Medicine, Lower Maudlin Street, Bristol, UK. g.fatemifar@bristol.ac.uk
authors.forename: Ghazaleh
authors.initials: G
authors.lastname: Fatemifar
authors.forename: Clive J
authors.initials: CJ
authors.lastname: Hoggart
authors.forename: Lavinia
authors.initials: L
authors.lastname: Paternoster
authors.forename: John P
authors.initials: JP
authors.lastname: Kemp
authors.forename: Inga
authors.initials: I
authors.lastname: Prokopenko
authors.forename: Momoko
authors.initials: M
authors.lastname: Horikoshi
authors.forename: Victoria J
authors.initials: VJ
authors.lastname: Wright
authors.forename: Jon H
authors.initials: JH
authors.lastname: Tobias
authors.forename: Stephen
authors.initials: S
authors.lastname: Richmond
authors.forename: Alexei I
authors.initials: AI
authors.lastname: Zhurov
authors.forename: Arshed M
authors.initials: AM
authors.lastname: Toma
authors.forename: Anneli
authors.initials: A
authors.lastname: Pouta
authors.forename: Anja
authors.initials: A
authors.lastname: Taanila
authors.forename: Kirsi
authors.initials: K
authors.lastname: Sipila
authors.forename: Raija
authors.initials: R
authors.lastname: Lähdesmäki
authors.forename: Demetris
authors.initials: D
authors.lastname: Pillas
authors.forename: Frank
authors.initials: F
authors.lastname: Geller
authors.forename: Bjarke
authors.initials: B
authors.lastname: Feenstra
authors.forename: Mads
authors.initials: M
authors.lastname: Melbye
authors.forename: Ellen A
authors.initials: EA
authors.lastname: Nohr
authors.forename: Susan M
authors.initials: SM
authors.lastname: Ring
authors.forename: Beate
authors.initials: B
authors.lastname: St Pourcain
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Timpson
authors.forename: George
authors.initials: G
authors.lastname: Davey Smith
authors.forename: Marjo-Riitta
authors.initials: MR
authors.lastname: Jarvelin
authors.forename: David M
authors.initials: DM
authors.lastname: Evans
mesh_terms: D001827:Body Height / Q000235:genetics*; D002877:Chromosomes, Human; D003817:Dentition; D005145:Face / Q000033:anatomy & histology*; D005260:Female; D005387:Finland; D056426:Genetic Loci; D058685:Genetic Pleiotropy; D055106:Genome-Wide Association Study; D006801:Humans; D008137:Longitudinal Studies; D020641:Polymorphism, Single Nucleotide; D014078:Tooth Eruption / Q000235:genetics*