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Title: Genome-Wide Association Study Reveals Multiple Loci Associated with Primary Tooth Development during Infancy}
Article:
Abstract:
Tooth development is a highly heritable process which relates to other growth and developmental processes, and which interacts with the development of the entire craniofacial complex. Abnormalities of tooth development are common, with tooth agenesis being the most common developmental anomaly in humans. We performed a genome-wide association study of time to first tooth eruption and number of teeth at one year in 4, 564 individuals from the 1966 Northern Finland Birth Cohort( NFBC1966) and 1, 518 individuals from the Avon Longitudinal Study of Parents and Children( ALSPAC). We identified 5 loci at P<5×10−8, and 5 with suggestive association( P<5×10−6). The loci included several genes with links to tooth and other organ development( KCNJ2, EDA, HOXB2, RAD51L1, IGF2BP1, HMGA2, MSRB3). Genes at four of the identified loci are implicated in the development of cancer. A variant within the HOXB gene cluster associated with occlusion defects requiring orthodontic treatment by age 31 years.
Introduction:
Heritability of primary tooth emergence is estimated to be over 70%[1]. Abnormalities in tooth development are common with tooth agenesis alone affecting up to 10% of the population, ranking it as the most common developmental anomaly in humans[2]. Such abnormalities contribute to a variety of challenging and expensive orthodontic, prosthetic and surgical treatments and account for approximately 6% of all dental health care attendances[3]. Many genes implicated in primary dentition have regulatory functions important to several developmental processes in the embryo[4], and the developing tooth is a useful model for the study of organogenesis[5]. However, despite substantial research into tooth development in mice and human malformation syndromes[5], the genetic determinants of the normal variation in human tooth development have not been established. To identify genetic loci regulating primary dentition we performed a general population based genome-wide association( GWA) study of tooth development in infancy among individuals from the 1966 Northern Finland Birth Cohort( NFBC1966) and the Avon Longitudinal Study of Parents and Children( ALSPAC). Specifically, we tested for associations with time to first tooth eruption and number of teeth by one year of age. These phenotypes are relevant to later tooth development because teeth largely acquire their final form at a very early age[6]. The availability of longitudinal birth cohort data allowed us to investigate life-course associations with dental occlusion defects.
Discussion:
Teeth and several other organs have common growth and developmental pathways during early life[21]. The genes at the loci identified in our study have roles in organogenesis, growth and developmental processes, and cancer. Mutations in three of the genes lead to altered organogenesis and development; KCNJ2( teeth, jaws, palates, ears, fingers, toes), EDA( teeth, hair, sweat glands, salivary glands) and IGF2BP1( intestines)[8],[13],[22]. Of the loci at suggestive levels of significance, the HOXB gene cluster is an established regulator of development, and the HMGA2 gene has previously been associated with adult height[20]. Normal development and cancer both involve shifts between cell proliferation and differentiation[23] and genes regulating organ-specific growth are known to be involved in oncogenesis[24]. A previous study identified a common genetic link between an abnormal tooth development and cancer[25]. From our identified loci, IGF2BP1 and RAD51L1 have been implicated in cancer[11],[14] as have HOXB2, 2q35, and HMGA2[19],[26],[27]. We provide the first detailed insight into the genetic architecture of primary dentition and our findings could have implications for the study of other developmental and organogenic processes. Exploiting the availability of longitudinal cohort data[28] we found an association between a variant within the HOXB gene cluster and the requirement for orthodontic treatment due to defective occlusion by the age of 31 years. Further GWA studies of developmental processes during infancy may establish whether the genetic determinants of infant development can contribute to the study of chronic diseases, such as cancer, that occur later in life.
Genome-wide association studies have been used to identify genetic variants conferring susceptibility to diseases , intermediate phenotypes , and physiological traits such as height , hair color , and age at menarche . Here we analyze the NFBC1966 and ALSPAC birth cohorts to investigate the genetic determinants of a key developmental process: primary tooth development . The prospective nature of our studies allows us to exploit accurate measurements of age at first tooth eruption and number of teeth at one year , and also provides the opportunity to assess whether genetic variants affecting these traits are associated with dental problems later in the life course . Of the genes that we find to be associated with primary tooth development , several have established roles in tooth development and growth , and almost half have proposed links with the development of cancer . We find that one of the variants is also associated with occlusion defects requiring orthodontic treatment later in life . Our findings should provide a strong foundation for the study of the genetic architecture of tooth development , which as well as its relevance to medicine and dentistry , may have implications in evolutionary biology since teeth represent important markers of evolution .