ABSTRACT The ultimate objective of the proposed study is to discover genes influencing variation in human dentognathic morphology. This will be accomplished through a series of analyses aimed at elucidating fundamental aspects of the genetic architecture of the human dentognathic complex. Significant health problems related to the dentition and jaws (the dentognathic complex) range from aesthetic issues due to malocclusion, to increase risk of caries, impaction, and infection due to dental crowding, to significant congenital deformities (e.g., orofacial clefting). The etiology of dentognathic disorders is complex. Both hereditary and environmental factors have been identified as factors influencing the variation of these traits. The proposed study is designed to examine normal variation in, and the relationships between, dentognathic traits in a population where environmental factors (diet, dental care) are relatively homogeneous. We contend that an understanding of the influences genetic and environmental factors have on the dentognathic complex must rest on a solid foundation of detailed knowledge of the genetic components underlying the development of normal variation. Understanding the nature of genetic influences on the regions of the cranium is of critical importance to a wide variety of clinicians. As it becomes increasingly possible to incorporate gene therapy and tissue engineering when approaching repair of orofacial dysmorphology, studies elucidating the genetic underpinnings of continuous phenotypes typifying normal morphological variation are of critical importance. Examination of genetic contributions to normal variation in the dentognathic complex will be addressed in two specific aims: 1) Characterize variation in biomedically-relevant phenotypes describing dental and dental arcade morphology and explore fundamental aspects of the genetic architecture of dentognathic morphology. 2) Identify chromosomal regions (Quantitative Trait Loci; QTL) harboring genes that influence variation in dentognathic measures. Four measurements describing each tooth and 32 dental arcade measures will be taken from high quality dental casts of participants of the Jiri Helminth Study, Jiri, Nepal. A maximum-likelihood variance decomposition method for pedigree data implemented in the software program SOLAR is the analytic platform for the analyses. Heritability of each trait will be estimated, and genetic correlations will be examined between all trait pairs. Linkage analysis will identify QTL harboring genes influencing variation in adult dentognathic morphology. The proposed study of the genetic architecture of the dentognathic complex will provide information critical in characterizing the genetic underpinnings of normal dentognathic morphology in humans.

PROJECT NARRATIVE The goal of the proposed study is particularly timely for public health. Deformities of the jaws and teeth are among the most common congenital defects with effects on individuals ranging from minor aesthetic issues associated with malocclusion, to increased risk of caries, to deformities with significant health outcomes such as cleft palate. Identifying the genes responsible for normal variation in morphology of the jaws will provide important information for future gene therapy and tissue engineering treatment regimes.