Australian Dental Journal 1998;43:(4):000-000 Genetic aspects of dental disorders Grant C. Townsend* Michael J. Aldred† P. Mark Bartold‡ Abstract evidence of a genetic basis to each of these This paper reviews past and present applications of problems, for example, ‘My mother had chalky teeth quantitative and molecular genetics to dental too’ or ‘He’s inherited his father’s teeth and his disorders. Examples are given relating to cranio- mother’s jaws’ or ‘Bad gums run in my family’, it is facial development (including malocclusion), oral true to say that well-planned and executed scientific supporting tissues (including periodontal diseases) studies aimed at clarifying the genetic basis of these and dental hard tissues (including defects of enamel and dentine as well as dental caries). conditions are few and far between. This is partly Future developments and applications to clinical because their aetiologies are multifactorial, making dentistry are discussed. Early investigations it difficult to design well-controlled studies. confirmed genetic bases to dental caries, perio- Furthermore, most researchers of dental caries and dontal diseases and malocclusion, but research periodontal diseases have concentrated on environ- findings have had little impact on clinical practice. The complex multifactorial aetiologies of these mental aetiological fa c t o rs, for example, dental conditions, together with methodological problems, plaque, dietary fac t o rs, and oral hygiene, presumably have limited progress until recently. Present studies because these have been thought to be most are clarifying previously unrecognized genetic and important. phenotypic heterogeneities and attempting to unravel the complex interactions between genes A multifactorial aetiology for all three conditions and environment by applying new statistical model- has generally been assumed, with both genetic and ling approaches to twin and family data. Linkage environmental contributions to observed variability. studies using highly polymorphic DNA markers are The paucity of evidence of any clear-cut single gene providing a means of locating candidate genes, including quantitative trait loci (QTL). In future, as effects has meant that genetic research in these areas knowledge increases; it should be possible to has had little impact up to now on clinical dental implement preventive strategies for those practice. genetically-predisposed individuals who are As Neale and Cardon1 have pointed out, several identified to be at risk. questions need to be answered before a complete Key words: H e r e d i t y, caries, periodontal diseases, understanding can be gained about how genetic malocclusion, gene mapping, enamel defects, dentine defects. fa c t o rs influence a feature or disorder. These include: (Received for publication July 1997. Accepted August 1997.) . How important are genetic effects on human differences? Introduction . What kinds of action and interaction occur between gene products in the pathways between The three most common problems in dentistry genotype and phenotype? today remain dental caries, periodontal diseases and malocclusion. While there has always been anecdotal . Are the genetic effects on a trait consistent across sexes? . Are there some genes that have particularly This paper is based on presentations made at a Symposium titled Genetics of Common Dental Disorders held at the 36th Annual outstanding effects when compared with others? Scientific Meeting of the Intern ational Association for Dental Research Australian and New Zealand Division in Sydney from 29 . Whereabouts on the human gene map are these September to 1 October 1996. genes located? *Department of Dentistry, The University of Adelaide. †School of Dental Science, The University of Melbourne. Modern methods of quantitative genetic analysis ‡Department of Dentistr y, The University of Queensland. allow the first three questions to be addressed and 000 Australian Dental Journal 1998;43:4. 2 Table 1. Abbreviations used in the text the sum of the effects of all the genes influencing the AD Autosomal dominant feature under study, a dominance component (Vd) AR Autosomal recessive resulting from the interaction of alleles at a single CIPD Chronic inflammatory periodontal disease cDNA Complementary DNA gene locus, and an epistatic component (Vi) due to CpG Coding part of gene the interaction of genes at different loci: that is, DI Dentinogenesis imperfecta Vg=Va+Vd+Vi. The environmental variance can be DNA Deoxyribonucleic acid DNP1 Dentine matrix protein 1 p a rtitioned into a common env i r o n m e n t a l DPP Dentine phosphoprotein component (Vec) shared by family members and a DZ Dizygous EOP Early onset periodontitis specific environmental component (Vew). h2 Heritability estimate Heritability estimates, h2, that can range in value HLA Human leukocyte antigen LOD Logarithm of odds from 0 to 1.0 (or 0-100 per cent) indicate how much LJP Localized juvenile periodontics of the observed variation of a character can be mRNA Messenger RNA MSTRA Minnesota study of twins reared apart attributed to genetic effects. The ratio Vg/Vp is Mx Genetic modelling program referred to as broad-sense heritability whereas the MZ Monozygous ratio Va/Vp is termed narrow-sense heritability. A p Short arm of chromosome PCR Polymerase chain reaction list of abbreviations used in this paper is provided in PMN Polymorphonuclear leukocyte Table 1. PRP Proline-rich proteins q Long arm of chromosome It is important to realize that heritability estimates QTL Quantitative trait locus need to be interpreted with caution as they relate RFLP Restriction fragment length polymorphism RNA Ribonucleic acid only to the population under study at a particular SPP1 Osteopontin time, including the prevailing env i r o n m e n t a l SSCP Single strand chain polymorphism 3 Va Additive genetic variance influences. Furthermore, as Smith and Bailit have Vd Dominance variance noted, ‘contrary to popular opinion, the extent to Ve Environmental variance which genes determine a trait has no relationship Vec Common environmental variance Vew Specific environmental variance whatsoever with the success of environmental inter- Vg Genetic variance vention’. Traditional quantitative genetic analyses in Vi Epistasis variance VNTR Variable number of tandem repeat human populations deal with variation between Vp Phenotypic variance individuals not with mean values. For this reason it XAI X-linked amelogenesis imperfecta is inappropriate to say for example that ‘tooth size is YAC Yeast artificial chromsome ⌰ Theta – recombination fraction strongly genetic’ – rather one should say that ‘variation in tooth size between individuals has a strong genetic component’. provide some insight into the fourth. Resolution of Genetic and environmental factors have often the fifth question requires application of the been assumed to be independent for the purposes of methods of molecular genetics. analysis, but in practice this is unlikely to be the case. Three factors that should be considered are: Analysis of multifactorial traits a s s o rt i ve mating whereby there is non-random Rigorous statistical analysis of multifac t o rial traits pa i ring between mates for the trait under inves t i g at i o n ; began with R. A. Fisher’s seminal paper2 in which he genotype-environmental correlation when different sh owed how the corre l ations between relati ves of genotypes are not distributed at random in all different degree could be explained using the possible environments; and genotype-environment principles of Mendelian inherit a n c e . Although the interaction in which environmental effects on impact of quantitati ve genetics has been considerable phenotype differ according to genotype. in agriculture where selective breeding is possible, U n f o rt u n at e l y, most previous genetic studies of until recently most studies in human populations dental disorders have been based on assumptions have been confined to partitioning observed vari at i o n that have never been tested. into genetic and environmental components based on comparisons between relat i ves, for example, Twin studies parents and offspring, siblings, half-sibs, twins. The classical twin approach for separating the The variability between individuals in a trait’s effects of nature and nurture involves comparing phenotype (Vp) can be considered to result from a identical (monozygous) twins and non-identical combination of the genetic variance (Vg) and the (dizygous) twins. Differences between monozygous environmental variance (Ve). Assuming that there is (MZ) twin pairs reflect environmental fa c t o rs , no interaction between these two sources of vari at i o n , whereas differences between dizygous (DZ) twin Vp=Vg+Ve, genetic variance can be partitioned pairs are due to both genetic and environmental fu rther into an additive component (Va) representing factors. Therefore, greater similarities between MZ Australian Dental Journal 1998;43:4. 000 3 twin pairs compared with DZ twin pairs can be these methods to clarify the genetic basis of dental interpreted as reflecting genetic influences on the disorders has been limited by the difficulties of feature(s) being studied. obtaining data from large family pedigrees and also The traditional twin analysis method based on in identifying appropriate polymorphic marker loci.9, 1 0 c o rr e l ations is limited, but the development of s o p h i s t i c ated genetic modelling methods made Molecular approaches possible with improved computing power