Genetic Association of MMP10, MMP14, and MMP16 with Dental Caries.

Matrix metalloproteinases (MMPs), which degrade extracellular proteins as part of a variety of physiological processes, and their inhibitors have been implicated in the dental caries process. Here we investigated 28 genetic variants spanning the MMP10, MMP14, and MMP16 genes to detect association with dental caries experience in 13 age- and race-stratified (n = 3,587) samples from 6 parent studies. Analyses were performed separately for each sample, and results were combined across samples by meta-analysis. Two SNPs (rs2046315 and rs10429371) upstream of MMP16 were significantly associated with caries in an individual sample of white adults and via meta-analysis across 8 adult samples after gene-wise adjustment for multiple comparisons. Noteworthy is SNP rs2046315 (p = 8.14 × 10-8) association with caries in white adults. This SNP was originally nominated in a genome-wide-association study (GWAS) of dental caries in a sample of white adults and yielded associations in a subsequent GWAS of surface level caries in white adults as well. Therefore, in our study, we were able to recapture the association between rs2046315 and dental caries in white adults. Although we did not strengthen evidence that MMPs 10, 14, and 16 influence caries risk, MMP16 is still a likely candidate gene to pursue.

Genetic Association of MPPED2 and ACTN2 with Dental Caries.

The first genome-wide association study of dental caries focused on primary teeth in children aged 3 to 12 yr and nominated several novel genes: ACTN2, EDARADD, EPHA7, LPO, MPPED2, MTR, and ZMPSTE24. Here we interrogated 156 single-nucleotide polymorphisms (SNPs) within these candidate genes for evidence of association with dental caries experience in 13 race- and age-stratified samples from 6 independent studies (n = 3600). Analysis was performed separately for each sample, and results were combined across samples via meta-analysis. MPPED2 was significantly associated with caries via meta-analysis across the 5 childhood samples, with 4 SNPs showing significant associations after gene-wise adjustment for multiple comparisons (p < .0026). These results corroborate the previous genome-wide association study, although the functional role of MPPED2 in caries etiology remains unknown. ACTN2 also showed significant association via meta-analysis across childhood samples (p = .0014). Moreover, in adults, genetic association was observed for ACTN2 SNPs in individual samples (p < .0025), but no single SNP was significant via meta-analysis across all 8 adult samples. Given its compelling biological role in organizing ameloblasts during amelogenesis, this study strengthens the hypothesis that ACTN2 influences caries risk. Results for the other candidate genes neither proved nor precluded their associations with dental caries.

Preadolescent children of substance-dependent fathers with antisocial personality disorder: psychiatric disorders and problem behaviors.

We compared psychiatric disorders and problem behavior scores in pre-adolescent children of fathers with alcohol or other drug dependence and ASP (SD+/ASP+), children whose fathers had substance dependence without ASP (SD+/ASP-), and children whose fathers were without either disorder (SD-/ASP-). SD+/ASP+ children showed elevated rates of major depression, conduct disorder, attention deficit hyperactivity disorder, oppositional defiant disorder, and separation anxiety disorder when compared to SD+/ASP- and SD-/ASP- children. SD+/ASP+ children had higher internalizing and externalizing problem behavior scores than the other two groups of children. The results suggest that SD+/ASP+ children are at significant risk for internalizing and externalizing psychopathology.

Quantitative trait linkage analysis of the liability underlying a common oligogenic disease.

We utilized pedigree discriminant and factor analytic approaches to combine multivariate phenotypic information into a single liability phenotype in the isolate and general populations. We applied two-stage relative-pair quantitative trait linkage analysis to detect genetic contributions to variation in the resulting liability phenotypes. Linkage analysis revealed several regions of suggestive linkage in both the general and isolate populations, the majority of which appear in retrospect to be false positives. A likely explanation is an overall lack of power given that we tested hypotheses in data from only one replicate. However, it may be possible that a construct that ignores affection status when using liability-associated characteristics as indicators of this construct is not the most effective approach in modeling the liability underlying a complex phenotype.

Developmental sources of variation in liability to adolescent substance use disorders.

This review provides a synthesis of the literature on the complex sequence of maturational, psychosocial, and neuroadaptive processes that lead to substance use disorders (SUD) in adolescence. A brief overview introduces the concepts of liability to SUD and epigenesis. A theory is presented explaining how affective, cognitive, and behavioral dysregulation in late childhood is exacerbated during early and middle adolescence by family and peer factors, as well as puberty, leading to substance use. Continued exacerbation of the three components of dysregulation by drug and non-drug stressors during late adolescence is posited to result in neuroadaptations that increase the likelihood of developing SUD, particularly in high-risk individuals. Implications for etiologic research as well as clinical and preventive interventions are discussed.

Antisociality, substance dependence, and the DRD5 gene: a preliminary study.

A pilot population-based study of a microsatellite polymorphism at the DRD5 locus in adult European-Americans showed its association with childhood symptom counts for oppositional defiant disorder (ODD) in males and females and adult antisocial personality disorder (ASPD) in females. No association with childhood conduct disorder symptom count was observed. ODD mediated the genotype-ASPD relationship in females. Neither ODD nor ASPD significantly mediated the relationship between the genotype and the liability to substance dependence (SD). The data suggest involvement of the DRD5 locus in the variation and sexual dimorphism of SD liability and antisociality and in the developmental continuity of antisociality.

Genetic studies of substance abuse.

Genetic studies of substance abuse indicate that variation in the risk for the disorder in the population is contributed by differences in both individual genotypes and environment. Recent developments in genetics raise the possibility of disentangling the complex system of genotype-environment interaction that determines the development of the individual behavioral phenotype. This paper reviews the concepts, methods and results pertaining to genetic investigation of substance abuse.

Segregation analysis of attention deficit hyperactivity disorder.

We performed segregation analysis on 495 nuclear families, ascertained for the father's substance abuse diagnosis, in an attempt to determine the role of genetic and other influences in determining the variability of DSM-III-R-defined attention deficit hyperactivity disorder (ADHD). For our analyses, ADHD was treated as a quantitative variable, utilizing the semicontinuous scale provided by the 15-item symptom count within DSM-III-R. Analyses consisted of both class A and class D regressive models for which covariate effects (socioeconomic status) and sex dependence were estimated. Segregation analysis of the quantitative trait (ADHD symptom count) in the entire data set supported a transmissible non-Mendelian major effect. Models which were sex-dependent and included covariate effects provided the best fit to the data. In addition, similar analyses were performed on a 130-nuclear family subgroup of the data set in which at least one of the members of the nuclear family met DSM-III-R diagnostic criteria for ADHD. The sex-dependent Mendelian codominant model was best supported by the data, while other models could be rejected. Incorporating covariate effects did not provide a better fit for the data. Thus, this study is consistent with Mendelian transmission of ADHD symptom count in a clinically relevant population. Overall, our results support the presence of a heritable continuous trait of which ADHD represents an extreme.

An association between a microsatellite polymorphism at the DRD5 gene and the liability to substance abuse: pilot study.

We have conducted a population-based association study of substance abuse and a microsatellite at the dopamine D5 receptor locus (DRD5) in a sample of European-American males and females with substance dependence (SA) or without any psychiatric disorder. Overrepresentation of the most frequent allele (148 bp) was found in males in the SA group (OR = 2.2, P = .02); this finding was reproduced in females (OR = 5.4, p < .001). The difference in the frequencies of this allele between SA males and SA females was statistically significant. The genotype coded in accordance with the dose of this allele correlated with substance abuse liability in males and females (stronger in females) and with novelty seeking in females. There was no evidence of correlation between the genotypes of spouses that could be induced by assortative mating for the liability to substance abuse. The data suggest that the DRD5 locus is involved in the variation and sex dimorphism of substance abuse liability.

Mating assortment and the liability to substance abuse.

Assortative mating can exert a profound influence on the phenotypic composition of the population since it may result in an increase in the frequency of the genotypes associated with extreme phenotypes. Applied to the risk for a disorder such as substance abuse, this would mean a possibility for an increase in the risk and severity of the disorder in consecutive generations. This paper reviews the theoretical and empirical literature on mechanisms related to mate resemblance for the liability to substance abuse, sources and consequences of such resemblance, and suggests directions for further research.

A dinucleotide repeat polymorphism at the gene for monoamine oxidase A and measures of aggressiveness.

The relationship between measures of aggressiveness (personality questionnaire scales, conduct disorder diagnosis, and symptom count) and a recently discovered dinucleotide repeat length polymorphism at the monoamine oxidase type A (MAOA) gene (MAOCA-1) as a candidate locus was examined in adolescents using polymerase chain reaction. No significant correlation between aggression scales and repeat length at the MAOCA-1 marker was found, whereas the categorical diagnosis of conduct disorder showed a nonsignificant trend for an association with the marker. Alternative explanations of this trend are discussed. The data obtained suggest that the polymorphism studied is not associated with the variation in aggressiveness.

Salivary cortisol responses and the risk for substance abuse in prepubertal boys.

Investigations of adults with a psychoactive substance use disorder (PSUD) or antisocial behavior have reported diminished secretion of the adrenal "stress" hormone, cortisol. Consequently, we determined whether prepubertal sons of PSUD fathers, at high risk for later PSUD, differed from controls on salivary cortisol concentrations before, and after, an anticipated stressor. The roles of problematic behavioral disposition and state anxiety in the cortisol responses were also examined. A significant risk-group x time interaction for salivary cortisol concentrations was found, with high-risk boys secreting less salivary cortisol than controls when anticipating the task. High-risk boys also had significantly higher scores for aggressive delinquency and impulsivity that wholly accounted for the risk-group x time effect on salivary cortisol. Thus, cortisol hyporesponsivity was associated with the dysregulated behaviors prevalent among high-risk boys. The results suggest that cortisol hyporesponsivity could be a "marker" for later antisociality and PSUD.

Preliminary evidence for an association of a dinucleotide repeat polymorphism at the MAOA gene with early onset alcoholism/substance abuse.

An association between the liability to early onset alcoholism/substance abuse and a recently discovered dinucleotide repeat length polymorphism at the MAOA gene (MAOCA-1) was examined using polymerase chain reaction (PCR). A significant correlation between the presence/absence of the disorder and the length of the MAOCA-1 repeat was found in males, but not females, with "long" alleles (repeat length above 115 bp) associated with both increased risk for the disorder and lower age of onset of substance abuse. These preliminary data suggest that further exploration of the relationship between the MAOA gene and behavioral traits in an expanded sample is warranted.

Aggressivity, inattention, hyperactivity, and impulsivity in boys at high and low risk for substance abuse.

Aggressivity, inattention, hyperactivity, and impulsivity are cardinal dimensions of externalizing behavior problems of childhood. They are diagnostic and clinical features of childhood disorders, and are thought to be linked to the subsequent development of adult disorders such as substance abuse (SA). Little is known, however, about the convergent and discriminant validity of these four constructs. We used multiple measures to develop indices of aggressivity, inattention, hyperactivity, and impulsivity in a sample of 10- to 12-year-old boys (N = 183) with and without a family history of SA. Data were taken from mother reports, child reports, teacher reports, and laboratory tasks. The study aims were (1) to test the convergent and discriminant validity of aggressivity, inattention, hyperactivity, and impulsivity; (2) to examine whether the data were consistent with a model specifying the four constructs as indicators of one superordinate factor; and (3) to differentiate boys with and without a family history of SA in construct scores. The results supported the convergent and discriminant validity of the four constructs. Although discriminable, the constructs covaried strongly and were consistent with a model specifying them as indicators of a single superordinate factor. Boys with a family history of substance abuse scored higher than control boys on aggressivity, inattention, and impulsivity scores, but the groups did not differ on hyperactivity scores. The results are discussed in terms of the role of childhood behavior problems in vulnerability to SA.

Antisocial symptoms in preadolescent boys and in their parents: associations with cortisol.

Conduct disorder (CD) symptom counts in preadolescent boys, and antisocial personality disorder (ASP) and childhood conduct disorder symptom counts in their parents, were used as dimensional measures of behavioral deviation. A significant correlation was found for CD and ASP symptom counts between the two parents and between CD symptom counts of the children and parental CD and ASP symptom counts. Although socioeconomic level correlated negatively with parental symptom counts, no association was observed between parental socioeconomic status and children's CD symptom counts. Saliva cortisol level in the children was negatively associated with their CD symptom count and with their fathers' ASP count. Cortisol level was also lower among sons whose fathers had CD as children and subsequently developed ASP compared with the cortisol level in sons whose fathers either did not have any Axis I psychiatric disorder or did not develop ASP.

A genetic study of alcoholism in the Moscow population: preliminary findings.

This article reports the preliminary results of a family study of alcoholism in the Moscow population. A comparison of male and female alcoholic inpatients revealed differences between them in the patterns of alcoholism development and in the frequencies of the disorder among male and female probands' parents and siblings. Those differences, particularly those observed in the fathers of the female and male probands, may suggest that the liability and genetic predisposition to alcoholism in female alcoholics, on the average, are higher than those in male alcoholics. There were also differences between male and female probands in the frequencies of the types of drinking behavior (including alcoholism) we used to characterize individual phenotypes as to the liability to alcoholism in the probands' parents and spouses, indicating that the higher the liability and/or genetic predisposition to alcoholism the higher the probability of the proband's marriage to an individual with a higher liability to the disorder. The data on the comparison of the probands' children with their parents affectedness imply the possibility of a relationship between the genetic predisposition to alcoholism and the risk for mental and somatic disturbances in offspring of alcoholics.