Case control and family-based studies of tryptophan hydroxylase gene A218C polymorphism and suicidality in adolescents.

The association of suicidality with polymorphism A218C in intron 7 of tryptophan hydroxylase (TPH) gene remains controversial. The aim of this study was to use family-based methods to examine this association in adolescents in order to eliminate the difficulty of sampling a control group from the same ethnic population. Eighty-eight inpatient adolescents who recently attempted suicide were assessed by structured interview for detailed clinical history, diagnoses, suicide intent, suicide risk, impulsivity, aggression, and depression. DNA samples were collected from all subjects, from both biological parents of 40 subjects and from one parent of 9 subjects; TPH allele frequencies were calculated and tested for association to phenotype, stratified by severity, using the haplotype relative risk (HRR) and transmission disequilibrium test (TDT) methods (n = 49). The frequencies were also compared for all the Jewish subjects (n = 84) to the known frequencies of these alleles in healthy Jewish populations. There was no significant allelic association of A218C polymorphism with suicidal behavior or other phenotypic measures according to the HRR method (chi-square = 0.094; P = 0.76), the TDT (chi-square = 0.258; P = 0.61), or association analysis to known population frequencies (chi-square = 1.667, P = 0.19 for Ashkenazi, and chi-square = 0.810, P = 0.37 for non-Ashkenazi). Analysis of variance with the Scheffè test demonstrated a significant difference between CC and AA genotypes in suicide risk and depression among the patients (n = 88). The findings suggest that polymorphism A218C has no major relevance to the pathogenesis of adolescent suicidal behavior, but may have a subtle effect on some related phenotypes.

Symptom dimensions in obsessive-compulsive disorder: toward quantitative phenotypes.

The authors review evidence of symptom dimensions in obsessive-compulsive disorder (OCD) and their potential value as quantitative phenotypes in genetic studies of OCD and related conditions. Preliminary evidence supports the existence of four separate symptom dimensions. A small series of clinical and family genetic studies support the validity of one or more of these dimensions. However, critical data concerning the distribution of these dimensions in the general population are lacking, and the hereditability of these traits has yet to be established.

Genetic aspects of obsessive-compulsive disorder.

Developments in molecular genetic methods have proved to be powerful tools in the search for genes involved in complex diseases, and they hold the promise of understanding the genetic basis of OCD. The next step in understanding the genetics of OCD is the localization and characterization of the genes that confer susceptibility. A more complete understanding of the genetic basis of OCD and of the interactions between relevant genotypes and relevant environmental factors is important for clarification of the cause, pathogenesis, and treatment of this complex disorder. These genetic methods must be combined with careful clinical and epidemiologic work to correctly elucidate the cause of OCD. Future research also should define subsets of endophenotypes of the disorder. Factors such as neuropsychological functioning, personality testing, comorbidity, and age of onset are extremely useful in the continued study of genetic mechanisms involved in the cause of OCD.

Genetics and violence.

As is evident from this brief review, the genetic study of violence is maturing at an ever-increasing rate; much more work is needed to examine specific molecular genetic markers and their associated phenotypes, particularly in subjects with juvenile onset. It is also becoming clear that more work is needed to help delineate the specific phenotypes that are being transmitted within families. It is unlikely that we will find a gene or genes that are both necessary and sufficient for the manifestation of aggression and violence. It is more likely that specific genes will be associated with discrete factors that either increase the risk for the expression of violence or that are components of the violent phenotype. Thus, in addition to continuing research that examines the role of specific genetic factors in the manifestation of violence, more work is needed that will help further develop the nosology of violence and related behaviors. As noted previously, an understanding of the inherited phenotype is critical in the study of any disorder. It is especially important in the study of complex behaviors such as violence in which there may be several behavioral components that comprise the complete diagnostic category.

Functional and genomic analysis of the human mitochondrial intermediate peptidase, a putative protein partner of frataxin.

We showed recently that the yeast mitochondrial intermediate peptidase (YMIP polypeptide; gene symbol, OCT1) promotes mitochondrial iron uptake by catalyzing the maturation of iron-utilizing proteins and exacerbates the mitochondrial iron accumulation that results from loss of yeast frataxin, a mitochondrial protein required for mitochondrial iron efflux. This suggests that the human MIP (HMIP polypeptide; gene symbol MIPEP) may be one of the loci predicted to influence the clinical manifestations of Friedreich's ataxia (FRDA), an autosomal recessive neurodegenerative disease caused by lack of human frataxin. To begin to test this hypothesis, we have characterized HMIP at the functional and genomic levels. We show that HMIP can complement a yeast knock-out mutant lacking YMIP, demonstrating that HMIP and YMIP are functional homologues. The MIPEP gene spans 57 kb and consists of 19 exons that correlate with the functional domains of HMIP. Primer extension analysis has identified a major transcript of the MIPEP gene expressed differentially and predominantly in tissues with high oxygen consumption, while sequence analysis of approximately 2 kb of 5'-flanking DNA has revealed putative Mt1/3/4, NF-kappaB, and AP-1 elements that may regulate MIPEP expression in these tissues. Using a new polymorphic (CA)(n) repeat in intron 4, MIPEP has been genetically mapped within a 7-cM interval between markers D13S283 and D13S217 on 13q12. This work provides the basis for molecular analysis of MIPEP in FRDA and possibly other neurodegenerative diseases.

The inheritance of obsessive-compulsive disorder.

The influence of genetic factors has been suggested from the earliest descriptions of obsessive-compulsive disorder (OCD), and a number of studies have been conducted to determine to what extent OCD is heritable. Evidence for the influence of genetic factors has come from twin and family aggregation studies. Furthermore, drug-treatment and functional neuroimaging studies have added strength to the genetic investigations by emphasizing the neurobiologic aspects of OCD.

Molecular approaches to child psychopathology.

Basic research into the genetics of childhood psychiatric disorders has substantially increased during the last two decades. Specific genetic mutations have been characterized in some developmental disorders (e.g., fragile X syndrome and Prader-Willi syndrome), but thus far identification of etiological gene mutations in psychiatric illnesses has been unsuccessful. Several psychiatric disorders serve as examples of the current state of molecular approaches in child psychopathology. Investigations to date of Gilles de la Tourette's syndrome (GTS) have not resulted in the discovery of a gene of major effect. Some studies have implicated the D2 and D4 dopamine receptors as having a direct role in the etiology of GTS, but other studies have disputed those findings. However, the dopamine D2 receptor may modulate the severity of GTS. Obsessive-compulsive disorder has a reported association with a low-activity allele of the enzyme catechol-O-methyltransferase; however, the low-activity genotype is also seen in a significant proportion of unaffected individuals. For reading disability two distinct phenotypes (phonological awareness and single-word reading) have been linked to separate loci on chromosomes 6 and 15. Attention deficit hyperactivity disorder (ADHD) has a reported association with the dopamine transporter. Findings of a genetic locus for the personality trait of novelty seeking remain controversial.

Symptoms of obsessive-compulsive disorder.

OBJECTIVE: Obsessive-compulsive disorder encompasses a broad range of symptoms that represent multiple psychological domains, including perception, cognition, emotion, social relatedness, and diverse motor behaviors. The purpose of these analyses was to evaluate the correlational relationships of the symptoms of obsessive-compulsive disorder. METHOD: This study examined the 13 a priori categories used to group types of obsessions and compulsions in the Yale-Brown Obsessive Compulsive Scale symptom checklist in two independent groups of patients with obsessive-compulsive disorder (N = 208 and N = 98). A principal-components factor analysis with varimax rotation was performed, followed by a series of other exploratory analyses. RESULTS: The two data sets yielded nearly identical results. Four factors--obsessions and checking, symmetry and ordering, cleanliness and washing, and boarding--emerged in each data set, in total accounting for more than 60% of the variance. CONCLUSIONS: Obsessive-compulsive disorder is a multidimensional and etiologically heterogeneous condition. The four symptom dimensions identified in this study are largely congruent with those identified in earlier reports. These factors may be of value in future genetic, neurobiological, and treatment response studies.

Obsessive compulsive symptoms in Gilles de la Tourette syndrome and obsessive compulsive disorder: differences by diagnosis and family history.

The distribution of obsessive compulsive symptoms was compared in 16 individuals with primary obsessive compulsive disorder (OCD) and 16 individuals with Gilles de la Tourette syndrome (GTS) and associated obsessive compulsive behaviors (OCB). The two groups showed significant differences in the distribution of OC symptomatology. Furthermore, those OCD probands who shared a similar symptom profile with GTS individuals all had a positive family history of OCD. All of the other OCD probands were isolated cases. Implications of this finding on the etiology and pathogenesis of the two disorders are discussed.

The genetics of Tourette syndrome.

Tourette syndrome has significant genetic determinants. The mode of transmission, while mildly controversial, generally is thought to be due to a single major locus inherited either as an autosomal dominant trait with reduced penetrance, or as a trait with intermediate inheritance in which some heterozygotes manifest the disorder. These is evidence for a Tourette syndrome spectrum of symptoms that includes obsessive-compulsive disorder. Systematic genome linkage studies of Tourette syndrome are progressing, but to date there are no significant linkage findings, although the search has included many neurologically relevant candidate genes.

A family study of obsessive-compulsive disorder.

OBJECTIVE: The goal of this study was to determine 1) whether obsessive-compulsive disorder is familial, 2) whether there is a familial relationship between obsessive-compulsive disorder and Gilles de la Tourette's syndrome and chronic tics, and 3) whether different familial types of obsessive-compulsive disorder exist. METHOD: In this family study, all available first-degree relatives of 100 probands with obsessive-compulsive disorder were interviewed directly with structured interviews, and best-estimate diagnoses were assigned. In addition to the 466 first-degree relatives of the probands, 113 comparison subjects who were first-degree relatives of 33 psychiatrically unaffected subjects were studied with the same interviews. RESULTS: The rates of obsessive-compulsive disorder and subthreshold obsessive-compulsive disorder were significantly greater among the relatives of the probands with obsessive-compulsive disorder (10.3% and 7.9%, respectively) than among the comparison subjects (1.9% and 2.0%, respectively). Furthermore, the rate of tics (Tourette's disorder and chronic tics) was also significantly greater among the relatives of the probands (4.6%) than among the comparison subjects (1.0%). The relatives of female probands with obsessive-compulsive disorder were more likely to have tics, and the relatives of probands with early onset were at higher risk for both obsessive-compulsive disorder and tics. CONCLUSIONS: Obsessive-compulsive disorder is a heterogeneous condition. Some cases are familial and related to tic disorders, some cases are familial and unrelated to tics, and in other cases there appears to be no family history of either obsessive-compulsive disorder or tics.