The influence of phenotype on the outcome of linkage analysis of schizophrenia.
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Chromosomes, Human, Pair 2↗
Biomedical subjects
T Reich
Publications and source records attributed to T Reich.
Polarized x-ray-absorption spectroscopy of the uranyl ion: Comparison of experiment and theory.
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Journal Article↗
Diagnostic accuracy and confusability analyses: an application to the Diagnostic Interview for Genetic Studies.
The dominant, contemporary paradigm for developing and refining diagnoses relies heavily on assessing reliability with kappa coefficients and virtually ignores a core component of psychometric practice: the theory of latent structures. This article describes a psychometric approach to psychiatric nosology that emphasizes the diagnostic accuracy and confusability of diagnostic categories. We apply these methods to the Diagnostic Interview for Genetic Studies (DIGS), a structured psychiatric interview designed by the NIMH Genetics Initiative for genetic studies of schizophrenia and bipolar disorder. Our results show that sensitivity and specificity were excellent for both DSM-III-R and RDC diagnoses of major depression, bipolar disorder, and schizophrenia. In contrast, diagnostic accuracy was substantially lower for subtypes of schizoaffective disorder-especially for the DSM-III-R definitions. Both the bipolar and depressed subtypes of DSM-III-R schizoaffective disorder had excellent specificity but poor sensitivity. The RDC definitions also had excellent specificity but were more sensitive than the DSM-III-R schizoaffective diagnoses. The source of low sensitivity for schizoaffective subtypes differed for the two diagnostic systems. For RDC criteria, the schizoaffective subtypes were frequently confused with one another; they were less frequently confused with other diagnoses. In contrast, the DSM-III-R subtypes were often confused with schizophrenia, but not with each other.
Bipolar Disorder↗
Psychiatric diagnoses in the child and adolescent members of extended families identified through adult bipolar affective disorder probands.
OBJECTIVE: To investigate the type and distribution of psychiatric disorders in the child and adolescent members of extended pedigrees identified through bipolar probands. METHOD: The child and adolescent offspring (24 male, 26 female, aged 6 to 17 years) and the adult parents (60) of 14 bipolar pedigrees ascertained for the National Institutes of Mental Health Genetics Initiative Study of Bipolar Affective Disorder were personally assessed using structured psychiatric interviews. A parent was also interviewed about each child or adolescent offspring. RESULTS: Twelve of the 50 interviewed offspring received a lifetime DSM-III-R diagnosis of an affective disorder. This included six cases of bipolar disorder, five cases of major depressive disorder, and one case of dysthymia. Eight of the offspring who received an affective disorder diagnosis also qualified for an anxiety disorder (four), a disruptive behavior disorder (two), or both (two). Offspring who had a parent with an affective disorder had a 5.1-fold higher risk for receiving an affective disorder diagnosis than did offspring with healthy parents. CONCLUSIONS: In a consecutive series of families identified through a proband with bipolar disorder, there were significant increases in the prevalence of affective disorder diagnoses in the child and adolescent offspring. The distribution of illness in offspring was compatible with the presence of important genetic factors which contribute to early-onset affective illness.
Adolescent↗
Can we subtype alcoholism? A latent class analysis of data from relatives of alcoholics in a multicenter family study of alcoholism.
We attempt to identify distinctive subtypes of alcoholics using latent class analysis with data from 2551 relatives of alcoholic probands, all participants in the Collaborative Study of the Genetics of Alcoholism. Latent class analysis is a multivariate technique using cross-classified data to identify unobserved ("latent") classes that explain the relationships among observed variables. Data on 37 life-time symptoms of alcohol dependence from 1360 female and 1191 male relatives were analyzed, with a 4 class solution selected as the best fitting among the 2 through 6 class solutions that were examined. We observed the following classes: class 1, nonproblem drinkers (39.6% male, 50% female); class 2, mild alcoholics (persistent desire to stop, tolerance, and blackouts) (31.8% male, 28.7% female); class 3, moderate alcoholics (social, health, and emotional problems) (18.9% male, 14.6% female); and class 4, severely affected alcoholics (withdrawal, inability to stop drinking, craving, health, and emotional problems) (9.7% male, 6.7% female). There was little evidence for the construct of alcohol abuse; endorsement probabilities for abuse symptoms (e.g., arrest and DWIs) were very low for all classes, whereas hazardous use was common among men in class 1. In addition to those in class 3 and class 4, a majority of men in class 2 qualified for DSM-III-R alcohol dependence, suggesting a biomodal distribution of drinkers and alcoholics, with little nondependent problem drinking among men in this high-risk sample. We conclude that, in this sample, alcoholism is not differentiated by symptom profiles but rather lies on a continuum of severity, with the possible exception of withdrawal, which characterized only class 4 individuals.
Adolescent↗
A genomic survey of alcohol dependence and related phenotypes: results from the Collaborative Study on the Genetics of Alcoholism (COGA).
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Alcoholism↗
Determinants of subcellular distribution of the glucocorticoid receptor.
Glucocorticoid receptor (GR) exchanges between an active nuclear form and a complexed inactive, steroid-sensitive cytoplasmic form. Using a semi-quantitative indirect immunofluorescence assay to measure the kinetics of subcellular redistribution of GR in response to challenge during G(o), we have found that the ability to bind DNA is an important determinant for localization and tight binding of GR to the nucleus. The transfer of GR DNA-binding mutants to the nucleus after treatment with hormone agonists and antagonists was markedly reduced. Further, mutant receptors localized to the nucleus were only weakly associated with the nuclear compartment as they were released into cytosol upon hypotonic lysis of the cell membrane. Moreover, after agonist withdrawal, GR redistributed to the cytoplasm more rapidly when unable to bind DNA. By contrast, withdrawal of the hormone antagonist RU486 was found to yield a form of wild type GR that was completely unable to redistribute to the cytoplasm. However, this did not appear to result from a block in nuclear export as selective inactivation of nuclear import with energy inhibitor released RU486-withdrawn GRs from the nucleus at the same rates as agonist-withdrawn receptors. In addition, GR mutants unable to bind DNA, which retained a significant presence in the cytoplasm both during and after antagonist treatment, also failed to redistribute. The effect of RU486 treatment did not appear to be mediated through a block in reassociation of GR into a steroid-responsive form as RU486-withdrawn wild type receptors retained full potential to activate transcription from a glucocorticoid-responsive promoter after a second challenge with hormone. Therefore, reassociation of GR into a steroid-responsive form appears to be independent of signals important for the retention of GR in the cytoplasm.
Animals↗
5 alpha-Reductase type 1 is localized to the outer nuclear membrane.
The subcellular distribution of the two isozymes of 5 alpha-reductase has been controversial. To resolve this issue which could provide clues about the respective functions of the two isozymes, two antisera were generated, one which was specific for the Type 1 5 alpha-reductase and one which recognized both isozymes. In COS cells transfected separately with the Type 1 or Type 2 cDNA, both isozymes were detected on Western blots at an M(r) of 26,000. Subfractionation of the COS cells resulted in the partitioning of both isozymes between the crude nuclear and cytosolic fractions, while cytoimmunofluorescence localized both reductases to the nuclear periphery. In rat liver homogenate, the 5 alpha-reductase was also detected at M(r) 26,000. The 5 alpha-reductase immunoreactivity was increased after castration of the animals with no further effect when castrated animals were treated with androgens. Although the rat liver expresses only the Type 1 5 alpha-reductase, the 5 alpha-reductase was distributed about equally between crude nuclear and cytosolic subfractions; this distribution could be shifted to the cytosolic fractions with harsher homogenization procedures. Further extensive subfractionation and extraction studies identified the rat liver Type 1 5 alpha-reductase as an integral membrane protein present in the outer nuclear membrane of the nuclear envelope and in rough endoplasmic reticulum. Thus, the subfractionation and cytoimmunofluorescence studies are consistent with the localization of the Type 1 5 alpha-reductase to the outer nuclear membrane of the nuclear envelope which is continuous with and indistinguishable from the endoplasmic reticulum. This study is the first to localize rat liver Type 1 5 alpha-reductase to the nuclear envelope to which the prostatic 5 alpha-reductase activity previously had been localized. We conclude that, contrary to previous tissue distribution studies, but consistent with investigations in transfected cells, both isozymes are similarly localized to the nuclear periphery.
3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
Sib-based detection of QTLs.
Association and transmission/nontransmission analyses were used in a split sample design to identify disease susceptibility alleles at two loci. Sib-pair analysis on various subsets of the data identified an additional four regions that yielded signals of disease predisposing quantitative trait loci (QTLs). Three of these four regions represented Type I errors. A new simulation indicates that a multiplex sampling strategy would substantially improve QTL detection for this oligogenic transmission model.
Alleles↗
A chromosome-based method to infer IBD scores for missing and ambiguous markers.
We propose a probability model to impute missing identical-by-descent (IBD) vectors for linkage analysis, when adjacent marker loci are typed and interference is estimable. A chromosome-based IBD distribution, conditioned on available marker data, is computed using a fast algorithm to estimate the joint probability of genes IBD at several equally spaced linked loci. Weighted IBD vectors are then used in various test statistics for linkage analysis. As an example, we analyzed the 18 affected sib pairs in the GAW9 Problem 1 data set using Risch's lod-score test.
Algorithms↗
The histories of withdrawal convulsions and delirium tremens in 1648 alcohol dependent subjects.
A small proportion of alcohol-dependent men and women experience delirium tremens (DTs) and/or convulsions during alcohol withdrawal. While some characteristics of individuals most likely to show these severe sequelae of the abstinence syndrome have been described, it is not clear whether these risk factors operate independently in their association with severe withdrawal. The Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) interview was used to evaluate 1648 alcohol dependent men and women (including 540 women). The background characteristics and drinking histories of the 160 men and 51 women (12.8% of the subjects) who reported ever having had at least one episode of DTs and/or convulsions during withdrawal were compared with the characteristics of the remaining alcohol dependent individuals. Compared to other alcohol-dependent subjects, those with histories of severe withdrawal reported a greater maximum number of drinks in any 24-hour period (40.9 +/- 25.71 versus 24.9 +/- 17.72), more withdrawal episodes (28.2 +/- 33.74 versus 15.9 +/- 26.84), more non-medicinal use of sedative-hypnotics (56.4% versus 32.9%) and a greater number of medical problems. Hierarchical logistic regression analysis revealed that the most powerful differences between those with histories of more and less severe withdrawals related to the maximum number of drinks per day and the total number of withdrawal episodes. The remaining variables still added significantly to the relationship to more severe withdrawal. The etiology of DTs and convulsions is complex and involves the interaction of diverse characteristics representing relatively unique domains. It is hoped that these data will help clinicians identify individuals most likely to have experienced severe withdrawal syndromes and will aid researchers attempting to understand more about the etiology of these problems.
Adult↗
An evaluation of type A and B alcoholics.
Evaluations of 1539 alcohol-dependent subjects (including 512 women) were carried out in an attempt to replicate the Type A/B dichotomy suggested by Babor et al. (1992). The subjects are participants in the Collaborative Study on the Genetics of Alcoholism (COGA), and each was evaluated using a face-to-face structured interview. Following the procedure of Babor et al. (1992), data were used to create 17 domains, and a k-means clustering method was invoked to generate a two-cluster solution. Thirty-one per cent of the males and 25% of the females fell into the Type B group, with overall R2 of 0.22 and 0.24 for males and females, respectively. The scores in each of the 17 domains and the analyses of the clinical characteristics for Type A and B subjects were, in general, consistent with the earlier onset and more severe course for Type B men and women. The ability of the domains to identify subgroups of alcoholics remained robust even after the exclusion of alcohol dependent subjects with antisocial personality disorder (ASPD) and those with an onset of alcohol dependence before age 25 years. The present analyses suggest that five of the 17 domains might be especially useful in identifying Type A and B groups.
Adult↗
Comparison of direct interview and family history diagnoses of alcohol dependence.
Using data from The Collaborative Study on the Genetics of Alcoholism, we compare direct interview diagnoses of alcohol dependence to those obtained by history from family members. Using a requirement of three or more positive implications by history, the specificity, sensitivity, and positive predictive values are 98%, 39%, and 45%, respectively. A logistic analysis found the gender of the relative and alcoholism in the informant to be significant, but not the gender of the informant. The partial odds ratio of a diagnosis at interview associated with a positive family history diagnosis was 13.6. The relationship between the informant and relative was significant, with negative reports from an offspring or mate more influential than a negative report from a parent or second-degree relative. We derived a recursive equation to combine a variable number of family history reports, wherein the probabilities associated with a single report are computed from the logistic analysis. This permits the use of family history information both as a proxy for an uninterviewed relative, as well as a second source of information to be used in the analysis of genetic family data.
Adult↗
Reliability of individual diagnostic criterion items for psychoactive substance dependence and the impact on diagnosis.
OBJECTIVE: Reliability of diagnostic criterion items for psychoactive substance dependence and the impact of each on the reliability of the diagnosis were analyzed. METHOD: As part of a reliability study for a new interview developed for the multisite Collaborative Study on the Genetics of Alcoholism (COGA), data were collected from both within-center and across centers. The impact of each diagnostic item on the reliability of the substance dependence diagnosis was studied by forcing each item to be reliable one at a time and recomputing the kappa statistic for the diagnosis. RESULTS: Findings indicated that the majority of individual diagnostic criterion items were reliable; 87% and 81% were in the fair or better range of reliability for the within- and cross-center studies, respectively. Individual kappa estimates were statistically similar for the two studies. Reliability findings for two classes of substance, alcohol and cocaine, were good, while those for stimulants were less satisfactory. CONCLUSIONS: Forcing items one at a time to be reliable did not affect reliability of the overall substance dependence diagnosis, because more than one criterion item changed from Time 1 to Time 2. Because no single item was influential, weighting criteria equally, as is done in the DSM and ICD classification systems, appears to be a reasonable approach.
Adolescent↗
Mathematical limits of multilocus models: the genetic transmission of bipolar disorder.
We describe a simple, graphical method for determining plausible modes of inheritance for complex traits and apply this to bipolar disorder. The constraints that allele frequencies and penetrances lie in the interval 0-1 impose limits on recurrence risks, KR, in relatives of an affected proband for a given population prevalence, KP. We have investigated these limits for KR in three classes of relatives (MZ co-twin, sibling, and parent/offspring) for the general single-locus model and for two types of multilocus models: heterogeneity and multiplicative. In our models we have assumed Hardy-Weinberg equilibrium, an all-or-none trait, absence of nongenetic resemblance between relatives, and negligible mutation at the disease loci. Although the true values of KP and the KR's are only approximately known, observed population and family data for bipolar disorder are inconsistent with a single-locus model or with any heterogeneity model. In contrast, multiplicative models involving three or more loci are consistent with observed data and, thus, represent plausible models for the inheritance of bipolar disorders. Studies to determine the genetic basis of most bipolar disorder should use methods capable of detecting interacting oligogenes.
Alleles↗
Linkage disequilibria at the D2 dopamine receptor locus (DRD2) in alcoholics and controls.
Because of its central role in the neuromodulation of appetitive behaviors, the D2 dopamine receptor gene (DRD2) has received considerable scrutiny as a possible candidate that may affect susceptibility to additive behaviors--especially alcoholism. Association studies that compare the frequencies of anonymous restriction fragment length polymorphisms (RFLPs) in alcoholics and controls have yielded equivocal results, suggesting that any role played by this receptor will account for only part of the variation. Since these RFLPs are not located in coding regions, the hypothesis has been advanced that the association seen in some studies results from linkage disequilibrium between these markers and one or more functional DRD2 alleles that affect susceptibility. To test this hypothesis, we have assayed four DRD2 RFLPs that span coding regions as well as a 3' flanking RFLP in an expanded sample of 88 unrelated Caucasian alcoholics and 89 unrelated race-matched controls. No significant difference for any RFLP frequency between these samples was observed, although for one marker (phD2-244), the alcoholic sample showed a significant departure from the Hardy-Weinberg equilibrium. The pattern of pairwise composite disequilibrium coefficients is broadly similar in the two samples, although when the five-marker haplotype frequencies are compared, a significant difference is revealed. This difference appears to be due to greater linkage disequilibrium of the control sample. These results do not support the involvement of the DRD2 region in the etiology of alcoholism.
Adult↗
Diagnostic interview for genetic studies. Rationale, unique features, and training. NIMH Genetics Initiative.
This article reports on the development and reliability of the Diagnostic Interview for Genetic Studies (DIGS), a clinical interview especially constructed for the assessment of major mood and psychotic disorders and their spectrum conditions. The DIGS, which was developed and piloted as a collaborative effort of investigators from sites in the National Institute of Mental Health (NIMH) Genetics Initiative, has the following additional features: (1) polydiagnostic capacity; (2) a detailed assessment of the course of the illness, chronology of psychotic and mood syndromes, and comorbidity; (3) additional phenomenologic assessments of symptoms; and (4) algorithmic scoring capability. The DIGS is designed to be employed by interviewers who exercise significant clinical judgment and who summarize information in narrative form as well as in ratings. A two-phase test-retest (within-site, between-site) reliability study was carried out for DSM-III-R criteria-based major depression, bipolar disorder, schizophrenia, and schizoaffective disorder. Reliabilities using algorithms were excellent (0.73 to 0.95), except for schizoaffective disorder, for which disagreement on estimates of duration of mood syndromes relative to psychosis reduced reliability. A final best-estimate process using medical records and information from relatives as well as algorithmic diagnoses is expected to be more reliable in making these distinctions. The DIGS should be useful as part of archival data gathering for genetic studies of major affective disorders, schizophrenia, and related conditions.
Adult↗
Prevalence of affective disorder in the child and adolescent offspring of a single kindred: a pilot study.
OBJECTIVE: The study determined the prevalence of psychiatric disorders among the child and adolescent offspring of an extended family identified through a proband with bipolar affective disorder. METHODS: All of the not mentally retarded offspring (ages 6 to 17 years) of a single extended bipolar affective disorder pedigree were studied. Data regarding psychiatric diagnoses, intelligence, school achievement, temperament, and family functioning were collected using structured and standardized instruments. RESULTS: When the child and adolescent offspring were stratified by degree of genetic relationship to an adult with an affective disorder, there were no differences in demographic variables, IQ, school achievement, or most temperamental and family characteristics. In contrast, there were increases in the rates of affective disorders and disruptive behavior disorders in the offspring that correlated with the degree of genetic relationship to an affected adult. CONCLUSIONS: The risk of developing an early onset affective disorder is correlated with the degree of genetic relatedness to affected adults in this single, extended family. This pilot study demonstrates that the inclusion of extended relatives in high-risk studies can enhance the discrimination of genetic and environmental contributions to the development of affective disorders.
Adolescent↗