Future of genetics of mood disorders research.

This report summarizes the deliberations of a panel with representation from diverse disciplines of relevance to the genetics of mood disorders. The major charge to the panel was to develop a strategic plan to employ the tools of genetics to advance the understanding, treatment, and outcomes for mood disorders. A comprehensive review of the evidence for the role of genetic factors in the etiology of mood disorders was conducted, and the chief impediments for progress in gene identification were identified.

Trans-NIH neuroscience initiatives on mouse phenotyping and mutagenesis.

In the post-genomic era, the laboratory mouse will excel as a premier mammalian system to study normal and disordered biological processes, in part because of low cost, but largely because of the rich opportunities that exist for exploiting genetic tools and technologies in the mouse to systematically determine mammalian gene function. Many robust models of human disease may therefore be developed, and these in turn will provide critical clues to understanding gene function. The full potential of the mouse for understanding many of the neural and behavioral phenotypes of relevance to neuroscientists has yet to be realized.

Glucose-induced increase in memory performance in patients with schizophrenia.

Previous investigations have found that increasing circulating glucose availability can increase memory performance in rodents, healthy humans, and individuals with dementia of the Alzheimer's type. In this study, patients with schizophrenia, healthy control subjects, and controls with bipolar affective disorder were tested using double-blind treatment with either 50 g anhydrous dextrose plus 4 mg sodium saccharin (for "taste") or 23.7 mg saccharin alone, followed by cognitive testing on a complex battery.

Schizophrenia genetics at the millennium: cautious optimism.

As the new millennium approaches, research into the genetic aspects of schizophrenia has already made an impressive start toward an integrated model which is discovering roles for genetic agents, environmental agents and experiences, and chance factors. The best model follows that proposed for understanding such complex diseases as coronary artery disease and diabetes. Genetic information has come from both genetic epidemiology and molecular genetics.

Detection and replication of linkage to a complex human disease.

Efforts to map susceptibility loci for complex human diseases frequently result in weak evidence for linkage, followed by failures to convincingly replicate. If a disease locus influences both affection status (AF) and a quantitative trait, a variant of the extreme discordant sib pair (EDSP) strategy may be used to judiciously sample families for a replication study. This approach was evaluated by conducting joint segregation and linkage analysis of four bivariate phenotypes, each comprising AF and one quantitative trait (Q2, Q3, Q4, Q5), and undertaking a genomic scan of the GAW10 Problem 2B data set.

At issue: genes, experience, and chance in schizophrenia--positioning for the 21st century.

Genetic factors make important contributions to the etiologies of schizophrenia. The mode of familial inheritance remains unknown, but it is highly likely that multiple genes and idiosyncratic environmental factors are involved. Rapidly evolving genetic technologies have been applied in the genetic analysis of schizophrenia, and several genomic regions have been posited as harboring susceptibility genes.

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.

Multivariate genetic analysis of an oligogenic disease.

Joint multivariate segregation and linkage analysis provides a method for simultaneously analyzing data on affection status, correlated phenotypic traits, environmental risk factors, and other covariates. The power of this approach for mapping disease susceptibility loci of small effect (oligogenes) was evaluated by analyzing the GAW9 Problem 2 data set. The program REGRESS, which assumes a pleiotropy model in which one locus influences both affection status (AF) and a quantitative trait, was used to conduct joint segregation and linkage analysis of bivariate phenotypes, each comprising AF and one quantitative trait (Q2, Q3, Q4).

Latent structure of DSM-III-R Axis II psychopathology in a normal sample.

The Personality Disorder Examination was administered to 302 normal controls in the New York High-Risk Project in order to elicit Axis II diagnoses (revised 3rd edition of the Diagnostic and Statistical Manual of Mental Disorders; American Psychiatric Association, 1987) and quantitative dimensions of psychopathology. LISREL confirmatory factor analysis was used to evaluate the Axis II hypothesis of 3 orthogonal factors. There was considerable overlap among personality disorders.

Measuring liability to schizophrenia: progress report 1994: editors' introduction.

The first aim of this issue of the Schizophrenia Bulletin is to provide an up-to-date review of the major domains of research in the experimental psychopathology of schizophrenia, in which important contributions to our understanding of putative pathophysiologic mechanisms have been made. This research has identified several biobehavioral traits as measures of enhanced liability to schizophrenia. Rather than present a substantive review of the research on a particular trait, the authors of several articles focus on a critical appraisal and evaluation of the literature since 1987 in their particular area.

Indicators of liability to schizophrenia: perspectives from genetic epidemiology.

Research in genetic epidemiology has provided powerful evidence that genetic factors contribute to the familial transmission of schizophrenia. However, the precise mode of inheritance has not been elucidated, and no disease-susceptibility locus has been identified. Genetically complex illnesses such as schizophrenia can be characterized by multiple intermediate correlated traits or risk factors that likely play important roles in the susceptibility of individuals to developing the illness.

Association between major depressive disorder and physical illness.

The association between major depressive disorder (MDD) and self-reported histories of specific physical illnesses was investigated in 320 controls and 1968 first-degree relatives and 254 spouses of probands in the NIMH Collaborative Depression study. The Schedule for Affective Disorders and Schizophrenia-Lifetime Version was used to assign Research Diagnostic Criteria (RDC) diagnoses and a structured self-report instrument was used to assess lifetime medical history. Lifetime MDD was diagnosed in 914 subjects, 402 of whom had been hospitalized or received somatic treatment ('treated' MDD).

Linkage analysis of a complex disease: application to familial Alzheimer's disease.

Evidence for linkage of the Alzheimer's gene to markers on chromosomes 19 and 21 was assessed using single-locus and two-locus models of inheritance. Families were divided into groups determined by their average age at onset. The youngest group produced higher lod scores for markers on chromosome 21 while an older group showed evidence for linkage to markers on chromosome 19.

Replicated psychometric correlates of schizophrenia.

Objective: The authors' goals are to use scales from the MMPI hypothesized in their previous research to be correlates of liability to schizophrenia to differentiate DSM-III schizophrenia from bipolar and unipolar affective illness and to cross-validate these correlates in an independently ascertained sample of patients with Research Diagnostic Criteria (RDC) schizophrenia or affective disorder.

Method: The criterion sample consisted of 83 patients consecutively admitted to a state-operated community mental health center. Diagnosis of schizophrenia; bipolar disorder, manic; and major depression were assigned by using DSM-III.

Current perspectives on the genetics of unipolar depression.

Evidence regarding the heritability of unipolar depression is evaluated. The data reviewed here support the involvement of genetic factors in the etiology of unipolar depression and its suitability for independent genetic inquiry, despite our inability to identify the mode(s) of transmission or identify a candidate locus. Continued progress in testing etiologic hypotheses requires (a) clarification of the mode of transmission; (b) resolution of phenotypic and potential genotypic heterogeneity; (c) general agreement on a "gold standard" for assessment of the unipolar phenotype; (d) the continued application of available quantitative methods to take into account the effects of ascertainment bias, sex effects, cohort effects, and variable/late age at onset; and (e) incorporation of quantitative indicators correlated with liability in multivariate analysis to improve the stability/validity of phenotypic determinations in segregation and linkage analysis.

Discerning the latent structure of hypothetical psychosis proneness through admixture analysis.

The application of psychometric procedures to a normal population sample to detect individuals with increased liability for schizophrenia is a useful methodological adjunct to the traditional genetic high-risk strategy. A necessary and reasonable step in the process of establishing the utility of a viable psychometric index of schizotypy is the formal investigation of the latent structure of psychometric values. The present study used admixture analysis to examine the distribution of scores on the Perceptual Aberration Scale (PAS), an objective measure of hypothetical psychosis-proneness, in a randomly ascertained sample of 18-year-old university students (n = 707).

Psychometric deviance in offspring at risk for schizophrenia: II. Resolving heterogeneity through admixture analysis.

The longitudinal and prospective study of offspring at risk for schizophrenia is complicated by within-group heterogeneity in liability, as only a subgroup of those at risk will ultimately become affected. Here, we attempt to resolve such heterogeneity in the New York High-Risk Project by conducting an admixture analysis of values on a psychometric index of liability to schizophrenia derived from the Minnesota Multiphasic Personality Inventory (MMPI). We fit mixtures of components to the overall distribution in 171 children from three criterion groups: offspring at risk (HR) for schizophrenia, psychiatric comparison (PC) offspring at risk for affective illness, and normal comparison (NC) offspring not at increased risk for psychiatric morbidity.

Psychometric deviance in offspring at risk for schizophrenia: I. Initial delineation of a distinct subgroup.

Psychometric signs from the Minnesota Multiphasic Personality Inventory (MMPI), which measure substantive disturbances in thinking, social relatedness, volition, and affective expressivity, were evaluated as possible indicators of transmissible liability specific to schizophrenia. Children of three criterion groups in the New York High-Risk Project--offspring at high risk (HR) for schizophrenia, psychiatric comparison (PC) offspring at risk for affective disorders, and normal comparison (NC) offspring not at augmented risk for psychiatric morbidity--were tested before the expression of schizophrenic psychopathology, when the subjects ranged in age from 13 to 26 years. The rate of psychometric deviance in the HR group (23%) was significantly higher than that in either the PC (7%) or NC (2%) groups, and profile analyses showed that the HR subgroup could be delineated by qualitative distinctions in personality functioning.