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PubMed2006

Are neurologic examination abnormalities heritable? A preliminary study.

BACKGROUND: Neurologic examination abnormalities (NEA) are more prevalent among patients with schizophrenia as well as their unaffected relatives when compared with healthy controls, suggesting that NEA may be endophenotypes for schizophrenia. We estimated the heritability of NEA in moderately sized pedigrees. We also evaluated correlations between NEA and cognitive performance in order to examine their construct validity. METHODS: Members of eight extended families, each consisting of two first degree relatives with schizophrenia/schizoaffective disorders, as well as available first- to fifth-degree relatives were examined (n=96 participants). A modification of the Neurological Evaluation Scale (NES) was employed, augmented with localizing signs. Where feasible, we used untransformed data such as error counts and completion time, rather than ordinal measures. Heritability was estimated using the variance component method, implemented in SOLAR. RESULTS: Statistically significant heritability (h2) estimates were obtained for several measures (p<0.05, h2+/-standard error: rapid alternating movements, right-sided completion time, 0.99+/-0.19; alternating fist-palm test, completion time, 0.77+/-0.19 s, errors, 0.70+/-0.32; fist-ring test, right-sided completion time, 0.53+/-0.23 s, left-sided completion time, 0.70+/-0.21 s; go-no go task, correct responses, 0.93+/-0.33; audio-visual integration, correct responses, 0.79+/-0.54). For most items, heritability analysis was hampered by insufficient data variability (infrequent errors). Correlational analyses show some degree of divergence among types of NEA, repetitive motor tasks being associated with most domains of cognitive functioning other than executive functioning, and cognitive-perceptual tasks being associated with memory and executive functioning. CONCLUSIONS: Significant familial influences on certain aspects of neurologic performance were detected. These heritable measures were also correlated with heritable neurocognitive measures.

Adolescent↗

PubMed2006

Project among African-Americans to explore risks for schizophrenia (PAARTNERS): recruitment and assessment methods.

The Project among African-Americans to Explore Risks for Schizophrenia (PAARTNERS) is a multi-site, NIMH-funded study that seeks to identify genetic polymorphisms that confer susceptibility to schizophrenia among African-Americans by linkage mapping and targeted association analyses. Because deficits in certain dimensions of cognitive ability are thought to underlie liability to schizophrenia, the project also examines cognitive abilities in individuals affected by schizophrenia and their extended family members. This article describes PAARTNERS study design, ascertainment methods and preliminary sample characteristics. We aim to recruit a sample of 1260 African-American families, all of whom have at least one proband with schizophrenia or schizoaffective disorder. The data collection protocol includes a structured Diagnostic Interview for Genetic Studies, Family Interview for Genetic Studies, focused neurocognitive assessment, medical records review, and the collection of blood or buccal cells for genetic analyses. We have currently completed study procedures for 106 affected sib-pair, 457 case-parent trio and 23 multiplex families. A total of 289 probands have completed the best estimate final diagnosis process and 1153 probands and family members have been administered the computerized neuropsychological battery. This project lays the foundation for future analysis of cognitive and behavioral endophenotypes. This novel integration of diagnostic, neurocognitive and genetic data will also generate valuable information for future phenotypic and genetic studies of schizophrenia.

Adult↗

PubMed2006

Self-face recognition and theory of mind in patients with schizophrenia and first-degree relatives.

OBJECTIVE: The hypothesized relationship between theory of mind (ToM) and self-face recognition as well as its potential genetic associations has not been previously explored in patients with schizophrenia and in first-degree relatives with schizotypal personality traits. METHOD: Ten patients diagnosed with schizophrenia, 10 of their first-degree relatives and 10 healthy controls were included. To assess self-face recognition (SFR), participants were presented images of faces of themselves and others and asked to make rapid 'unfamiliar', 'familiar' and 'self' judgments. As a measure of ToM, subjects were administered the Revised Mind in the Eyes Test (MET [Baron-Cohen, S., Wheelwright, S., Hill, J., Raste, Y., and Plumb, I., 2001. The "Reading the Mind in the Eyes" Test revised version: a study with normal adults, and adults with Asperger syndrome or high-functioning autism. J Child Psychol Psychiatry 42(2), 241-251.]). Schizotypal characteristics in relatives and controls were assessed using a modified version of the Schizotypal Personality Questionnaire (SPQ [Raine, A., 1991. The SPQ: a scale for the assessment of schizotypal personality based on DSM-III-R criteria. Schizophrenia Bulletin 17(4), 555-564.]). RESULTS: Patients took longer and were less accurate on the SFR task than their relatives who in turn performed worse than healthy controls. Specific ToM deficits in schizophrenia were replicated. There was a relationship between accuracy rates on the MET and SFR tasks. High levels of schizotypal traits such as social anxiety, constricted affect and no close friends were important for both tasks. CONCLUSIONS: Face recognition deficits and ToM deficits in schizophrenia are apparent. The critical influence of high levels of select schizotypal traits is also highlighted. A deficit in relatives of schizophrenia patients raises the possibility that ToM and face recognition deficits may be candidate endophenotypes for schizophrenia. Support for the hypothesized link between ToM and face recognition is provided.

Adult↗

PubMed2006

The relationship between sensorimotor gating and clinical improvement in acutely ill schizophrenia patients.

It has been suggested that sensorimotor gating deficits as indexed by prepulse inhibition (PPI) of the acoustic startle reflex represent an endophenotypic marker of psychotic conditions such as schizophrenia (SCZ). This hypothesis has been questioned as several studies have found that PPI levels change with improvement in symptoms and are responsive to medications. We tested PPI in a sample of acutely decompensated schizophrenia patients who were re-tested after 2 weeks of hospital treatment. PPI was assessed at three interstimulus intervals (30, 60, and 120 ms) in 23 SCID-diagnosed SCZ patients shortly after admission to an inpatient psychiatric hospital. Eight of these patients were initially tested in a medication-free state, and all were re-tested approximately 2 weeks later after initiation or increase/change of antipsychotic medications. Symptom ratings were collected at both sessions. 20 nonpatient comparison subjects (NCS) were also tested at a 2-week interval. While SCZ patients showed lower PPI at the first session than NCS, after 2 weeks of treatment their PPI increased to levels not different than those of NCS. In contrast, the PPI of NCS remained consistent over a 2-week period. For the SCZ patients, increase in PPI was correlated with a decrease in symptom scores. Our results suggest that PPI can be improved by short-term treatment, and that improvement in sensorimotor gating is associated with treatment-related improvement of symptoms of schizophrenia.

Acoustic Stimulation↗

PubMed2004

Regulation of neocortical interneuron development and the implications for neurodevelopmental disorders.

Neurodevelopmental disorders typically have complex endophenotypes, which can include abnormalities in neuronal excitability, processing of complex information, as well as behaviors such as anxiety and social interactions. Converging experimental and clinical evidence suggests that altered interneuron development may underlie part of the pathophysiological process of such disorders. Consistent with this, mice with abnormal hepatocyte growth factor signaling exhibit disturbances in the development of specific interneuron subclasses that are paralleled by seizure activity and a complex behavioral phenotype. Mutations in molecules that regulate different aspects of interneuron development could provide the heterogeneity in genetic susceptibility that, when combined with environmental disturbances, results in a phenotypic spectrum that serves as the hallmark pathophysiology for autism, mental retardation, schizophrenia and other neurodevelopmental disorders.

Animals↗

PubMed2001

Clinical and neurochemical effect of acute tryptophan depletion in unaffected relatives of patients with bipolar affective disorder.

BACKGROUND: The lowering of mood induced by an acute tryptophan depletion (ATD) has been proposed as a candidate endophenotype for the vulnerability to manic-depressive illness. This study tests this hypothesis in relatives of probands from well-characterized multiplex families affected with bipolar affective disorder (BAD). METHODS: In a double-blind, crossover design, 20 unaffected relatives (URs) and 19 control subjects received either a 100-g amino acid (AA) drink devoid of tryptophan or a placebo, respectively. Clinical and biochemical effects of ATD were compared between unaffected relatives of BAD probands and age- and sex-matched control subjects. RESULTS: At 5 hours after AA drink ingestion, relative to the placebo, ATD resulted in 74% and 84% decreases in total plasma tryptophan concentrations in control subjects and relatives of patients with BAD, respectively. Unlike control subjects unaffected relatives experienced a lowering of mood during ATD but not with the placebo. Furthermore, URs tended to show increased impulsivity in the ATD condition. Measurements obtained before ingestion of the AA drink indicated that, relative to control subjects URs exhibited lower serotonin platelet concentrations, lower affinity, and fewer binding sites of the serotonin transporter for imipramine; these differences were unaffected by ATD. CONCLUSION: These results replicate and extend previous findings suggesting that URs of patients with BAD are more susceptible to low tryptophan availability. This finding may bear significance in the purported role of serotonergic mechanisms in the vulnerability to depressive syndrome and/or illness.

Acute Disease↗

PubMed2002

Duration mismatch negativity in biological relatives of patients with schizophrenia spectrum disorders.

BACKGROUND: One of the most consistent findings in schizophrenia research over the past decade is a reduction in the amplitude of an auditory event-related brain potential known as mismatch negativity (MMN), which is generated whenever a deviant sound occurs in a background of repetitive auditory stimulation. The reduced amplitude of MMN in schizophrenia was first observed for deviant sounds that differ in duration relative to background standard sounds, and similar findings have been observed for sounds that are deviant in frequency. The aim of this study was to determine whether first-degree relatives of schizophrenia patients show a similar reduction in MMN amplitude to duration deviants. METHODS: We measured MMN to duration increments (deviants 100 msec vs. standards 50 msec) in 22 medicated patients with a diagnosis in the schizophrenia spectrum, 17 individuals who were first-degree unaffected relatives of patients, and 21 healthy control subjects. RESULTS: Mismatch negativity amplitude was reduced in patients and relatives compared with control subjects. There were no significant differences between patients and relatives. In contrast, the subsequent positive component, P3a, was larger in relatives compared with patients. CONCLUSIONS: These findings suggest that a reduced MMN amplitude may be an endophenotype marker of the predisposition to schizophrenia.

Acoustic Stimulation↗

PubMed2002

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. The National Institute of Mental Health (NIMH) portfolios in the Genetics Research Branch and the Division of Mental Disorders, Behavioral Sciences, AIDS, and all genetics training activities were reviewed. Despite some promising leads, there are still no confirmed linkage findings for mood disorders. Impediments to gene finding include the lack of phenotypic validity, variation in ascertainment sources and methodology across studies, and genetic complexity. With respect to linkage, the committee recommended that a large-scale, integrated effort be undertaken to examine existing data from linkage and association studies of bipolar disorders using identical phenotypes and statistical methods across studies to determine whether the suggestive linkage findings at some loci can be confirmed. Confirmation would justify more intensive approaches to gene finding. The committee recommended that the NIMH support continued efforts to identify the most heritable subtypes and endophenotypes of major depression using the tools of genetic epidemiology, neuroscience, and behavioral science. The field of genetic epidemiology was identified as an important future direction because population-based, epidemiologic studies of families and unrelated affected individuals assume increasing importance for common chronic diseases. To prepare for shifts to more complex genetic models, the committee recommended that the NIMH develop new interdisciplinary training strategies to prepare for the next generation of genetics research.

Genetic Linkage↗

PubMed2003

How specific are deficits in mismatch negativity generation to schizophrenia?

BACKGROUND: Mismatch negativity (MMN) is an auditory event-related potential that provides an index of auditory sensory memory. Deficits in MMN generation have been repeatedly demonstrated in chronic schizophrenia. Their specificity to schizophrenia has not been established. METHODS: Mismatch negativity to both duration and frequency deviants was investigated in gender- and age-matched patients with schizophrenia or schizoaffective disorder (n = 26), bipolar disorder (n = 16), or major depression (n = 22) and healthy control subjects (n = 25). RESULTS: Only patients with schizophrenia demonstrated significantly smaller mean MMN than did healthy control subjects. Detailed analyses showed significantly smaller MMN to both duration and frequency deviants in patients with schizophrenia than in healthy control subjects; however, the reduction of frequency MMN in patients with schizophrenia was not significant in the comparison across all groups. Mismatch negativity topography did not differ among groups. No consistent correlations with clinical, psychopathologic, or treatment variables were observed. CONCLUSIONS: Mismatch negativity deficits, and by extension deficits in early cortical auditory information processing, appear to be specific to schizophrenia. Animal and human studies implicate dysfunctional N-methyl-D-aspartate receptor functioning in MMN deficits. Thus MMN deficits may become a useful endophenotype to investigate the genetic underpinnings of schizophrenia, particularly with regard to the N-methyl-D-aspartate receptor.

Adult↗

PubMed2003

Familial loading associates with impairment in visual span among healthy siblings of schizophrenia patients.

BACKGROUND: The effect of familial loading on neurocognitive deficits in relatives of schizophrenia patients has been detected in family and twin studies. The present study examined this effect among healthy siblings of schizophrenia patients in a Finnish isolate with high prevalence of schizophrenia. METHODS: We assessed performance in verbal and visual span tasks, in tests measuring intelligence, and in declarative verbal memory and learning tasks in 31 and 67 healthy siblings from families with one schizophrenia patient, or with two or more patients, respectively. The differences between the groups were tested using linear mixed effects models. RESULTS: An effect of familial loading was detected in the backward visual span task, measuring immediate visual memory with requirements from the visual domain of working memory. In this task, the healthy siblings from multiply affected families performed worse than those from the singleton families. CONCLUSIONS: The finding that the multiplex vs. singleton differences were selective to the backward visual span task, strengthens the view that the visual domain of working memory may provide a valuable endophenotypic marker for genetic schizophrenia studies.

Adult↗

PubMed2000

P300 subcomponent abnormalities in schizophrenia: III. Deficits In unaffected siblings of schizophrenic probands.

BACKGROUND: Reduced P300 amplitude is a robust finding in patients with schizophrenia. In previous investigations, we reported reductions of specific subcomponents of the auditory oddball P300 that were independent of acute symptomatology and persistent over time, consistent with a trait abnormality. To clarify whether these stable deficits represented genetic markers of vulnerability to schizophrenia, event-related brain potentials (ERPs) from patients were compared to those from their own healthy siblings and unrelated control subjects. METHODS: Auditory P300 ERPs were acquired from 11 schizophrenic patients, 12 healthy siblings and 23 matched control subjects. Five P300 subcomponents were identified using current source density measures: frontal, bilateral parietal, and bilateral temporal. RESULTS: Consistent with previous reports, patients had reduced parietal and frontal P300 amplitudes. The healthy siblings of the schizophrenic probands had an isolated reduction of the frontal P300. CONCLUSIONS: Frontal P300 amplitude is a potential endophenotypic marker of genetic vulnerability to schizophrenia in individuals who otherwise show no evidence of clinical symptomatology. Given the functional interpretation of the frontal P300 as a physiological correlate of cognitive orienting, this supports the hypothesis that impairments of the neural substrate underlying attentional mechanisms are selective indicators of genetic susceptibility to schizophrenia in high-risk individuals.

Adult↗

PubMedDate not supplied

Smooth pursuit and antisaccade eye movements in siblings discordant for schizophrenia.

Smooth pursuit eye movement (SPEM) and antisaccade deficits have been proposed as endophenotypes in the search for schizophrenia genes. We assessed these measures in 24 schizophrenia patients, 24 of their healthy siblings, and 24 healthy controls closely matched to the siblings. Between-group differences were assessed using a random effects regression model taking into account the relatedness between patients and siblings. Patients showed reduced SPEM gain, increased frequency of saccades during pursuit, increased antisaccade error rate, and reduced antisaccade gain compared to controls. Siblings performed intermediate, i.e. between patients and controls, on most measures, but were particularly characterised by reduced antisaccade gain. SPEM gain at one target velocity was significantly correlated between patients and siblings, highlighting the necessity of taking into account within-family correlations in the statistical analysis of between-group differences. It is concluded that subtle SPEM and antisaccade deficits are observed in clinically unaffected siblings of schizophrenia patients; these deficits may be useful markers of genetic liability to schizophrenia.

Adult↗

PubMed2001

Definition of the phenotype.

Definition of the phenotype is a key issue in designing any genetic study whose goal is to detect disease genes. This chapter describes strategies to increase the power to detect susceptibility loci for complex diseases. A narrowly defined disease phenotype can offer advantages over broad definitions. Studies of clinical disease can also benefit from judicious selection of endophenotypes and related quantitative traits for analysis. The effect of diagnostic and measurement error is also discussed; power is maximized when strategies to reduce error are incorporated into a study design.

Alleles↗

PubMed2000

Fixation stability in schizophrenia, bipolar, and control subjects.

A few investigators have suggested that visual fixation abnormalities may serve as an endophenotype of liability for schizophrenia. However, the data are equivocal. Conflicting reports regarding the specificity of fixation deficits to schizophrenia may be attributable to methodological differences. Thirty-four schizophrenia patients, 20 bipolar patients, and 30 non-patient controls were presented targets for central fixation. Fixation was scored in terms of frequency of saccades as well as qualitative ratings. Analysis of variance on the number of saccades produced during fixation revealed that the three groups did not differ. Similarly, we observed that the schizophrenia patients did not differ from either bipolar patients or controls in terms of ratings of fixation quality. It appears that schizophrenia patients are not characterized by poor visual fixation. The findings are discussed in terms of the viability of visual fixation as a marker of schizophrenic diathesis, as well as possible implications for the analysis of schizophrenia patients' visual search performance.

Adult↗

PubMed1998

Psychiatric genetics: search for phenotypes.

Failure to obtain convincing results in psychiatric genetics can partly be attributed to the fact that progress in molecular biology and genetic epidemiology has not been followed by an equivalent development in phenotypic description. Instead of relying entirely on classical nosological approaches, we argue that identifying more homogeneous forms of diseases through a'candidate symptom approach' among affected subjects and an endophenotype approach that identifies sub-clinical traits among non-affected relatives might yield better results. Examples where these strategies have already been fruitful when applied to complex diseases are presented in this review. Focusing on vulnerability traits might stimulate the redefinition of traditional psychiatric syndromes and help to bridge the gap between clinical and experimental approaches.

Animals↗

PubMed2002

The soft bipolar spectrum redefined: focus on the cyclothymic, anxious-sensitive, impulse-dyscontrol, and binge-eating connection in bipolar II and related conditions.

The bipolar II spectrum represents the most common phenotype of bipolarity. Numerous studies indicate that in clinical settings this soft spectrum might be as common--if not more common than--major depressive disorders. The proportion of depressive patients who can be classified as bipolar II further increases if the 4-day threshold for hypomania proposed by the DSM-IV is reconsidered. The modal duration of hypomanic episodes is 2 days; highly recurrent brief hypomania is as short as 1 day, and when complicated by major depression, it should be classified as a variant of bipolar II. Another variant of the bipolar II pattern is represented by major depressive episodes superimposed on cyclothymic or hyperthymic temperamental characteristics. The literature is unanimous in supporting the idea that depressed patients who experience hypomania during antidepressant treatment belong to the bipolar II spectrum. So-called alcohol- or substance-induced mood disorders may have much in common with bipolar II spectrum disorders, in particular when mood swings outlast detoxification. Finally, many patients within the bipolar II spectrum, especially when recurrence is high and the interepisodic period is not free of affective manifestations, may meet criteria for personality disorders. This is particularly true for cyclothymic bipolar II patients, who are often misclassified as borderline personality disorder because of their extreme mood instability. Subthreshold mood lability of a cyclothymic nature seems to be the common thread that links the soft bipolar spectrum. The authors submit this to represent the endophenotype likely to be informative in genetic investigations. Mood lability can be considered the core characteristics of the bipolar II spectrum, and it has been validated prospectively as a sensitive and specific predictor of bipolar II outcome in major depressives. In a more hypothetical vein, cyclothymic-anxious-sensitive temperamental disposition might represent the mediating underlying characteristic in the complex pattern of anxiety, mood, and impulsive disorders that bipolar II spectrum patients display throughout much of their lifetimes. The foregoing conclusions, based on clinical experience and the research literature, challenge several conventions in the formal classificatory system (i.e., ICD-10 and DSM-IV). The authors submit that the enlargement of classical bipolar II disorders to include a spectrum of conditions subsumed by a cyclothymic-anxious-sensitive disposition, with mood reactivity and interpersonal sensitivity, and ranging from mood, anxiety, impulse control, and eating disorders, will greatly enhance clinical practice and research endeavors. Prospective studies with the requisite methodologic sophistication are needed to clarify further the relationship of the putative temperamental and developmental variables to the complex syndromic patterns described herein. The authors believe that viewing these constructs as related entities with a common temperamental diathesis will make patients in this realm more accessible to pharmacologic and psychological approaches geared to their common temperamental attributes. The authors submit that the use of the term "spectrum" is distinct from a simple continuum of subthreshold and threshold cases. The underlying temperamental dimensions postulated by the authors define the disposition for soft bipolarity and its variation and dysregulation in anxious disorders and dyscontrol in appetitive, mental, and behavioral disorders, much beyond affective disorders in the narrow sense.

Affect↗

PubMed2000

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.

Alleles↗

PubMed2002

Introducing genetic psychophysiology.

Genetic psychophysiology examines interindividual variation in psychophysiological traits using behavioral genetic and molecular genetic techniques. It aims to delineate the pathways that lead from genomic variation to individual differences in cognitive abilities, affect regulation, and mental and physical health. This editorial provides an introduction to the twin design and gene finding strategies using psychophysiological endophenotypes. It also gives a brief outline of the papers presented in this special issue on genetic psychophysiology. Its main objective, and the objective of the entire special issue, is to interest psychophysiologists in the enormous potential of research in this area and to foster the development of collaborative relationships between psychophysiologists and molecular and behavioral geneticists that are necessary to move research in this area forward.

Animals↗