PubMed Health⌕ Search

Biomedical subjects

Irving I Gottesman

Publications and source records attributed to Irving I Gottesman.

At least 19 recordsLinked to original sources
PubMed2006

Marriage and genetic variation across the lifespan: not a steady relationship?

The prevalence of marriage varies across the lifespan, as does its importance to reproduction and the nurturance of children. We examined genetic and environmental influences on self-reported marriage at each decade from 20 through 70 years of age, using data collected for the Duke Dementia Study, a followed-up subset of the World War II Veteran Twin Registry. Genetic influences best fit a common factor model, supplemented by another, age-specific, genetic factor at age 30. Broad heritability increased from age 20 through 40, and then decreased to zero by ages 60 and 70. A longitudinal Cholesky model best described environmental influences on marriage across the lifespan. Shared environmental factors showed their greatest influence at age 20, no influence at 30 or 40 years, and then, reappeared with influence at 60 and 70. Variance due to error and unique environmental influences increased steadily to age 50 years and then declined slightly.

Emotions↗
PubMed2006

Deconstructing schizophrenia: an overview of the use of endophenotypes in order to understand a complex disorder.

The genetics of schizophrenia has been approached utilizing a variety of methods. One emerging strategy is the use of endophenotypes in order to understand and identify the functional importance of genetically transmitted, brain-based deficits across schizophrenia kindreds. The endophenotype strategy is a topic of this issue of Schizophrenia Bulletin. Endophenotypes are quantitative, heritable, trait-related deficits typically assessed by laboratory-based methods rather than clinical observation. Endophenotypes are seen as closer to genetic variation than are clinical symptoms of schizophrenia, and are therefore closely linked to heritable risk factors. There has been a broad expansion of opportunities available to psychiatric neuroscientists who use the endophenotype strategy to understand the genetic basis of schizophrenia. In this context, genetic variation such as single nucleotide polymorphisms (SNPs) induces abnormalities in endophenotypic domains such as neurocognition, neurodevelopment, metabolism, and neurophysiology. This article discusses the challenges that abound in genetic research of schizophrenia, including issues in ascertainment, epistasis, ethnic diversity, and the potentially normalizing effects of second-generation antipsychotic medications on neurocognitive and neurophysiological measures. Robust strategies for meeting these challenges are discussed in this review and the subsequent articles in this issue. This article summarizes conceptual advances and progress in the measurement and use of endophenotypes in schizophrenia that form the basis of the multisite National Institute of Mental Health Consortium on the Genetics of Schizophrenia. The endophenotype strategy offers powerful and exciting opportunities to understand the genetically conferred neurobiological vulnerabilities and possible new strong inference and molecularly based treatments for schizophrenia.

Antipsychotic Agents↗
PubMed2006

Reconciling disparate prevalence rates of PTSD in large samples of US male Vietnam veterans and their controls.

BACKGROUND: Two large independent studies funded by the US government have assessed the impact of the Vietnam War on the prevalence of PTSD in US veterans. The National Vietnam Veterans Readjustment Study (NVVRS) estimated the current PTSD prevalence to be 15.2% while the Vietnam Experience Study (VES) estimated the prevalence to be 2.2%. We compared alternative criteria for estimating the prevalence of PTSD using the NVVRS and VES public use data sets collected more than 10 years after the United States withdrew troops from Vietnam. METHODS: We applied uniform diagnostic procedures to the male veterans from the NVVRS and VES to estimate PTSD prevalences based on varying criteria including one-month and lifetime prevalence estimates, combat and non-combat prevalence estimates, and prevalence estimates using both single and multiple indicator models. RESULTS: Using a narrow and specific set of criteria, we derived current prevalence estimates for combat-related PTSD of 2.5% and 2.9% for the VES and the NVVRS, respectively. Using a more broad and sensitive set of criteria, we derived current prevalence estimates for combat-related PTSD of 12.2% and 15.8% for the VES and NVVRS, respectively. CONCLUSION: When comparable methods were applied to available data we reconciled disparate results and estimated similar current prevalences for both narrow and broad definitions of combat-related diagnoses of PTSD.

Case-Control Studies↗
PubMed2006

Toward constructing an endophenotype strategy for bipolar disorders.

Research aimed at elucidating the underlying neurobiology and genetics of bipolar disorder, and factors associated with treatment response, have been limited by a heterogeneous clinical phenotype and lack of knowledge about its underlying diathesis. We used a survey of clinical, epidemiological, neurobiological, and genetic studies to select and evaluate candidate endophenotypes for bipolar disorder. Numerous findings regarding brain function, brain structure, and response to pharmacological challenge in bipolar patients and their relatives deserve further investigation. Candidate brain function endophenotypes include attention deficits, deficits in verbal learning and memory, cognitive deficits after tryptophan depletion, circadian rhythm instability, and dysmodulation of motivation and reward. We selected reduced anterior cingulate volume and early-onset white matter abnormalities as candidate brain structure endophenotypes. Symptom provocation endophenotypes might be based on bipolar patients' sensitivity to sleep deprivation, psychostimulants, and cholinergic drugs. Phenotypic heterogeneity is a major impediment to the elucidation of the neurobiology and genetics of bipolar disorder. We present a strategy constructed to improve the phenotypic definition of bipolar disorder by elucidating candidate endophenotypes. Studies to evaluate candidate endophenotypes with respect to specificity, heritability, temporal stability, and prevalence in unaffected relatives are encouraged.

Bipolar Disorder↗
PubMed2005

Phenotypic differences in genetically identical organisms: the epigenetic perspective.

Human monozygotic twins and other genetically identical organisms are almost always strikingly similar in appearance, yet they are often discordant for important phenotypes including complex diseases. Such variation among organisms with virtually identical chromosomal DNA sequences has largely been attributed to the effects of environment. Environmental factors can have a strong effect on some phenotypes, but evidence from both animal and human experiments suggests that the impact of environment has been overstated and that our views on the causes of phenotypic differences in genetically identical organisms require revision. New theoretical and experimental opportunities arise if epigenetic factors are considered as part of the molecular control of phenotype. Epigenetic mechanisms may explain paradoxical findings in twin and inbred animal studies when phenotypic differences occur in the absence of observable environmental differences and also when environmental differences do not significantly increase the degree of phenotypic variation.

Animals↗
PubMed2005

The Washington University Twin Study of alcoholism.

Genetic contributions to the liability to develop alcoholism in males of Northern and Western European ancestry are well-established. However, questions remain concerning the role of genetic variation in the etiology of alcoholism among non-white populations, among women, and the possibility of etiological heterogeneity in subtypes of alcoholism. The answers to these questions are needed to help define phenotypes for molecular genetic studies searching for QTLs for alcoholism. Twins from 295 pairs were consecutively ascertained at inpatient and outpatient psychiatric and alcohol treatment facilities in St. Louis, MO in 1981-1986. Probands and willing cotwins were evaluated by structured psychiatric interviews, psychometric assessment, and lifetime treatment records. One hundred fifty-four probands met criteria for alcohol abuse/dependence (AAD), including twins from 45 MZ, 50 same-sex DZ, and 59 opposite-sex pairs. Twin-pair resemblance was evaluated for AAD and alcohol dependence (AD), as well as for subsets defined by gender, patterns of comorbidity, ethnic background, and clinical features. Among males, heritability of AAD and AD was substantial, with little evidence for common environmental contributions to family resemblance. Pair resemblance among females was also substantial, but similar for MZ and DZ pairs, yielding near-zero heritability estimates. However, based on these sample sizes, the sex differences were not statistically significant. The results confirm prior studies of strong genetic influences on alcoholism in males, but suggest lower genetic influence in females. Power to test other sources of heterogeneity was limited, but the results suggest no evidence for higher heritability for male early onset alcoholism or for alcoholism with comorbid antisocial personality.

Adolescent↗
PubMed2005

Theories of schizophrenia: a genetic-inflammatory-vascular synthesis.

BACKGROUND: Schizophrenia, a relatively common psychiatric syndrome, affects virtually all brain functions yet has eluded explanation for more than 100 years. Whether by developmental and/or degenerative processes, abnormalities of neurons and their synaptic connections have been the recent focus of attention. However, our inability to fathom the pathophysiology of schizophrenia forces us to challenge our theoretical models and beliefs. A search for a more satisfying model to explain aspects of schizophrenia uncovers clues pointing to genetically mediated CNS microvascular inflammatory disease. DISCUSSION: A vascular component to a theory of schizophrenia posits that the physiologic abnormalities leading to illness involve disruption of the exquisitely precise regulation of the delivery of energy and oxygen required for normal brain function. The theory further proposes that abnormalities of CNS metabolism arise because genetically modulated inflammatory reactions damage the microvascular system of the brain in reaction to environmental agents, including infections, hypoxia, and physical trauma. Damage may accumulate with repeated exposure to triggering agents resulting in exacerbation and deterioration, or healing with their removal. There are clear examples of genetic polymorphisms in inflammatory regulators leading to exaggerated inflammatory responses. There is also ample evidence that inflammatory vascular disease of the brain can lead to psychosis, often waxing and waning, and exhibiting a fluctuating course, as seen in schizophrenia. Disturbances of CNS blood flow have repeatedly been observed in people with schizophrenia using old and new technologies. To account for the myriad of behavioral and other curious findings in schizophrenia such as minor physical anomalies, or reported decreased rates of rheumatoid arthritis and highly visible nail fold capillaries, we would have to evoke a process that is systemic such as the vascular and immune/inflammatory systems. SUMMARY: A vascular-inflammatory theory of schizophrenia brings together environmental and genetic factors in a way that can explain the diversity of symptoms and outcomes observed. If these ideas are confirmed, they would lead in new directions for treatments or preventions by avoiding inducers of inflammation or by way of inflammatory modulating agents, thus preventing exaggerated inflammation and consequent triggering of a psychotic episode in genetically predisposed persons.

Animals↗
PubMed2005

MMPI vulnerability indicators for schizophrenia and attention deficit disorder: UCLA family study of biological parents of offspring with childhood-onset schizophrenia or ADHD.

Minnesota Multiphasic Personality Inventory (MMPI) scores were examined for 50 parents of children with an onset of schizophrenia prior to 14 years of age, 153 parents of children with attention deficit hyperactivity disorder (ADHD), and 168 parents of community comparison children. The parents were participants in the UCLA Family Study. The mean scores on all standard MMPI scales were within normal limits for all three groups of participants. Parents of schizophrenia probands were significantly higher on scale Sc than parents of community comparison children. Previous research has shown that scale Sc may be associated with a genetic liability to developing schizophrenia. Thus, scale Sc shows promise as an indicator of a heightened risk for the development of schizophrenia. The parents of the ADHD probands were significantly higher on standard clinical scale Pd than community comparison parents. Mothers of both schizophrenia and ADHD probands shared some personality indicators of stress reactivity. Although this study, like all non-adoptee family studies, cannot disentangle genetic effects on the development of these personality characteristics from environmental effects, we speculate that the emotional distress resulting in higher levels of the MMPI characteristics seen in the patients' mothers reflects the impact of raising a psychiatrically ill offspring.

Adult↗
PubMed2005

Deconstructing, reconstructing, preserving Paul E. Meehl's legacy of construct validity.

The question of the status of cause-and-effect explanations of human behavior that posit physically existing causative factors and those that, on the other hand, posit hypothetical entities in the form of "useful fictions" has a long history. The influence of the works of Jeremy Bentham and Hans Vaihinger, as well as the later influence of Francis Galton, is described. Issues of the validity of hypothetical constructs and related problems of measurement and definition as found in psychoanalytic theory construction and in trait theory are examined. The significant and continuing interest generated by the landmark studies of K. MacCorquodale and P. E. Meehl (1948) and L. J. Cronbach and P. E. Meehl (1955) as well as the central importance of P. E. Meehl's thinking are described.

Humans↗
PubMed2005

Human development: biological and genetic processes.

Adaptation is a central organizing principle throughout biology, whether we are studying species, populations, or individuals. Adaptation in biological systems occurs in response to molar and molecular environments. Thus, we would predict that genetic systems and nervous systems would be dynamic (cybernetic) in contrast to previous conceptualizations with genes and brains fixed in form and function. Questions of nature versus nurture are meaningless, and we must turn to epigenetics--the way in which biology and experience work together to enhance adaptation throughout thick and thin. Defining endophenotypes--road markers that bring us closer to the biological origins of the developmental journey--facilitates our understanding of adaptive or maladaptive processes. For human behavioral disorders such as schizophrenia and autism, the inherent plasticity of the nervous system requires a systems approach to incorporate all of the myriad epigenetic factors that can influence such outcomes.

Adaptation, Psychological↗
PubMed2004

Glial fibrillary acidic protein is reduced in cerebellum of subjects with major depression, but not schizophrenia.

Glial fibrillary acidic protein (GFAP) is a major protein of astrocyte intermediate filaments and a specific marker for astrocytes. Alterations in levels of GFAP may reflect pathological regulation of neuronal function and survival as well as abnormal synaptogenesis and neurotransmission. We employed quantitative gel electrophoresis and Western blotting to measure levels of GFAP in cerebella of 60 subjects divided equally among schizophrenia, bipolar disorder, major depression, and normal controls. GFAP levels were reduced by 32%, 17% and 14.5% in depressed, bipolar, and schizophrenic cerebella, respectively, versus controls. Only the depressed value was significantly different (p=0.015 Post-hoc Bonferroni test). Measurement of beta-actin levels showed no differences between the various groups. No significant effects of confounding variables were found. This is the first demonstration of GFAP reductions in cerebellum of subjects with mood disorders and schizophrenia, thereby adding to the reports of reductions in GFAP/glial cell counts in other brain regions of subjects with major depression, thus suggesting a downregulation of glial function in this disorder.

Adult↗
PubMed2004

Evaluation of familial influences on the course and severity of schizophrenia among US and Indian cases.

BACKGROUND: Prior studies suggest familial (possibly genetic) influences on the course of schizophrenia. AIMS: The aim of this study was to compare familial influences on the course and severity of schizophrenia in two independent samples. METHOD: Thirteen selected measures were compared among affected sibling pairs (ASPs) from Pittsburgh, USA and New Delhi, India (48 US pairs, 53 Indian pairs). For each ASP proband, an unrelated patient was selected randomly from a suitable pool of cases ascertained in the same study (Sibpair proband-comparison case or S-C pairs). Correlations between these pairs were compared. RESULTS: The correlations varied by item and by site. Significant correlations for longitudinal course and pattern of severity were noted among the ASPs from USA, but did not remain significant following corrections for multiple comparisons. Comparisons between the correlations for ASPs and the S-C pairs, used to estimate familial effects, yielded trends for the ASP correlations to be numerically larger than the S-C correlations in both samples. Separate cross-site comparisons revealed several significant differences with regard to several demographic and clinical variables. The possible impact of the cross-site variations on the observed ASP correlations is discussed. CONCLUSIONS: Though familial factors did not appear to have a significant impact on course/severity using this novel design, the suggestive trends need to be examined in larger samples.

Adult↗
PubMed2003

Signal transduction and genes-to-behaviors pathways in psychiatric diseases.

Although psychiatric diseases are among the most common and destructive of all human illnesses, the molecular and cellular mechanisms underlying their complex origins remain to be elucidated. Dysfunction of critical intracellular signaling pathways is very likely to be involved. This conclusion is based on a number of observations, including the short- and long-term cellular effects of psychiatric drugs; the critical role signaling pathways play in neurotransmitter, neuropeptide, and neurohormone communication; and the fact that signaling pathways are principle regulators of the diverse array of behavioral symptoms experienced by patients. The genomics era has brought to psychiatry an abundance of genetic linkage and candidate gene findings. The difficult task--now under way--is to discern the functional relevance of these results. Recent evidence suggests the involvement of the ubiquitous protein phosphatase 2B (calcineurin), a critical regulator of many signal transduction pathways, as a schizophrenia susceptibility gene. It is likely that genetic findings in severe psychiatric disorders will continue to implicate direct and indirect modulation of critical intracellular signaling pathways.

Animals↗
PubMed2003

The Schizophrenia Proneness (SzP) scale: an MMPI-2 measure of schizophrenia liability.

We examined the psychometric properties and construct validity for a Minnesota Multiphasic Personality Inventory-2 Schizophrenia Proneness (SzP) scale (Bolinskey et al., 2001) and provided normative statistics. Premorbid participants were offspring of parents with schizophrenia-related illness (SRI), with comparison groups of offspring of parents with major affective disorders and offspring of normals. Postmorbid participants were twins affected with SRI; their unaffected relatives served as a comparison group. Results suggest that an SzP T score of 65 or above is an effective indicator of personality processes associated with increased liability to developing SRI.

Adult↗
PubMed2003

Socioeconomic status modifies heritability of IQ in young children.

Scores on the Wechsler Intelligence Scale for Children were analyzed in a sample of 7-year-old twins from the National Collaborative Perinatal Project. A substantial proportion of the twins were raised in families living near or below the poverty level. Biometric analyses were conducted using models allowing for components attributable to the additive effects of genotype, shared environment, and nonshared environment to interact with socioeconomic status (SES) measured as a continuous variable. Results demonstrate that the proportions of IQ variance attributable to genes and environment vary nonlinearly with SES. The models suggest that in impoverished families, 60% of the variance in IQ is accounted for by the shared environment, and the contribution of genes is close to zero; in affluent families, the result is almost exactly the reverse.

Biometry↗