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Biomedical subjects

Ming T Tsuang

Publications and source records attributed to Ming T Tsuang.

At least 55 records · Page 3Linked to original sources
PubMed2005

Heritability of word recognition in middle-aged men varies as a function of parental education.

Although it is of lifelong importance, reading ability is studied primarily in children and adolescents. We examined variation in word recognition in 347 middle-aged male twin pairs. Overall heritability (a2) was 0.45, and shared environmental influences (c2) were 0.28. However, parental education moderated heritability such that a2 was 0.21 at the lowest parental education level and 0.69 at the highest level; c2 was 0.52 and 0.00, respectively. This constitutes a parental education x environment interaction. The higher heritability was due to a decrease in the magnitude of shared environmental factors, rather than an increase in the magnitude of genetic factors. Other cognitive studies have reported gene x environment interactions, but patterns may differ as a function of age or specific cognitive abilities. Our results suggest that shared environmental factors in families with low parental education have long-lasting effects on word recognition ability, well beyond any critical period for developing reading proficiency.

Cognition↗
PubMed2005

The application of a random effects model to censored twin data.

The authors propose a random effects model to analyze the latent genetic and environmental effects on determining censored outcomes in twin studies. In this model, six normally distributed random effects are used to describe the correlation within twin pairs. The authors employ a Monte Carlo Expectation-Maximization approach for obtaining maximum likelihood estimates of fixed effects and the variances of random effects. The variances of the random effects are reparameterized to be equivalent to genetic and environmental effects in traditional twin models. The authors illustrate this model using data from the Vietnam Era Twin Registry to explore the magnitude of the genetic influence on twin similarity for the age of onset of alcohol abuse. Our results show genetic factors contribute about one third of twin similarity in the age of onset of alcohol abuse in male twins. The application of this model to twin data is discussed.

Humans↗
PubMed2005

Sex differences in prefrontal cortical brain activity during fMRI of auditory verbal working memory.

Functional imaging studies of sex effects in working memory (WMEM) are few, despite significant normal sex differences in brain regions implicated in WMEM. This functional MRI (fMRI) study tested for sex effects in an auditory verbal WMEM task in prefrontal, parietal, cingulate, and insula regions. Fourteen healthy, right-handed community subjects were comparable between the sexes, including on WMEM performance. Per statistical parametric mapping, women exhibited greater signal intensity changes in middle, inferior, and orbital prefrontal cortices than men (corrected for multiple comparisons). A test of mixed-sex groups, comparable on performance, showed no significant differences in the hypothesized regions, providing evidence for discriminant validity for significant sex differences. The findings suggest that combining men and women in fMRI studies of cognition may obscure or bias results.

Acoustic Stimulation↗
PubMed2005

Searching for the liability to schizophrenia: concepts and methods underlying genetic high-risk studies of adolescents.

Conceptualizations of the liability for schizophrenia help guide the development of research protocols, which, in turn, provide empirical confirmations or disconfirmations of the conceptualization's tenets. This paper focuses on a conception of liability and its relationships to genetic adolescent high-risk studies. Specifically, the derivation and nature of a proposed multidimensional syndrome of liability to schizophrenia ("schizotaxia") are outlined, followed by a representative review of features reported in previous high-risk studies that may be related to schizotaxia, and a perspective on future high-risk investigations. Overall, genetic high-risk studies generally confirm the concept of liability in the offspring of parents with schizophrenia, as expressed by deficits or abnormalities in multiple dimensions. It is concluded that high-risk studies on the liability to schizophrenia provide an important tool with which to explore the etiology and development of schizophrenia, in part by contributing to the identification and validation of specific liability syndromes.

Adolescent↗
PubMed2005

Heritability of SF-36 among middle-age, middle-class, male-male twins.

OBJECTIVE: We sought to examine the relative importance of genetic and environmental factors for the MOS SF-36; a widely used, valid, and reliable measure of health-related quality of life and to discuss incorporating genetic influences into health services research. DATA SOURCES: Data are from a nationally distributed, nonclinical cohort of 2928 middle age, middle-class, male-male twin members of the Vietnam Era Twin Registry. STUDY DESIGN: This was a secondary data analysis, classic twin heritability analysis. DATA COLLECTION: A telephone survey was used to collect information on alcohol-related problems and health services use, including the SF-36. PRINCIPAL FINDINGS: Variance component analyses indicated that additive genetic factors accounted for 17% to 33% of the variance for each of the 8 domains of the SF-36. Shared environment accounted for 0% to 12% of the variance for each domain, with the majority of variance for each domain accounted for by nonshared, or unique environment and error. Physical and mental health summary measures indicated that approximately one-third of the variance was accounted for by additive genetic factors and the remainder accounted for by nonshared environment and error. Clinical condition, history of alcohol dependence, had a small-but-significant influence for all domains. Including condition proved to be a better-fitting model. However, confidence intervals temper uniform statistical significance for genetic factors. CONCLUSIONS: This study assessed the heritability of the SF-36 in a nonclinical, community sample of middle age, middle-class all-male twins. The moderate genetic effects on SF-36 domain and summary measures are new findings and thus may affect interpretations of SF-36 as a measure of health-related quality of life. Ideally, trait-based measures should identify genetic sources of variation and thus help understand any bias of the true effects of SF-36. Still the majority of variance is accounted for by nonshared or unique environmental factors and error. By extension, increased understanding of the importance of genetic and environmental factors that influence either predictors or outcomes of interest will expand the level of scientific debate in health services research and improve predictability.

Adult↗
PubMed2004

Heterogeneity of schizophrenia: a study of individual neuropsychological profiles.

Based on a strategy developed by Seidman et al. (Seidman, L.J., Faraone, S.V., Kremen, W.S., Pepple, J.R., Lyons, M.J., Tsuang, M.T., 1993. Neuropsychological dysfunctions in the non-psychotic first-degree relatives of schizophrenic patients, Poster presented at the annual meeting of the Society for Research and Psychopathology. Chicago, IL) we examined neuropsychological heterogeneity in schizophrenia using clinical neuropsychological descriptions of individual cases as the starting point. We blindly rated neuropsychological profiles of 74 schizophrenia patients and 91 normal controls based primarily on prototypes from the clinical literature in neuropsychology. Patients were classified as having the following profile types: within normal limits (WNL) (23%, n=17), frontal/abstraction (46%, n=34), widespread/diffuse (14%, n=10), left temporal/verbal memory (8%, n=6) and other (9%, n=7). As expected based on our classification scheme, the groups had different profile shapes (group x function interactions). They were also significantly different from one another in terms of overall severity (main effects); however, severity differences were not inherent in the definition of all groups. Longer duration of illness and greater overall cognitive impairment were observed as one went from the left temporal to the frontal to the widespread groups. Longitudinal studies are needed to determine whether the different neuropsychological profiles reflect true subgroup differences or within-person change over time. Further research-probably including neuroimaging and genetic studies-will also be needed to determine the validity and the utility of this strategy for identifying neuropsychological profile types.

Adult↗
PubMed2004

The retrospective measurement of prenatal and perinatal events: accuracy of maternal recall.

Adverse obstetric events have been implicated as risk factors for schizophrenia. Many studies have relied on retrospective recall of these events, given typical adult onset of schizophrenia, when most studies ascertain their samples. The goal of this study was to assess the validity of an interview for the long-term recall of prenatal and perinatal events. Ninety-six women from the Providence and Boston cohorts of the National Collaborative Perinatal Project were administered a brief structured telephone interview regarding their recall of pregnancy-related events that had occurred 22 years or more prior to interview. Women accurately reported major medical events such as cesarean section, breech delivery, and multiple birth (kappa=1) and demographic items, such as age at birth and parity. Medical interventions and major medical conditions such as placental (kappa=-0.01) and cord (kappa=-0.10) difficulties were not accurately reported. Estimated birthweight, low birthweight, and length of gestation were recalled with reasonable accuracy. Women who completed high school generally recalled events more accurately than those who did not. It is therefore important to attend to the sources of information, the mode of interviewing, the specific type of event, and sociodemographic characteristics of the informant to improve the accuracy of retrospective data on obstetric events, and to increase the validity of findings relating these to the onset of schizophrenia.

Adolescent↗
PubMed2004

Decreased absolute amygdala volume in cocaine addicts.

The amygdala is instrumental to a set of brain processes that lead to cocaine consumption, including those that mediate reward and drug craving. This study examined the volumes of the amygdala and hippocampus in cocaine-addicted subjects and matched healthy controls and determined that the amygdala but not the hippocampus was significantly reduced in volume. The right-left amygdala asymmetry in control subjects was absent in the cocaine addicts. Topological analysis of amygdala isosurfaces (population averages) revealed that the isosurface of the cocaine-dependent group undercut the anterior and superior surfaces of the control group, implicating a difference in the corticomedial and basolateral nuclei. In cocaine addicts, amygdala volume did not correlate with any measure of cocaine use. The amygdala symmetry coefficient did correlate with baseline but not cocaine-primed craving. These findings argue for a condition that predisposes the individual to cocaine dependence by affecting the amygdala, or a primary event early in the course of cocaine use.

Adult↗
PubMed2004

DRD2 -141C insertion/deletion polymorphism is not associated with schizophrenia: results of a meta-analysis.

The gene DRD2, which codes for dopamine receptor D2, has been considered a prime candidate for allelic association testing with schizophrenia based on the strong evidence for involvement of this protein in disease pathophysiology. Recent meta-analyses confirmed a small but reliable association between schizophrenia and the cysteine-coding allele of the Cys311Ser polymorphism of DRD2. In the present study, we sought to determine if another polymorphism (the -141C insertion/deletion) in the same gene, which has been reported to be associated with schizophrenia in several individual studies, would show a similar pattern of association with the disease in a pooled dataset. The pooled odds ratio for the insertion allele obtained from 10 case-control studies was 1.1, which was not significant (P = 0.580); however, there was marked heterogeneity among the findings of individual studies, suggesting that some underlying factor influenced the size of their observed effects. Yet, neither ethnicity, the age of the control group, nor the gender composition of the samples reliably influenced effect size. Because linkage disequilibrium patterns between various DRD2 polymorphisms are not yet known, it remains possible that divergent meta-analytic findings at both commonly examined mutation sites within DRD2 are accurate. Haplotype analysis within this gene would be useful for definitively specifying the role of this gene in the etiology of schizophrenia.

Humans↗
PubMed2004

Evidence for linkage between regulatory enzymes in glycolysis and schizophrenia in a multiplex sample.

Observations of impaired glucose regulation in schizophrenia are long-standing, although their pathological and etiological significance is uncertain. One approach to the issue that minimizes environmental variables (e.g., medication and diet) is to determine whether genes related to glucose regulation show genetic linkage to schizophrenia. We examined the potential role of glucose metabolism in schizophrenia through a genome scan of affection status in schizophrenia and an empirical method for deriving P-values. Data were utilized from the NIMH Genetics Initiative for Schizophrenia dataset, which comprises a total sample consisting of 71 pedigrees containing 218 nuclear families and 987 individuals. A genome scan with 459 markers spaced at an average of 10 cM intervals was conducted using the linkage analysis program Genehunter separately for European- and African-American groups. Enzymes that regulate glycolysis were identified and the genes regulating these enzymes were located through the Online Mendelian Inheritance in Man (OMIM) website. The focus in this study was on genes located near previously reported schizophrenia susceptibility regions. The genome-wide significance of these genes to schizophrenia was assessed using permutation testing. When results were adjusted for multiple testing within and across ethnic groups, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2 (PFKFB2; chromosome 1q32.2) achieved genome-wide significance (P = 0.04). In addition, hexokinase 3 (HK3; chromosome 5q35.3) was also suggestive of linkage (P = 0.09). For the European-American sample, PFKFB2 (1q32.2), hexokinase 3 (HK3; 5q35.3), and pyruvate kinase 3 (PK3; chromosome 15q23) achieved significance at the 0.05 level. None of the genes showed significance in the African-American sample. Our results provide further support for the view that genes that regulate glucose metabolism may also influence susceptibility to schizophrenia. More generally, they support the view that relationships between glucose dysregulation and schizophrenia are inherent to the disorder, and are not merely epiphenomena related to medication or other treatment factors.

Black or African American↗
PubMed2004

Methylomics in psychiatry: Modulation of gene-environment interactions may be through DNA methylation.

Fine-tuning of neuronal connections during development is regulated through environmental interactions. Some fine-tuning occurs through changes in gene expression and/or epigenetic gene-specific DNA methylation states. DNA methylation occurs by transfer of a methyl group from S-adenosyl methionine to cytosine residues in the dinucleotide sequence CpG. Although CpG sequences spread throughout the genome are usually heavily methylated, those occurring in CpG islands in the promoter regions of genes are less methylated. In most cases, the extent of DNA methylation correlates with the extent of gene inactivation. Other known epigenetic mechanisms include histone deacetylation and chromatin remodeling, RNA inhibition, RNA modification, and DNA rearrangement. Exposure memory expressed as epigenetic DNA modifications allows genomic plasticity and short-term adaptation of each generation to their environment. Environmental factors that affect DNA methylation include diet, proteins, drugs, and hormones. Induced methylation changes may produce altered gene response upon subsequent hormonal stimulation. The gene-specific DNA methylation state may be preserved upon transmission through mitosis and meiosis. An increasing amount of data implicates a role for DNA methylation in multi-factorial psychiatric disorders. For example, L-methionine treatment can exacerbate psychosis; while valproate, a drug producing hypomethylated DNA, reduces such symptoms. Hypermethylation of the promoter region of the RELN gene correlates with reduced gene expression. This gene's protein Reelin, which is necessary for neuronal migration and synaptogenesis, is reduced in schizophrenia and bipolar disorder, suggesting hypermethylation of the promoter region in these disorders. Some evidence implicates methylation of the promoter regions of the DRD2 and HTR2A genes in schizophrenia and mood disorders as well. DNA methylation usually increases with age, although hypomethylation of the promoter region of the amyloid A4 precursor gene during aging may play a role in Alzheimer's disease. More studies are needed to define the role of methylomics and other epigenetic phenomena in the nervous system.

CpG Islands↗
PubMed2004

Functional magnetic resonance imaging during auditory verbal working memory in nonpsychotic relatives of persons with schizophrenia: a pilot study.

BACKGROUND: First-degree relatives of persons with schizophrenia carry elevated genetic risk for the illness and show deficits on high-load information processing tasks. We used functional magnetic resonance imaging (fMRI) to test whether nonpsychotic relatives show altered functional activation in the prefrontal cortex (PFC), thalamus, hippocampus, and anterior cingulate during a working memory task requiring interference resolution. METHODS: Twelve nonpsychotic relatives of persons with schizophrenia and 12 healthy control subjects were administered an auditory, verbal working memory version of the Continuous Performance Test during fMRI. An asymmetric, spin-echo, T2*-weighted sequence (15 contiguous, 7-mm axial slices) was acquired on a full-body MR scanner. Data were analyzed by Statistical Parametric Mapping (SPM). RESULTS: Compared with control subjects, relatives showed greater task-elicited activation in the PFC and the anterior and dorsomedial thalamus. When task performance was controlled, relatives showed significantly greater activation in the anterior cingulate. When effects of other potentially confounding variables were controlled, relatives generally showed significantly greater activation in the dorsomedial thalamus and anterior cingulate. CONCLUSIONS: This pilot study suggests that relatives of persons with schizophrenia have subtle differences in brain function in the absence of psychosis. These differences add to the growing literature identifying neurobiological vulnerabilities to schizophrenia.

Adult↗
PubMed2004

Meta-analysis of association between the T102C polymorphism of the 5HT2a receptor gene and schizophrenia.

A meta-analysis of whole-genome linkage scans confirmed linkage between schizophrenia and markers on the long arm of chromosome 13. The gene HTR2A, which codes for the 5HT2a receptor, is located in this area. The T102C single nucleotide polymorphism of HTR2A has been the subject of much research. The production of the C-allele form of HTR2A is significantly less than that of the T-allele form in normal controls and schizophrenic patients. Although the association of schizophrenia with the C allele of HTR2A was confirmed by a meta-analysis 5 years ago, there was a continuous debate because negative findings were also considerable, which may have been due to ethnic differences in association. We performed another meta-analysis, since the number of available studies of this association has recently doubled. In the meta-analysis of 31 case-control association studies, we found a significant association between the C allele of the T102C polymorphism and schizophrenia, which was more pronounced in European samples than in the entire sample. We found significant heterogeneity in the allele-wise analysis (C vs. T) and homozygous genotype-wise analysis (CC vs. TT), both of which were at least partially explained by differences between samples from Asian and European countries. In East Asian countries, there was not a significant association with the C allele or CC homozygosity, indicating strong genetic differences and noncombinability of data between European and East Asian populations. Interestingly, the frequency of the T allele was much higher in East Asian patients and controls (59.5% and 57.5%, respectively) than in European patients and controls (40% and 43.5%, respectively). In five family-based association studies, we did not find significant evidence for association of the C allele with schizophrenia; yet, the pooled OR was 1.3 (95% CI=0.9-1.8, z=1.47, p=0.14), which is consistent with the results of the case-control studies. The effects of other genes, environmental effects on DNA methylation, or different methods of classification may be the causes for such heterogeneity, but more study in this area is needed.

Gene Expression↗
PubMed2004

Genetic and environmental contributions to the development of alcohol dependence in male twins.

BACKGROUND: Information on the heritability of the development of alcohol dependence could provide a better understanding of the importance of genetic components in disease transition. OBJECTIVE: To examine the genetic and nongenetic contributions to the age at onset of regular alcohol use, the age at diagnosis of alcohol dependence, and the transition from regular alcohol use to alcohol dependence. DESIGN: Classic twin study. SETTING: General community. PARTICIPANTS: This study included 3372 twin pairs of known zygosity from the Vietnam Era Twin Registry. The diagnosis of DSM-III-R-defined alcohol dependence and related information were obtained through telephone-administered interviews conducted in 1992. MAIN OUTCOME MEASURES: Standardized proportions due to genetic vs nongenetic factors of the total variation in twin resemblance on the age at onset of regular alcohol use, the age at meeting criteria for a diagnosis of alcohol dependence, and the transition period from regular alcohol use to a diagnosis of alcohol dependence. RESULTS: Genetic influence accounted for 49% of the variation in the age at diagnosis of alcohol dependence. After adjusting for co-occurring psychiatric diseases, additive genetic factors still explained more than 37% of the variance in age at onset of alcohol dependence and at least 25% of the variance in the transition period between regular drinking and the diagnosis of alcohol dependence. Additionally, after grouping participants as early and late regular users of alcohol, the genetic effects on the transition period for early regular users were statistically significantly greater than those for late regular users. CONCLUSION: Our results demonstrate a substantial heritable basis for alcohol dependence according to its developmental sequence, including age at onset of regular use, age at diagnosis, and the transition period between regular use and diagnosis.

Adult↗
PubMed2004

A genome-wide scan of symptom dimensions in bipolar disorder pedigrees of adult probands.

Although twin and adoption show bipolar disorder (BP) has a strong genetic component, few chromosomal regions have been consistently implicated by molecular genetic studies. To address this issue, we sought to determine if quantitative dimensions of bipolar disorder symptoms would be useful for detecting genes that underlie the susceptibility to bipolar disorder. Subjects were 520 individuals diagnosed with bipolar I, bipolar II or schizoaffective disorder, bipolar type who had participated in the NIMH genetics initiative for bipolar disorder. We constructed symptom scores from 29 psychiatric symptoms recorded in the Diagnostic Interview for Genetic Studies (DIGS). Principal components factor analysis followed by a varimax rotation was used to extract symptom dimensions. Factor scores were calculated for all genotyped individuals in the sample, regardless of affection status. Heritable factors were used in a variance-components linkage analysis, which utilized the exact likelihoods of allele-sharing identical-by-descent for each pair of relatives within each pedigree. The principal components factor analysis resulted in five independent dimensions: depressed state, psychosis, sleep disturbances, psychomotor acceleration, and irritability. Two factors were significantly heritable: depression (h2=0.53, p<0.001) and irritable vs. euphoric mania (h2=0.35, p=0.03). These were subsequently used in a linkage analysis that resulted in LOD scores of <2.0, which are not statistically significant. The five constructs developed through factor analysis appear to be consistent with previous factor analyses. Notably, only the dimensions associated with the type of mood disturbance showed high heritability, which suggests that careful measurements of depression, euphoria and irritability may be particularly useful in clarifying the genetic etiology of bipolar disorder in future studies.

Adult↗
PubMed2004

An overview of the genetics of psychotic mood disorders.

This article presents a conceptual review of the genetic underpinnings of psychotic mood disorders. Both unipolar and bipolar forms of mood disorder sometimes feature psychotic symptoms. Some evidence from epidemiological research suggests that psychotic forms of mood disorder specifically might be heritable. Linkage studies of mood disorders in general have also provided some support for that notion, as have associated studies involving serotonin and dopamine genes and psychotic mood disorder. Some research suggests there might be a genetic connection between schizophrenia and bipolar disorder, undermining the Kraepelinian dichotomous classification of the psychoses. Future research should continue to examine psychotic forms of mood disorder using both epidemiological and molecular approaches.

Affective Disorders, Psychotic↗
PubMed2004

A twin study of sexual behavior in men.

The role of genetic and environmental influences on age of initiation of first sexual relations and engaging in sexual activity with multiple partners (10 or more partners in 1 year) was investigated in male twins (N = 6,744) from the Vietnam Era Twin Registry. Individual differences in both types of sexual behaviors were heritable, but only age of onset of sexual relations was significantly influenced by the environment shared by the twins. There was a moderate negative correlation between age of initiation of sexual relations and the multiple partners variable; initiating sexual relations earlier was associated with a higher probability of having multiple partners. The additive genetic influence on age of initiation also influenced the multiple partners variable. The substantial unique environmental influences on each variable were uncorrelated with each other. The data suggest that the observed association between age of initiation of sexual relations and having multiple partners is due to genetic influences common to both behaviors.

Adult↗