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Biomedical subjects

Ming T Tsuang

Publications and source records attributed to Ming T Tsuang.

At least 73 records · Page 4Linked to original sources
PubMed2004

Genetic and environmental contributions to age of onset of alcohol dependence symptoms in male twins.

AIMS: To investigate genetic and environmental influences on the development of specific alcohol dependence symptoms. DESIGN AND PARTICIPANTS: A classical twin study of 3372 male-male twin pairs in the Vietnam Era Twin (VET) Registry based on telephone interviews about alcohol use. MEASUREMENTS: The nine diagnostic symptoms according to the Diagnostic and Statistical Manual of Mental Disorder, version III (revised) (DSM-III-R) definition of alcohol dependence. Symptoms were grouped into those based on impaired control, biological effects and social consequences (Beresford's classification) or early versus late symptoms (Nelson's classification). Survival models with random effects were used to examine the age of onset of each symptom. FINDINGS: Approximately 38% of the variation in age of onset of each symptom group based on Beresford's classification is due to additive genetic factors. The age of onset of late symptoms from Nelson's classification appears to be most affected by genetic factors. Estimates of genetic effects for impaired control symptoms are greatly decreased when twins with comorbid psychiatric disorders are excluded. CONCLUSIONS: Our results support the heritability of age of onset of DSM-III-R-defined symptoms for alcohol dependence. However, no symptom group in Beresford's classification could be identified as more heritable than other symptom groups. A strong association between genetic vulnerability and co-occurring diseases for symptoms indicative of impaired control could be found. In addition, our findings show that the late symptom group could be a good candidate for subsequent genetic research.

Adult↗
PubMed2004

Stability, consistency, and heritability of electrodermal response lability in middle-aged male twins.

We examined individual differences in nonspecific electrodermal response (EDR) lability in terms of retest stability, cross-situational consistency, and heritability in a sample of 345 adult monozygotic and dizygotic twin pairs. We also examined the phenotypic and genetic relationships between EDR lability and speed of habituation of the specific EDR to a nonsignal stimulus. Individual variation in EDR lability showed substantial retest stability and cross-situational consistency and also predicted resistance to specific EDR habituation. Structural equation modeling showed that the covariation among EDR lability measures and resistance to specific EDR habituation operated through a single latent phenotype, which was influenced in approximately equal measure by genetic and unique environmental factors. We discuss these findings in terms of an information processing account of individual differences in phasic EDR activation.

Adult↗
PubMed2004

A novel permutation testing method implicates sixteen nicotinic acetylcholine receptor genes as risk factors for smoking in schizophrenia families.

Smoking is a common correlate of schizophrenia, which leads to medical morbidity. Although twin and adoption studies have consistently implicated genes in the etiology of both smoking and schizophrenia, finding genes has been difficult. Several authors have suggested that clinical or neurobiological features associated with schizophrenia, such as smoking, might improve the ability to detect schizophrenia susceptibility genes by identifying genes related to the etiology of that feature. The objective of this study is to assess evidence for linkage of sixteen nicotinic acetylcholine receptor genes and smoking in schizophrenia families, using data from the NIMH Genetics Initiative for schizophrenia. Sixteen nicotinic acetylcholine receptor genes were selected prior to analysis. We used a multipoint sibling pair linkage analysis program, SIBPAL2, with a smoking trait in schizophrenia families. The significance of the group of candidate genes, in addition to each individual candidate gene, was assessed using permutation testing, which adjusted for multiple comparisons. The group of genes showed significant linkage to the smoking trait after adjusting for multiple comparisons through permutation testing (p = 0.039). In addition, two of the individual candidate genes were significant (CHRNA2, p = 0.044) and (CHRNB2, p = 0.015) and two genes were marginally significant (CHRNA7, p = 0.095; CHRNA1, p = 0.076). The significance of the complex hypothesis, involving sixteen genes, implicates the nicotinic system in smoking for schizophrenic families. Individual gene analysis suggests that CHRNA2 and CHRNB2 may play a particular role in this involvement. Such findings help prioritize genes for future case control studies. In addition, we provide a novel permutation method that is useful in future analyses involving a single hypothesis, with multiple candidate genes.

Adult↗
PubMed2004

Three potential susceptibility loci shown by a genome-wide scan for regions influencing the age at onset of mania.

OBJECTIVE: The age at onset of bipolar disorder is associated with clinical features of the illness, including duration, severity, and pattern of comorbidity with other disorders. Age at onset is familial and heritable, and it correlates inversely with the prevalence of bipolar disorder among relatives. Because age at onset may have utility in resolving the complexity and heterogeneity of the disorder, the authors sought to identify chromosomal loci that harbor the genes influencing this trait. METHOD: A genome scan of 539 genotyped people in 97 families ascertained for the NIMH Bipolar Disorder Genetics Initiative was performed by using multipoint variance-components linkage analysis. RESULTS: The age at onset of mania was significantly heritable in these families. Three chromosomal regions yielded nonsignificant but suggestive multipoint lod scores greater than 2.5, with the strongest evidence observed at markers D12S1292, GATA31B, and GATA50C, on chromosomes 12p, 14q, and 15q, respectively. CONCLUSIONS: Although firm conclusions await an independent replication, these results suggest that three regions of the genome may contain genes influencing the age at onset of mania in bipolar disorder. To the authors' knowledge, these regions have not been implicated previously in risk for the disorder, suggesting that separate sets of genes influence disease susceptibility and the age at which it appears.

Adolescent↗
PubMed2004

Lifetime and 12-month prevalence of psychiatric disorders in 8,169 male Vietnam War era veterans.

OBJECTIVE: This study reports the prevalence of psychiatric disorders among a nationally distributed sample of Vietnam Era veterans assessed using standardized psychiatric interviewing methods. METHODS: In 1992, the National Institute of Mental Health Diagnostic Interview Schedule was administered by telephone to 8,169 middle-aged males who served in the military during the Vietnam era (1965-1975). RESULTS: Approximately 72% of respondents reported a lifetime history and 36% reported a 12-month history of at least one psychiatric disorder. The most prevalent psychiatric disorders included alcohol abuse and/or dependence (54% lifetime, 17% 12 month), nicotine dependence (48% lifetime, 22% 12 month), and posttraumatic stress disorder (10% lifetime, 4.5% 12 month). CONCLUSIONS: Because of possible participation bias, these results likely represent conservative estimates of psychiatric disorder prevalences among the more than eight million Vietnam Era veterans and reinforces the major public health challenge of preventing, identifying, and treating psychiatric illness in American veterans.

Adult↗
PubMed2004

Gene-environment interactions in mental disorders.

Research clearly shows that both nature and nurture play important roles in the genesis of psychopathology. In this paper, we focus on 'gene-environment interaction' in mental disorders, using genetic control of sensitivity to the environment as our definition of that term. We begin with an examination of methodological issues involving gene-environment interactions, with examples concerning psychiatric and neurological conditions. Then we review the interactions in psychiatric disorders using twin, adoption and association designs. Finally, we consider gene-environment interactions in selected neurodevelopmental disorders (autism and schizophrenia).

Journal Article↗
PubMed2003

Association of a genetic marker at the corticotropin-releasing hormone locus with behavioral inhibition.

BACKGROUND: Behavioral inhibition to the unfamiliar (BI), a heritable temperamental profile involving an avoidant response to novel situations, may be an intermediate phenotype in the development of anxiety disorders. Corticotropin-releasing hormone (CRH) is a key mediator of the stress response through its effects on the hypothalamic-pituitary-adrenal axis and limbic brain systems. Transgenic mice overexpressing CRH exhibit BI-like behaviors, implicating this gene in the development of the phenotype. METHODS: We genotyped a marker tightly linked to the CRH locus in 85 families of children who underwent laboratory-based behavioral assessments of BI and performed family-based association analyses. RESULTS: We observed an association between an allele of the CRH-linked locus and BI (p =.015). Among offspring of parents with panic disorder, this association was particularly marked (p =.0009). We further demonstrate linkage disequilibrium between this marker and single nucleotide polymorphisms encompassing the CRH gene. CONCLUSIONS: These results are consistent with the possibility that variants in the CRH gene are associated with anxiety proneness.

Anxiety Disorders↗
PubMed2003

Schizophrenia is not associated with DRD4 48-base-pair-repeat length or individual alleles: results of a meta-analysis.

BACKGROUND: The gene DRD4, coding for dopamine receptor D4, was considered a candidate for association with schizophrenia based on its upregulation in postmortem schizophrenic brain and affinity for clozapine. Many studies sought allelic association of a 48-base-pair repeat in DRD4 exon 3 with schizophrenia, but found no strong evidence for a relationship. The present work sought to determine if this observation reflected the true absence of association or the low power of individual studies. METHODS: We performed four meta-analyses, sequentially considering the two-, four-, and seven-repeat alleles as risk alleles, and then considering repeat length of the 48-base-pair segment as a risk factor. Each meta-analysis included at least 2,300 cases and 2,100 controls from 14-16 studies. RESULTS: The pooled odds ratio from each analysis approximated 1.0, and none were significant. Heterogeneity was not observed, although gender moderated the effects of repeat length and the seven-repeat allele. CONCLUSIONS: Despite over 90% power to detect a significant odds ratio of 1.4 or less, none was observed. This polymorphism seems not to influence risk for most schizophrenia cases; however, a sex-dependent relationship, or a role in some clinical features of the disorder, cannot be excluded and should be pursued experimentally.

Adult↗
PubMed2003

CAG-repeat length in exon 1 of KCNN3 does not influence risk for schizophrenia or bipolar disorder: a meta-analysis of association studies.

Schizophrenia and bipolar disorder both show some evidence for genetic anticipation. In addition, significant expansion of anonymous CAG repeats throughout the genome has been detected in both of these disorders. The gene KCNN3, which codes for a small/intermediate conductance, calcium-regulated potassium channel, contains a highly polymorphic CAG-repeat array in exon 1. Initial evidence for association of both schizophrenia and bipolar disorder with increased CAG-repeat length of KCNN3 has not been consistently replicated. In the present study, we performed several meta-analyses to evaluate the pooled evidence for association with CAG-repeat length of KCNN3 derived from case-control and family-based studies of both disorders. Each group of studies was analyzed under two models, including a test for direct association with repeat length, and a test for association with dichotomized repeat-length groups. No evidence for a linear relationship between disease risk and repeat length was observed, as all pooled odds ratios approximated 1.0. Results of dichotomized allele-group analyses were more variable, especially for schizophrenia, where case-control studies found a significant association with longer repeats but family-based studies implicated shorter alleles. The results of these meta-analyses demonstrate that the risks for both schizophrenia and bipolar disorder are largely, if not entirely, independent of CAG-repeat length in exon 1 of KCNN3. This study cannot exclude the possibility that some aspect of this polymorphism, such as repeat-length disparity in heterozygotes, influences risk for these disorders. Further, it remains unknown if this polymorphism, or one in linkage disequilibrium with it, contributes to some distinct feature of the disorder, such as symptom severity or anticipation.

Bipolar Disorder↗
PubMed2003

Family-based association study of the NOTCH4 gene in schizophrenia using Japanese and Chinese samples.

BACKGROUND: A family based association study in a British sample found the NOTCH4 gene to be associated with schizophrenia; however, all six replication studies failed to confirm the finding. METHODS: We performed a family based association study of NOTCH4 and schizophrenia in 123 trios (16 Japanese and 107 Chinese). In addition to the original study's polymorphisms, we examined four new single nucleotide polymorphisms (SNPs)--SNPs_A, B, C and D--around SNP1 of the original study. We genotyped all samples for SNPs_A-D and for SNP1 and (CTG)n of the original study. RESULTS: We found no significant associations between NOTCH4 and schizophrenia or its subtypes for all polymorphisms, regardless of gender. The finding remained negative when the Chinese sample was analyzed separately. Exploratory analyses suggested that SNP_A may be associated with early-onset schizophrenia and that SNP1 may be associated with schizophrenia characterized by numerous negative symptoms. CONCLUSIONS: NOTCH4 is not a significant susceptibility gene for schizophrenia when clinical heterogeneity is ignored; however, NOTCH4 may be associated with early-onset schizophrenia or schizophrenia with many negative symptoms, but these findings should be interpreted cautiously.

Adult↗
PubMed2003

Family-based association study of markers on chromosome 22 in schizophrenia using African-American, European-American, and Chinese families.

Several studies suggest that loci at chromosome 22q11.2-q13 might be linked to susceptibility to schizophrenia. Here we performed family-based association studies on chromosome 22q using 12 DNA microsatellite markers in African-American, European-American, and Chinese pedigrees. The marker D22S683 showed significant linkage and association with schizophrenia in not only the European-American sample but also in a combined sample (European-American and Chinese samples). Notably, D22S683 is located nearby and between D22S278 and D22S283, which have shown linkage and association to schizophrenia in prior reports. However, we found no significant association for the African-American sample. In conclusion, our data provide further support for the idea that the region around D22S683 contains a susceptibility gene for schizophrenia.

Adult↗
PubMed2003

Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: Schizophrenia.

Schizophrenia is a common disorder with high heritability and a 10-fold increase in risk to siblings of probands. Replication has been inconsistent for reports of significant genetic linkage. To assess evidence for linkage across studies, rank-based genome scan meta-analysis (GSMA) was applied to data from 20 schizophrenia genome scans. Each marker for each scan was assigned to 1 of 120 30-cM bins, with the bins ranked by linkage scores (1 = most significant) and the ranks averaged across studies (R(avg)) and then weighted for sample size (N(sqrt)[affected casess]). A permutation test was used to compute the probability of observing, by chance, each bin's average rank (P(AvgRnk)) or of observing it for a bin with the same place (first, second, etc.) in the order of average ranks in each permutation (P(ord)). The GSMA produced significant genomewide evidence for linkage on chromosome 2q (PAvgRnk<.000417). Two aggregate criteria for linkage were also met (clusters of nominally significant P values that did not occur in 1,000 replicates of the entire data set with no linkage present): 12 consecutive bins with both P(AvgRnk) and P(ord)<.05, including regions of chromosomes 5q, 3p, 11q, 6p, 1q, 22q, 8p, 20q, and 14p, and 19 consecutive bins with P(ord)<.05, additionally including regions of chromosomes 16q, 18q, 10p, 15q, 6q, and 17q. There is greater consistency of linkage results across studies than has been previously recognized. The results suggest that some or all of these regions contain loci that increase susceptibility to schizophrenia in diverse populations.

Bipolar Disorder↗
PubMed2003

The genetics of pediatric-onset bipolar disorder.

Although bipolar disorder in adults has been extensively studied, early-onset forms of the disorder have received less attention. We review several lines of evidence indicating that pediatric- and early adolescent-onset bipolar disorder cases may prove the most useful for identifying susceptibility genes. Family studies have consistently found a higher rate of bipolar disorder among the relatives of early-onset bipolar disorder patients than in relatives of later-onset cases, which supports the notion of a larger genetic contribution to the early-onset cases. Comorbid pediatric bipolar disorder and attention-deficit/hyperactivity disorder (ADHD) may also define a familial subtype of ADHD or bipolar disorder that is strongly influenced by genetic factors and may, therefore, be useful in molecular genetic studies. There are no twin and adoption studies of pediatric bipolar disorder, but the heritability of this subtype is expected to be high given the results from family studies. Thus, pediatric- and early adolescent-onset bipolar disorder may represent a genetically loaded and homogeneous subtype of bipolar disorder, which, if used in genetic linkage and association studies, should increase power to detect risk loci and alleles.

Adolescent↗
PubMed2003

Structural brain abnormalities among relatives of patients with schizophrenia: implications for linkage studies.

Several studies suggest that the nonschizophrenic relatives of schizophrenic patients exhibit structural brain abnormalities that may be manifestations of genes that predispose to schizophrenia. In this work, we examine the utility of such measures for linkage analyses. Subjects were 45 nonpsychotic first-degree adult relatives of schizophrenic patients and 48 normal controls. Sixty contiguous 3-mm coronal, T1-weighted 3D magnetic resonance images of the entire brain were acquired on a 1.5-T magnet. We used factor analysis to derive MRI-based phenotypes for analysis. The factor analyses produced three factors that significantly discriminated relatives from controls. We used a linear combination of the three factor scores to derive an MRI phenotype. A receiver operating characteristic (ROC) analysis of this phenotype estimated an area under the curve (AUC) statistic of 0.85. The phenotype also discriminated nonpsychotic relatives having two schizophrenic relatives from those having only one. The nonpsychotic relatives of schizophrenic patients show deviant values on MRI measures of brain structure and the distribution of these deviations among relatives and controls suggests that if these results can be replicated, an MRI-derived phenotype could be useful for genetic linkage and association analyses.

Adult↗
PubMed2003

Family study of affective spectrum disorder.

BACKGROUND: Affective spectrum disorder (ASD) represents a group of psychiatric and medical conditions, each known to respond to several chemical families of antidepressant medications and hence possibly linked by common heritable abnormalities. Forms of ASD include major depressive disorder (MDD), attention-deficit/hyperactivity disorder, bulimia nervosa, cataplexy, dysthymic disorder, fibromyalgia, generalized anxiety disorder, irritable bowel syndrome, migraine, obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, premenstrual dysphoric disorder, and social phobia. Two predictions of the ASD hypothesis were tested: that ASD, taken as a single entity, would aggregate in families and that MDD would coaggregate with other forms of ASD in families. METHODS: Probands with and without MDD, together with their first-degree relatives, were interviewed using the Structured Clinical Interview for DSM-IV and a supplemental interview for other forms of ASD. The familial aggregation and coaggregation of disorders were analyzed using proband predictive logistic regression models, including a novel bivariate model for the presence or absence of each of 2 disorders in a relative as predicted by the presence or absence of each of 2 disorders in the associated proband. RESULTS: In the 178 interviewed relatives of 64 probands with MDD and 152 relatives of 58 probands without MDD, the estimated odds ratio (95% confidence interval) for the familial aggregation of ASD as a whole was 2.5 (1.4-4.3; P =.001) and for the familial coaggregation of MDD with at least one other form of ASD was 1.9 (1.1-3.2; P =.02). CONCLUSIONS: Affective spectrum disorder aggregates strongly in families, and MDD displays a significant familial coaggregation with other forms of ASD, taken collectively. These results suggest that forms of ASD may share heritable pathophysiologic features.

Anxiety Disorders↗
PubMed2003

A twin study of the neuropsychological consequences of stimulant abuse.

BACKGROUND: Previous studies document neuropsychological deficits associated with stimulant abuse, but findings are inconsistent. METHODS: We identified 50 twin pairs in which only 1 member had heavy stimulant abuse (cocaine and/or amphetamines) ending at least 1 year before the evaluation. The co-twin control research design controls for familial vulnerability and makes it easier to identify neuropsychological deficits that are consequences of stimulant abuse. Subjects were administered an extensive neuropsychological test battery organized into the following 5 functions: attention, executive functioning, motor skills, intelligence, and memory. RESULTS: Multivariate tests showed that abusers performed significantly worse than nonabusers on functions of attention and motor skills. Within each of these functions, univariate tests showed that abusers performed significantly worse on certain tests of motor skills and attention. In contrast, abusers performed significantly better on one test of attention measuring visual vigilance. Within the abuser group, higher levels of stimulant use were largely uncorrelated with neuropsychological test scores, although a few significant correlations indicated better functioning with more stimulant use. CONCLUSIONS: With ideal controls, this study demonstrates that deficits in attention and motor skills persist after 1 year of abstinence from stimulant use and raises hypotheses regarding relative strengths on a vigilance task among abusers.

Adult↗
PubMed2003

Schizotaxia: current status and future directions.

Schizophrenia is a biologic disorder whose etiology involves a combination of genetic and environmental risk factors. In this review, the authors update the conceptual basis of schizotaxia, consider evidence for its validity, and look toward its likely evolution in the future.

Brain↗