Biomedical subjects

Michael C Neale

Publications and source records attributed to Michael C Neale.

At least 37 records · Page 2Linked to original sources

PubMed2005

Genome-wide linkage scan to identify Loci for age at first cigarette in Dutch sibling pairs.

The heritability of age at first cigarette was estimated in 5883 Dutch twins and siblings registered with the Netherlands Twin Register. Heritability was 60% for males and 39% for females. Shared environmental influences were found in females only (30%). Linkage analyses were performed on data of 422 DZ twins and siblings from 175 families, forming 368 sibling pairs. Genomic regions that may harbor susceptibility loci for age at first cigarette with LOD score greater than 2 were detected on chromosomes 5, 14 and 22. A simultaneous analysis of these three genomic regions showed that most of the variance was explained by the linkage effect on chromosome 5 (205 cM). This peak encloses the D1A dopamine receptor gene which is a functional candidate gene for smoking behavior.

Adolescent↗

PubMed2005

The US twin study of age-related macular degeneration: relative roles of genetic and environmental influences.

CONTEXT: Age-related macular degeneration (AMD) is the leading cause of irreversible blindness among older individuals in many parts of the world. The relative importance of genes and environment in the etiology of this major public health problem is not well understood. OBJECTIVE: To investigate the impact of genetic and environmental factors. PARTICIPANTS: Living twins in the National Academy of Sciences-National Research Council World War II Veteran Twin Registry born between 1917 and 1927. METHODS: Twins were surveyed for the known presence of macular degeneration. Enrolled twins underwent a standardized examination and fundus photography. Age-related macular degeneration evaluation was completed for 840 elderly male twins, 210 monozygotic and 181 dizygotic complete twin pairs, both concordant and discordant for presence or absence of AMD, and 58 singletons. A bivariate twin model incorporating initial screening ascertainment and age effects was employed to partition variation in liability to AMD and signs of maculopathy into additive genetic, common environment, and unique environment components. MAIN OUTCOME MEASURE: Heritability of AMD grade and signs of maculopathy based on clinical examination and fundus photographs. RESULTS: Of the 840 twins, 331 had no signs of maculopathy and 241 had early signs, while 162 had intermediate AMD and 106 had advanced AMD. Heritability (additive genetic) estimates were significant for overall AMD grade (0.46) and for intermediate (0.67) and advanced (0.71) AMD. Significant unique environmental proportions of variance were also observed for these AMD variables (0.37, 0.19, and 0.24, respectively). Shared or common environmental contributions were not significant (0.05-0.17). For specific macular drusen and retinal pigment epithelial characteristics, significant genetic (0.26-0.71) and unique environmental (0.28-0.64) proportions of variance were detected. CONCLUSIONS: Genetic factors play a substantial role in the etiology of AMD and associated macular characteristics, explaining 46% to 71% of the variation in the overall severity of the disease. Environmental factors unique to each twin also contribute to the occurrence of this disease. This quantification of relative genetic and environmental contributions to the development of AMD should guide future research on this important cause of blindness.

Aged↗

PubMed2005

The structure of genetic and environmental risk factors for anxiety disorders in men and women.

BACKGROUND: The anxiety disorders exhibit high levels of lifetime comorbidity with one another. Understanding the underlying causes of this comorbidity can provide insight into the etiology of the disorders and inform classification and treatment. OBJECTIVE: To explain anxiety disorder comorbidity by examining the structure of the underlying genetic and environmental risk factors. DESIGN: Lifetime diagnoses for 6 anxiety disorders (generalized anxiety disorder, panic disorder, agoraphobia, social phobia, animal phobia, and situational phobia) were obtained during personal interviews from a population-based twin registry. Multivariate structural equation modeling that allowed for sex differences was performed. SETTING: General community sample. PARTICIPANTS: More than 5000 members of male-male and female-female twin pairs from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders. MAIN OUTCOME MEASURES: Parameter estimates for best-fitting model. RESULTS: The full model, which contained 2 common genetic, shared environmental, and unique environmental factors plus disorder-specific factors, could be constrained to equality across male and female study participants. In the best-fitting model, the genetic influences on anxiety were best explained by 2 additive genetic factors common across the disorders. The first loaded most strongly in generalized anxiety disorder, panic disorder, and agoraphobia, whereas the second loaded primarily in the 2 specific phobias. Social phobia was intermediate in that it was influenced by both genetic factors. A small role for shared environmental influences was observed owing to a single common factor that accounted for less than 12% of the total variance for any disorder. Unique environmental influences could be explained by a single common factor plus disorder-specific effects. CONCLUSIONS: The underlying structure of the genetic and environmental risk factors for the anxiety disorders is similar between men and women. Genes predispose to 2 broad groups of disorders dichotomized as panic-generalized-agoraphobic anxiety vs the specific phobias. The remaining associations between the disorders are largely explained by a unique environmental factor shared across the disorders and, to a lesser extent, a common shared environmental factor.

Adult↗

PubMed2005

Endorsement frequencies and factor structure of DSM-III-R and DSM-IV Generalized Anxiety Disorder symptoms in women: implications for future research, classification, clinical practice and comorbidity.

UNLABELLED: We investigated dimensions of liability to Generalized Anxiety Disorder (GAD) and whether evidence exists for distinct pathological versus normal clusters in the population. Structured interviews were administered to a general population sample of 2,163 female twins in a cross-sectional design. Endorsement rates were estimated using full information maximum likelihood factor analyses of the DSM-III-R and DSM-IV GAD symptoms, which provides appropriate treatment of the stem-probe structure of the clinical interview. Endorsement rates were highest for symptoms retained in DSM-IV. For both DSM-III-R and DSM-IV, a two-factor model fit the data better than a single-factor model. There was no evidence for non-normality in the liability to GAD. For DSM-III-R, autonomic symptoms loaded on a factor with panic disorder, while fatiguability, difficulty concentrating and hypervigilance loaded on a factor with major depression. For DSM-IV, all items loaded on one factor, and muscle tension also loaded on a second. Major depression, panic, phobias and alcohol dependence diagnoses also loaded on the first factor. CONCLUSIONS: Future research involving structured interviews should take into account the stem-and-probe format and focus on common factors rather than separate disorders; GAD is not a unidimensional construct and pathological anxiety may differ only quantitatively from normal anxiety.

Adolescent↗

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

DSM criteria for major depression: evaluating symptom patterns using latent-trait item response models.

BACKGROUND: Expert committees of clinicians have chosen diagnostic criteria for psychiatric disorders with little guidance from measurement theory or modern psychometric methods. The DSM-III-R criteria for major depression (MD) are examined to determine the degree to which latent trait item response models can extract additional useful information. METHOD: The dimensionality and measurement properties of the 9 DSM-III-R criteria plus duration are evaluated using dichotomous factor analysis and the Rasch and 2 parameter logistic item response models. Quantitative liability scales are compared with a binary DSM-III-R diagnostic algorithm variable to determine the ramifications of using each approach. RESULTS: Factor and item response model results indicated the 10 MD criteria defined a reasonably coherent unidimensional scale of liability. However, person risk measurement was not optimal. Criteria thresholds were unevenly spaced leaving scale regions poorly measured. Criteria varied in discriminating levels of risk. Compared to a binary MD diagnosis, item response model (IRM) liability scales performed far better in (i) elucidating the relationship between MD symptoms and liability, (ii) predicting the personality trait of neuroticism and future depressive episodes and (iii) more precisely estimating heritability parameters. CONCLUSIONS: Criteria for MD largely defined a single dimension of disease liability although the quality of person risk measurement was less clear. The quantitative item response scales were statistically superior in predicting relevant outcomes and estimating twin model parameters. Item response models that treat symptoms as ordered indicators of risk rather than as counts towards a diagnostic threshold more fully exploit the information available in symptom endorsement data patterns.

Adolescent↗

PubMed2005

Genetic and environmental influences on illicit drug use and tobacco use across birth cohorts.

BACKGROUND: The prevalence of use of many psychoactive substances has changed considerably in recent years. While genetic factors impact on overall risk for substance use, we know little about whether the etiological importance of these factors differs across birth cohorts. One theory, which postulates that heritability of deviant traits increases in permissive environments, predicts a positive relationship across cohorts between prevalence and heritability of substance use. METHOD: The lifetime history of use of tobacco, cannabis, cocaine, sedatives and stimulants were assessed in 4826 twins from male-male and female-female pairs born in Virginia from 1934 to 1974. Using empirical methods based on prevalence by birth year, these twins were divided into three cohorts for each substance (e.g. for cannabis 1934-1953, 1954-1968 and 1969-1974). Structural equation modeling was performed using the Mx software package. RESULTS: Prevalence rates for psychoactive substance use differed substantially across cohorts, most markedly for cocaine, sedatives and stimulants, which were highest in the 1958-1963 cohort. However, for all substances, the best-fit model constrained estimates of the etiological role of genetic and environmental risk factors to be equal across both sex and cohort. CONCLUSIONS: We found no evidence in this sample for any systematic relationship between heritability and prevalence of psychoactive substance use--which should be a rough index of drug availability and/or acceptability. This sample had reasonable power to detect large changes in heritability across cohorts and at least moderate power to detect relatively small changes.

Adult↗

PubMed2005

People are variables too: multilevel structural equations modeling.

The article uses confirmatory factor analysis (CFA) as a template to explain didactically multilevel structural equation models (ML-SEM) and to demonstrate the equivalence of general mixed-effects models and ML-SEM. An intuitively appealing graphical representation of complex ML-SEMs is introduced that succinctly describes the underlying model and its assumptions. The use of definition variables (i.e., observed variables used to fix model parameters to individual specific data values) is extended to the case of ML-SEMs for clustered data with random slopes. Empirical examples of multilevel CFA and ML-SEM with random slopes are provided along with scripts for fitting such models in SAS Proc Mixed, Mplus, and Mx. Methodological issues regarding estimation of complex ML-SEMs and the evaluation of model fit are discussed. Further potential applications of ML-SEMs are explored.

Analysis of Variance↗

PubMed2005

Relationship between a high-risk haplotype in the DTNBP1 (dysbindin) gene and clinical features of schizophrenia.

OBJECTIVE: The purpose of this study was to determine whether a haplotype in the dystrobrevin binding protein 1 (DTNBP1) gene previously associated with schizophrenia not only increases the susceptibility to psychotic illness but also to a more or less clinically specific form of psychotic illness. METHOD: In the Irish Study of High-Density Schizophrenia Families, subjects with psychotic illness (N=755) were given lifetime ratings of clinical features according to the Operational Criteria Checklist for Psychotic Illness. Exploratory and confirmatory factor analyses were used to extract five factors-hallucinations, delusions, negative, manic, and depressive symptoms-and to create factor-derived scores. The family-based transmission disequilibrium test operationalized in the program TRANSMIT was used to determine whether a high-risk haplotype in the DTNBP1 gene was overtransmitted to subjects in the upper 20th and 40th percentiles for each factor score. These results were compared to baseline overtransmission by examining the empirical distribution of chi-square statistics in groups of 5,000 replicates in which 20% and 40% of ill subjects were randomly selected. This analysis was done for both narrow and broad definitions of psychotic illness. RESULTS: Subjects in the upper 40th percentile for the negative symptom factor--in both the narrowly (p=0.004) and broadly (p=0.01) defined illness groups--were more likely to inherit the high-risk haplotype than would be expected by chance. No other significant relationships between clinical features and high-risk haplotype transmission were observed. CONCLUSIONS: The etiologically relevant variation in DTNBP1, which is in presumptive linkage disequilibrium with the high-risk haplotype, may predispose individuals to a form of psychotic illness associated with high levels of negative symptoms. This finding supports previous evidence suggesting that genetic factors influence the clinical heterogeneity of schizophrenia.

Carrier Proteins↗

PubMed2005

The differential heritability of regular tobacco use based on method of administration.

Several large studies have demonstrated that the liability to smoke cigarettes is strongly genetically influenced. However, the role of genetic and environmental risk factors in the use of other common forms of tobacco use has yet to be studied. Data on the regular use of cigarettes, cigars, pipes, dip (moist snuff), and chewing tobacco from 2634 male twins were analyzed with ACE structural equation models. Twin similarity for regular cigarette and dip use was largely genetic in origin. However, twin resemblance for chewing tobacco was just about equally the result of genes and shared environment, and twin similarity for use of pipes and cigars was entirely the result of shared environmental factors. Thus, the genetic influences on the liability for regular tobacco use appear to vary based on tobacco type. The causes for the use of different forms of tobacco are complex and worthy of further study.

Adult↗

PubMed2005

Problems with using sum scores for estimating variance components: contamination and measurement noninvariance.

Twin studies of complex traits, such as behavior or psychiatric diagnoses, frequently involve univariate analysis of a sum score derived from multiple items. In this article, we show that absence of measurement invariance across zygosity can bias estimates of genetic and environmental components of variance. Specifically, if the item responses are considered as multiple indicators of a latent factor, and the aim is to partition the variance in the latent factor, then the factor loadings relating the items to the factor should be equal for monozygotic (MZ) and dizygotic (DZ) twins. While it seems unlikely, a priori, that these loadings should differ as a function of zygosity, certain special measurement situations are cause for concern. Ratings by parents, or self-ratings of phenotypes which are more easily observed in others than via introspection, may be tainted by the co-twin's phenotype to a greater extent in MZ than DZ pairs. We also show that the analysis of sum scores typically biases both MZ and DZ correlations compared to the true latent trait correlation. These two sources of bias are quantified for a range of values and are shown to be especially acute for sum scores based on binary items. Solutions to these problems include formal tests for measurement invariance across zygosity prior to analysis of the sum or scale scores, and multivariate genetic analysis at the individual item or symptom level.

Humans↗

PubMed2004

Candidate genes for nicotine dependence via linkage, epistasis, and bioinformatics.

Many smoking-related phenotypes are substantially heritable. One genome scan of nicotine dependence (ND) has been published and several others are in progress and should be completed in the next 5 years. The goal of this hypothesis-generating study was two-fold. First, we present further analyses of our genome scan data for ND published by Straub et al. [1999: Mol Psychiatry 4:129-144] (PMID: 10208445). Second, we used the method described by Cox et al. [1999: Nat Genet 21:213-215] (PMID: 9988276) to search for epistatic loci across the markers used in the genome scan. The overall results of the genome scan nearly reached the rigorous Lander and Kruglyak [1995: Nat Genet 11:241-247] criteria for "significant" linkage with the best findings on chromosomes 10 and 2. We then looked for correspondence between genes located in the 10 regions implicated in affected sibling pair (ASP) and epistatic linkage analyses with a list of genes suggested by microarray studies of experimental nicotine exposure and candidate genes from the literature. We found correspondence between linkage and microarray/candidate gene studies for genes involved with the mitogen-activated protein kinase (MAPK) signaling system, nuclear factor kappa B (NFKB) complex, neuropeptide Y (NPY) neurotransmission, a nicotinic receptor subunit (CHRNA2), the vesicular monoamine transporter (SLC18A2), genes in pathways implicated in human anxiety (HTR7, TDO2, and the endozepine-related protein precursor, DKFZP434A2417), and the micro 1-opioid receptor (OPRM1). Although the hypotheses resulting from these linkage and bioinformatic analyses are plausible and intriguing, their ultimate worth depends on replication in additional linkage samples and in future experimental studies.

Chromosome Mapping↗

PubMed2004

Effect of sex and haplotype on plasma tryptase levels in healthy adults.

BACKGROUND: The total level of alpha-tryptase and ss-tryptase in serum or plasma is used as a clinical indicator of the mast cell burden. OBJECTIVE: The effect of the tryptase haplotype and of sex on the total tryptase level of healthy individuals was determined. METHODS: A novel hot-stop PCR technique was used to determine the tryptase genotype, and a standard fluoroenzyme immunoassay was used to measure total plasma tryptase levels in 106 healthy subjects. Mx modeling and the QTL association routine of Mendel 5.0 were used to analyze the data. RESULTS: Tryptase haplotypes exhibit a 1 (betaalpha/betaalpha):2 (betabeta/betaalpha):1 (betabeta/betabeta) distribution, monomorphic for ss at 1 position and allelic for ss and alpha at the other position. The betaalpha haplotype has a frequency of 0.49. The betaalpha haplotype increases total tryptase levels by 0.5 ng/mL from the overall mean, whereas female sex increases the level by 0.2 ng/mL from the mean. CONCLUSION: The tryptase haplotype and sex each have a statistically significant effect on the total plasma tryptase level of healthy subjects.

Adult↗

PubMed2004

A twin study of genetic and environmental influences on tobacco initiation, regular tobacco use and nicotine dependence.

BACKGROUND: Numerous twin studies have reported significant genetic contributions to the variability of tobacco initiation (TI), while fewer studies have shown similar results for the persistence of smoking behavior, or nicotine dependence (ND). As the development of ND requires regular tobacco use (RTU) which in turn requires TI, a conditional approach is necessary. METHOD: We used structural equation modeling of multi-step conditional processes to examine the relationship between genetic and environmental risk factors for TI, RTU and ND. The tobacco variables were assessed by personal interview in female, male and opposite-sex twin pairs from the population-based Virginia Twin Registry. RESULTS: The results suggested that the liabilities to TI, RTU and ND were correlated. Over 80 % of the variance in liability to TI and RTU were shared, and a smaller proportion was shared between RTU and ND. The heritabilities were estimated at 75 %, 80 % and 60 % respectively for TI, RTU and ND. The variance specific to liability to RTU was entirely accounted for by additive genetic factors. Only a modest part of the heritability in liability of ND was due to genetic factors specific to ND. Shared environmental factors were not significant. No sex differences were found for the sources of variation or causal paths, but prevalences were significantly greater in males versus females. CONCLUSIONS: This study showed significant overlap in the contribution of genetic factors to individual differences in TI, RTU and ND. Furthermore, there was evidence for significant additional genetic factors specific to RTU and ND.

Adult↗

PubMed2004

Level of family dysfunction and genetic influences on smoking in women.

BACKGROUND: An adoption study of alcoholism suggests that in women, the impact of genetic risk factors become greater in the presence of conflict in the family of origin. Is the same true for cigarette smoking (CS)? METHOD: We obtained, in a sample of 1676 twins from female female twin pairs from a population-based register, a measure of maximum lifetime CS (divided into six ordinal categories) and family dysfunction (FD) assessed as the mean report of up to four informants (twin, co-twin, mother, father). Statistical analysis was conducted by traditional regression analysis and a moderator structural equation twin model using the computer program Mx. RESULTS: With increasing levels of FD, maximum CS increased substantially while correlations for CS in monozygotic (MZ) and dizygotic (DZ) twins decreased modestly. Regression analyses demonstrated reduced twin-pair resemblance for CS with increasing levels of FD. The best-fit structural equation model found high levels of heritability for CS and no evidence for a role of shared environment. With increasing levels of FD, the proportion of variance in CS due to genetic factors (i.e. heritability) decreased while that due to unique environmental effects increased. CONCLUSIONS: Several different statistical methods suggested that, contrary to prediction, heritability of CS decreased rather than increased with higher levels of dysfunction in the family of origin. The hypothesis that genetic effects for psychiatric and drug-use disorders become stronger in more adverse environments is not universally true.

Adult↗

PubMed2004

A twin study of early cannabis use and subsequent use and abuse/dependence of other illicit drugs.

INTRODUCTION: Cannabis use is strongly associated with the use and abuse/dependence of other illicit drugs. Gateway and common liabilities models have been employed to explain this relationship. We sought to examine this association using a combination of the discordant twin design and modeling methods. METHOD: We assess the relationship between early cannabis use and the subsequent use and abuse/ dependence of other illicit drugs in a population-based sample of male and female twin pairs using four analyses: (i) analysis of the association between early cannabis use and other illicit drug use and abuse/dependence in the entire sample of twins, (ii) assessment of the influence of early cannabis use in twin 1 on twin 2's use or abuse/dependence of other illicit drugs, (iii) use of twin pairs discordant for early cannabis use in a discordant twin design and (iv) a model-fitting procedure. RESULTS: We found: (i) a strong association between early cannabis use and use and abuse/dependence of other illicit drugs in the sample, (ii) twin 1's early cannabis use is significantly associated with the twin 2's other illicit drug use, (iii) the role of correlated genetic factors with some evidence for a causal influence, and (iv) the correlated liabilities model fits the data well. CONCLUSIONS: Early cannabis use is strongly associated with other illicit drug use and abuse/dependence. The relationship arises largely due to correlated genetic and environmental influences with persisting evidence for some causal influences.

Adult↗

PubMed2004

Cannabis and other illicit drugs: comorbid use and abuse/dependence in males and females.

Cannabis and other illicit drugs are often used or abused comorbidly. Two competing theories to explain this comorbidity are (i) the phenotypic causation (gateway) model and (ii) the correlated liabilities model. We used data from 1191 male and 934 female same-sex twin pairs to test 13 genetically informative models of comorbidity. Models were fit separately for use and abuse/dependence in both sexes. The correlated liabilities model provided a good fit to the data for cannabis and other illicit drug use, as well as abuse/dependence. The relationship between the use or abuse of cannabis and other illicit drugs is not entirely phenotypic, as depicted by the random multiformity of cannabis model, which is an adaptation of the gateway model. The comorbidity appears to arise from correlated genetic and environmental influences. There is some evidence for a model in which high-risk cannabis users may be at increased risk for other illicit drug use. For abuse/dependence, a model with causal pathways between the liability for cannabis and other illicit drug abuse/dependence also fits well. Overall, our results suggest that the use and abuse/dependence of cannabis and other illicit drugs are strongly linked via common risk factors that jointly influence their individual liabilities.

Cannabinoids↗

PubMed2004

The validity of the Neale and Kendler model-fitting approach in examining the etiology of comorbidity.

Given that knowledge regarding the etiology of comorbidity between disorders can have a significant impact on research regarding the classification, treatment, and etiology of the disorders, the ability to reject incorrect hypotheses regarding the causes of comorbidity is very important. A simulation study was conducted to assess the validity of the Neale and Kendler (1995) model-fitting approach in examining the etiology of comorbidity between two disorders. First, data were simulated under the assumptions of the 13 alternative comorbidity models described by Neale and Kendler. Second, model-fitting analyses testing the comorbidity models were conducted on the simulated datasets. Thirteen sets of data with varying model parameters were simulated to test Neale and Kendler's assertion that their model-fitting approach is appropriate across a range of potential prevalences and degrees of familiality. The validity of the model-fitting approach in examining unselected twin data and a combination of selected family data and unselected family data was explored. The model-fitting approach successfully discriminated several classes of comorbidity models, although discrimination between models within classes of related models was less accurate. Results suggest that the model-fitting approach can be a useful tool in examining the etiology of the comorbidity between disorders if the caveats of the present study's results are considered carefully. As predicted by Neale and Kendler, variations in the disorder prevalences and familial correlations did not affect the validity of their model-fitting approach, but affected the power to discriminate the correct model. As suggested by Neale and Kendler, the model-fitting approach can be applied to both unselected and selected data and to both twin and family data.

Comorbidity↗