Showing papers by "Michael C. Neale published in 2004"

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

Abstract: 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.

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

Abstract: 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.

The structure of perfectionism: a twin study.

Abstract: Background: Perfectionism may be a premorbid risk factor for eating disorders. Evidence of familial transmission suggests features of perfectionism may be genetically determined. This study examines the structure of perfectionism using classical twin design models. Methods: Independent (IP) and common (CP) pathway models are used to investigate the extent to which genetic and environmental factors can help to identify and differentiate three behavioral domains of Perfectionism as measured by a shortened version of the Multidimensional Perfectionism Scale (MPS) [Frost et al. (1990). Cognit. Ther. Res. 14: 449–468]. Three of the original subscales were included: Personal standards (PS), Doubts about actions (DA), Concern over mistakes (CM). We studied a sample of 1022 paired and unpaired female twins from the Mid-Atlantic Twin Registry. Results: MZ correlations were consistently higher than DZ twin correlations for all three composite subscales. The multivariate independent pathway model provided a better fit to the twin correlations then did the more parsimonious common pathway model suggesting the pattern of familial resemblance for the three subscales is not well characterized by a unidimensional perfectionism factor. CM phenotypic variance was completely accounted for by common heritability influences in both the IP and CP models. Based on the IP model results, there was evidence that PS and CM but not DA shared some common genetic effects, with DA and CM sharing some common environmental factors. Conclusions: These multivariate twin modeling results support conceptualizations of perfectionism as a multidimensional construct. The biometric structural results for the three subscales examined here suggest CM is the core feature of Perfectionism with DA and PS serving as indicators of CM. Although not the best fitting model, the common pathway model estimated this behavioral domain to be isomorphic with the construct of perfectionism. The better fitting independent pathway model provided evidence of non-trivial differences in the pattern of heritability for CM, DA, and PS.

Latent Differential Equation Modeling with Multivariate Multi-Occasion Indicators

Abstract: In the behavioral sciences, there is increasing interest in understanding and characterizing mechanisms of developmental and behavioral processes. Measurements of multiple indicators obtained on multiple occasions on a single individual may show some intraindividual change and intraindividual variability. Process-oriented theories may predict structural patterning in these ideographic measurements. Structural equations modeling techniques can be used to test such theories by fitting confirmatory models of the implied dynamical systems to repeated observations data. The current chapter explores one method for constructing and testing confirmatory latent variable structural models in which the latent constructs (a) evolve continuously over time and (b) have linear relationships between their derivatives. The method appears to generalize well and is expected to be able to be applied to systems well beyond the simple example presented here. The chapter will begin with a rationale for studying behavioral processes from a dynamical systems perspective, introduce latent differential equations confirmatory factor models, present the results of two simulations testing the viability of this model for estimating parameters of a simple linear system, and then discuss future substantive and methodological questions that this line of modeling may address.

The genetics of alcohol intake and of alcohol dependence

Abstract: Background: Because alcohol has multiple dose-dependent consequences, it is important to understand the causes of individual variation in the amount of alcohol used. The aims of this study were to assess the long-term repeatability and genetic or environmental causes of variation in alcohol intake and to estimate the degree of overlap with causes of susceptibility to alcohol dependence. Methods: Data were used from three studies conducted between 1980 and 1995 on volunteer adult male and female Australian twin subjects. In each study, alcohol intake was reported both as quantity X frequency and as past-week data. Repeatability was calculated as correlations between occasions and between measures, and the effects of genes and environment were estimated by multivariate model fitting to the twin pair repeated measures of alcohol use. Relationships between mean alcohol use and the lifetime history of DSM-III-R alcohol dependence were tested by bivariate model fitting. Results: Repeatability of the alcohol intake measures was between 0.54 and 0.85, with the highest repeatability between measures within study and the lowest repeatability between the first and last studies. Reported alcohol consumption was mainly affected by genetic factors affecting all times of study and by nonshared environmental factors (including measurement error) unique to each time of study. Genes that affect alcohol intake do affect alcohol dependence, but genetic effects unique to dependence are also significant; environmental effects are largely unique to either intake and dependence. Conclusions: Nearly all the repeatable component of variation in alcohol intake is due to genetic effects. Genes affecting intake also affect dependence risk, but there are other genes that affect dependence alone. Studies aiming to identify genes that affect alcohol use disorders need to test loci and candidate genes against both phenotypes.

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

Abstract: 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

Squeezing interval change from ordinal panel data: latent growth curves with ordinal outcomes.

Abstract: A didactic on latent growth curve modeling for ordinal outcomes is presented. The conceptual aspects of modeling growth with ordinal variables and the notion of threshold invariance are illustrated graphically using a hypothetical example. The ordinal growth model is described in terms of 3 nested models: (a) multivariate normality of the underlying continuous latent variables (yt) and its relationship with the observed ordinal response pattern (Yt), (b) threshold invariance over time, and (c) growth model for the continuous latent variable on a common scale. Algebraic implications of the model restrictions are derived, and practical aspects of fitting ordinal growth models are discussed with the help of an empirical example and Mx script (M. C. Neale, S. M. Boker, G. Xie, & H. H. Maes, 1999). The necessary conditions for the identification of growth models with ordinal data and the methodological implications of the model of threshold invariance are discussed.

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

Abstract: 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.

Linkage analysis of smoking initiation and quantity in Dutch sibling pairs

Abstract: The heritability of smoking initiation (SI) and number of cigarettes smoked (NC) was determined in 3657 Dutch twin pairs. For SI a heritability of 36% was found and for NC of 51%. Both SI and NC were also significantly influenced by environmental factors shared by family members. The etiological factors that influence these traits partly overlap. Linkage analyses were performed on data of 536 DZ twins and siblings from 192 families, forming 592 sibling pairs. Results suggested QTLs on chromosome 6 (LOD=3.05) and chromosome 14 (LOD=1.66) for SI and on chromosome 3 (LOD=1.98) for NC. Strikingly, on chromosome 10 a peak was found in the same region for both SI (LOD=1.92) and for NC (LOD=2.29) which may partly explain the overlapping etiological factors for SI and NC.

Clinical features of psychotic disorders and polymorphisms in HT2A, DRD2, DRD4, SLC6A3 (DAT1), and BDNF: a family based association study

Abstract: Schizophrenia is clinically heterogeneous and multidimensional, but it is not known whether this is due to etiological heterogeneity. Previous studies have not consistently reported association between any specific polymorphisms and clinical features of schizophrenia, and have primarily used case-control designs. We tested for the presence of association between clinical features and polymorphisms in the genes for the serotonin 2A receptor (HT2A), dopamine receptor types 2 and 4, dopamine transporter (SLC6A3), and brain-derived neurotrophic factor (BDNF). Two hundred seventy pedigrees were ascertained on the basis of having two or more members with schizophrenia or poor outcome schizoaffective disorder. Diagnoses were made using a structured interview based on the SCID. All patients were rated on the major symptoms of schizophrenia scale (MSSS), integrating clinical and course features throughout the course of illness. Factor analysis revealed positive, negative, and affective symptom factors. The program QTDT was used to implement a family-based test of association for quantitative traits, controlling for age and sex. We found suggestive evidence of association between the His452Tyr polymorphism in HT2A and affective symptoms (P = 0.02), the 172-bp allele of BDNF and negative symptoms (P = 0.04), and the 480-bp allele in SLC6A3 (= DAT1) and negative symptoms (P = 0.04). As total of 19 alleles were tested, we cannot rule out false positives. However, given prior evidence of involvement of the proteins encoded by these genes in psychopathology, our results suggest that more attention should be focused on the impact of these alleles on clinical features of schizophrenia.

Consultation and interprofessional collaboration: Modeling for the future

Abstract: Consultation and interprofessional collaboration by psychologists occur with individuals, groups, programs, and organizations. The practice of consultation and interprofessional collaboration involves interdisciplinary relationships, preparation, and advanced skill development within specialty areas of psychology (e.g., clinical, counseling, industrial-organizational, and school). The Workgroup on Consultation and Interdisciplinary Relationships engaged in a planning process at the Competencies Conference: Future Directions in Education and Credentialing in Professional Psychology to address fundamental issues regarding consultation and interprofessional collaboration in professional psychology. The Workgroup articulated working definitions, consensus points about psychologists as consultants and interprofessional collaborators, a consulting and interprofessional competency blueprint for preparation and assessment strategies, and future directions. This is one of a series of articles published in this issue of the Journal of Clinical Psychology Several other articles that resulted from the Competencies Conference will appear in Professional Psychology: Research and Practice and The Counseling Psychologist.

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

Abstract: 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.

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

Abstract: Background The total level of α-tryptase and s-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 (sα/sα):2 (ss/sα):1 (ss/ss) distribution, monomorphic for s at 1 position and allelic for s and α at the other position. The sα haplotype has a frequency of 0.49. The sα 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.

Combined linkage and association tests in mx.

Abstract: Statistical methods aimed at the detection of genes for quantitative traits suffer from two problems: (i) when a linkage approach is employed, relatively large sample sizes are usually required; and (ii) when an association approach is employed, effects of population stratification may blur genuine locus–trait associations. The variance components method proposed by Fulker et al. (1999) addressed both these problems; it is statistically powerful because it involves a combined analysis of linkage and association and can include information from multiplex families, which reduces the overall amount of necessary individual genotypes. In addition, it includes an explicit test for the presence of spurious association. After a brief illustration of the various ways in which population stratification may affect locus–trait associations, the implementation in Mx (Neale, 1997) of the method as proposed by Fulker et al. (1999) is discussed and illustrated. In addition, an extension to this method is proposed that allows the use of (variable) sibship sizes greater than two, the estimation of additive and dominance association effects, and the use of multiple alleles. These extensions can be implemented when parental genotypes are available or unavailable.

Sources of individual differences in stressful life event exposure in male and female twins.

Abstract: The roles of genetic and environmental influences on stressful life events were examined in 3938 twin pairs (MZ, same-sex DZ, and opposite-sex DZ) using a sex-limitation model. Life events were assessed by personal interview, and were categorized as being either personal (i.e., events that occur directly to the individual) or network (i.e., events that occur to someone within the individual's social network, thus affecting the individual indirectly). Consistent with previous reports, genetic factors were found to exert more influence on personal events than network events. Genetic correlations between males and females suggest that many of the same genetic factors are acting within both genders.

Mechanisms of asthma and allergic inflammation Rapid publication Effect of sex and haplotype on plasma tryptase levels in healthy adults

Abstract: Background: The total level of a-tryptase and s-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 (sa/sa):2 (ss/sa):1 (ss/ss) distribution, monomorphic for s at 1 position and allelic for s and a at the other position. The sa haplotype has a frequency of 0.49. The sa 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. (J Allergy Clin Immunol 2004:114; 48-51.)

Implications of absence of measurement invariance for detecting sex limitation and genotype by environment interaction.

Abstract: Using univariate sum scores in genetic studies of twin data is common practice. This practice precludes an investigation of the measurement model relating the individual items to an underlying factor. Absence of measurement invariance across a grouping variable such as gender or environmental exposure refers to group differences with respect to the measurement model. It is shown that a decomposition of a sum score into genetic and environmental variance components leads to path coefficients of the additive genetic factor that are biased differentially across groups if individual items are non-invariant. The arising group differences in path coefficients are identical to what is known as "scalar sex limitation" when gender is the grouping variable, or as "gene by environment interaction" when environmental exposure is the grouping variable. In both cases the interpretation would be in terms of a group-specific effect size of the genetic factor. This interpretation may be incorrect if individual items are non-invariant.

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

Abstract: 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. Language: en