Biomedical subjects

Michael C Neale

Publications and source records attributed to Michael C Neale.

At least 19 recordsLinked to original sources

PubMed2007

The heritability of cluster A personality disorders assessed by both personal interview and questionnaire.

BACKGROUND: Personality disorders (PDs) as assessed by questionnaires and personal interviews are heritable. However, we know neither how much unreliability of measurement impacts on heritability estimates nor whether the genetic and environmental risk factors assessed by these two methods are the same. We wish to know whether the same set of PD vulnerability factors are assessed by these two methods. METHOD: A total of 3334 young adult twin pairs from the Norwegian Institute of Public Health Twin Panel (NIPHTP) completed a questionnaire containing 91 PD items. One to 6 years later, 1386 of these pairs were interviewed with the Structured Interview for DSM-IV Personality (SIDP-IV). Self-report items predicting interview results were selected by regression. Measurement models were fitted using Mx. RESULTS: In the best-fit models, the latent liabilities to paranoid personality disorder (PPD), schizoid personality disorder (SPD) and schizotypal personality disorder (STPD) were all highly heritable with no evidence of shared environmental effects. For PPD and STPD, only unique environmental effects were specific to the interview measure whereas both environmental and genetic effects were found to be specific to the questionnaire assessment. For SPD, the best-fit model contained genetic and environmental effects specific to both forms of assessment. CONCLUSIONS: The latent liabilities to the cluster A PDs are highly heritable but are assessed by current methods with only moderate reliability. The personal interviews assessed the genetic risk for the latent trait with excellent specificity for PPD and STPD and good specificity for SPD. However, for all three PDs, the questionnaires were less specific, also indexing an independent set of genetic risk factors.

Adult↗

PubMed2007

A multivariate analysis of neuroanatomic relationships in a genetically informative pediatric sample.

An important component of brain mapping is an understanding of the relationships between neuroanatomic structures, as well as the nature of shared causal factors. Prior twin studies have demonstrated that much of individual differences in human anatomy are caused by genetic differences, but information is limited on whether different structures share common genetic factors. We performed a multivariate statistical genetic analysis on volumetric MRI measures (cerebrum, cerebellum, lateral ventricles, corpus callosum, thalamus, and basal ganglia) from a pediatric sample of 326 twins and 158 singletons. Our results suggest that the great majority of variability in cerebrum, cerebellum, thalamus and basal ganglia is determined by a single genetic factor. Though most (75%) of the variability in corpus callosum was explained by additive genetic effects these were largely independent of other structures. We also observed relatively small but significant environmental effects common to multiple neuroanatomic regions, particularly between thalamus, basal ganglia, and lateral ventricles. These findings are concordant with prior volumetric twin studies and support radial models of brain evolution.

Adolescent↗

PubMed2006

The inclusion of measured covariates in the Neale and Kendler model fitting approach.

Neale and Kendler (1995, Am J Hum Genet 57:935-953) described 13 comorbidity models, providing the most comprehensive set of alternative hypotheses regarding the possible causes of comorbidity to date. This research note describes an extension of the Neale and Kendler model fitting approach that permits the inclusion of measured covariates. An example of 13 models examining the comorbidity between alcohol dependence and illicit drug dependence is presented.

Alcoholism↗

PubMed2006

Genetic and environmental influences on dimensional representations of DSM-IV cluster C personality disorders: a population-based multivariate twin study.

BACKGROUND: The DSM-IV cluster C Axis II disorders include avoidant (AVPD), dependent (DEPD) and obsessive-compulsive (OCPD) personality disorders. We aimed to estimate the genetic and environmental influences on dimensional representations of these disorders and examine the validity of the cluster C construct by determining to what extent common familial factors influence the individual PDs. METHOD: PDs were assessed using the Structured Interview for DSM-IV Personality (SIDP-IV) in a sample of 1386 young adult twin pairs from the Norwegian Institute of Public Health Twin Panel (NIPHTP). A single-factor independent pathway multivariate model was applied to the number of endorsed criteria for the three cluster C disorders, using the statistical modeling program Mx. RESULTS: The best-fitting model included genetic and unique environmental factors only, and equated parameters for males and females. Heritability ranged from 27% to 35%. The proportion of genetic variance explained by a common factor was 83, 48 and 15% respectively for AVPD, DEPD and OCPD. Common genetic and environmental factors accounted for 54% and 64% respectively of the variance in AVPD and DEPD but only 11% of the variance in OCPD. CONCLUSION: Cluster C PDs are moderately heritable. No evidence was found for shared environmental or sex effects. Common genetic and individual environmental factors account for a substantial proportion of the variance in AVPD and DEPD. However, OCPD appears to be largely etiologically distinct from the other two PDs. The results do not support the validity of the DSM-IV cluster C construct in its present form.

Adult↗

PubMed2006

Dimensional representations of DSM-IV cluster A personality disorders in a population-based sample of Norwegian twins: a multivariate study.

BACKGROUND: The 'odd' or 'Cluster A' personality disorders (PDs) - paranoid, schizoid and schizotypal PDs - were created in DSM-III with little empirical foundation. We have examined the relationship between the genetic and environmental risk factors for dimensional representations of these three personality disorders. METHOD: These personality disorders were assessed using the Structured Interview for DSM-IV Personality (SIDP-IV) in 1386 young adult twin pairs from the Norwegian Institute of Public Health Twin Panel. Using Mx, a single-factor independent pathway twin model was fitted to the number of endorsed criteria for the three disorders. RESULTS: The best-fit model included genetic and unique environmental common factors and genetic and unique environmental effects specific to each personality disorder. Total heritability was modest for these personality disorders and ranged from 21% to 28%. Loadings on the common genetic and unique environmental factors were substantially higher for schizotypal than for paranoid or schizoid PD. The proportion of genetic liability shared with all Cluster A disorders was estimated at 100, 43 and 26% respectively for schizotypal, paranoid and schizoid PDs. CONCLUSION: In support of the validity of the Cluster A construct, dimensional representations of schizotypal, paranoid and schizoid PD are all modestly heritable and share a portion of their genetic and environmental risk factors. No evidence was found for shared environmental or sex effects for these PDs. Schizotypal PD most closely reflects the genetic and environmental liability common to all three Cluster A disorders. These results should be interpreted in the context of the limited power of this sample.

Adult↗

PubMed2006

Genetic and cultural transmission of smoking initiation: an extended twin kinship model.

BACKGROUND: Considerable evidence from twin and adoption studies indicates that genetic and shared environmental factors play a significant role in the initiation of smoking behavior. Although twin and adoption designs are powerful to detect genetic and environmental influences, they do not provide information on the processes of assortative mating and parent-offspring transmission and their contribution to the variability explained by genetic and/or environmental factors. METHODS: We examined the role of genetic and environmental factors for smoking initiation using an extended kinship design. This design allows the simultaneous testing of additive and non-additive genetic, shared and individual-specific environmental factors, as well as sex differences in the expression of genes and environment in the presence of assortative mating and combined genetic and cultural transmission. A dichotomous lifetime smoking measure was obtained from twins and relatives in the Virginia 30,000 sample. RESULTS: Results demonstrate that both genetic and environmental factors play a significant role in the liability to smoking initiation. Major influences on individual differences appeared to be additive genetic and unique environmental effects, with smaller contributions from assortative mating, shared sibling environment, twin environment, cultural transmission and resulting genotype-environment covariance. The finding of negative cultural transmission without dominance led us to investigate more closely two possible mechanisms for the lower parent-offspring correlations compared to the sibling and DZ twin correlations in subsets of the data: (i) age x gene interaction, and (ii) social homogamy. Neither mechanism provided a significantly better explanation of the data, although age regression was significant. CONCLUSIONS: This study showed significant heritability, partly due to assortment, and significant effects of primarily non-parental shared environment on smoking initiation.

Aged↗

PubMed2006

Extensions to the modeling of initiation and progression: applications to substance use and abuse.

Twin data can provide valuable insight into the relationship between the stages of phenomena such as disease or substance abuse. Initiation of substance use may be caused by factors that are the same as, partially shared with, or completely independent of those that cause progression from use to abuse. Comparison of rates of progression among the cotwins of twins who do vs. do not initiate provides indirect information about the relationship between initiation and progression. Existing models for this relationship have been difficult to extend because they are usually expressed in terms of explicit integrals. In this paper, the problem is overcome by regarding the analysis of twin data on initiation and progression as a special case of missing data, in which individuals who do not initiate are regarded as having missing data on progression measures. Using the general framework for the analysis of ordinal data with missing values available in Mx makes extensions that include other variables much easier. The effects of continuous covariates such as age on initiation and progression becomes simple. Also facilitated are the examination of initiation and progression in two or more substances, and transition models with two or more steps. The methods are illustrated with data on the effects of cohort on liability to cannabis use and abuse, bivariate analysis of tobacco use and dependence and cannabis use and abuse, and the relationships between initiation of smoking, regular smoking and nicotine dependence. Other suitable applications include the relationship between symptoms and diagnosis, such as fears and the progression to phobia.

Age Factors↗

PubMed2006

Methodological issues in the assessment of substance use phenotypes.

The measurement of behavior is inherently problematic, and this is especially true of substance use and abuse phenotypes. The contingent nature of many assessments, such that symptoms of abuse and dependence cannot be obtained from those who have not initiated substance use, presents special difficulties. Furthermore, it is not clear whether individual differences in liability to use, abuse and dependence are best characterized as dimensions or classes or a combination of both. This article outlines research designs and methods suitable for quantifying liability to substance use. The value of data collected from relatives is emphasized in this context, as they permit identification of models normally compromised because data on, e.g., substance dependence symptoms, are systematically missing in those who have not initiated use of the substance in question.

Disease Susceptibility↗

PubMed2006

Comorbidity between alcohol dependence and illicit drug dependence in adolescents with antisocial behavior and matched controls.

BACKGROUND: Knowledge regarding the causes of comorbidity among substance use disorders can have significant impact on future research examining the etiology of these disorders. Unfortunately, the conclusions of past studies examining the comorbidity among substance use disorders are conflicting; some studies emphasize familial influences common to multiple substances, while others emphasize substance-specific influences. Discrepancies in results may reflect different analytical approaches or differences in the samples. Here, we examine the causes of comorbidity between alcohol dependence and illicit drug dependence in adolescents. METHODS: We ascertained a clinical sample of adolescents treated for antisocial behavior and substance use disorders and their siblings and a matched control sample. A model fitting approach was used to test 13 alternative hypotheses for the causes of comorbidity. RESULTS: The best supported hypothesis for the comorbidity between alcohol dependence and illicit drug dependence was a model hypothesizing that comorbid disorders are alternate forms of a single underlying liability. The next best fitting models were two of the correlated liabilities models (correlated risk factors and reciprocal causation). DISCUSSION: The results suggest that the best hypotheses explaining the comorbidity between alcohol and illicit drug dependence in adolescents are that alcohol dependence and illicit drug dependence are manifestations of a single general liability to develop substance dependence or that there are separate liabilities that are highly correlated.

Adolescent↗

PubMed2006

Multiple sclerosis in twins from continental Italy and Sardinia: a nationwide study.

Knowledge about the balance between heritable and nonheritable risk in multiple sclerosis (MS) is based on twin studies in high-prevalence areas. In a study that avoided ascertainment limitations and directly compared continental Italy (medium-prevalence) and Sardinia (high-prevalence), we ascertained 216 pairs from 34,549 patients. This gives a twinning rate of 0.62% among MS patients, significantly less than that of the general population. In continental Italy, probandwise concordance was 14.5% (95% confidence interval, 5.1-23.8) for monozygotic and 4.0% (95% confidence interval, 0.8-7.1) for dizygotic twins. Results in Sardinia resemble those in northern populations but in limited numbers. Monozygotic concordance was 22.2% (95% confidence interval, 0-49.3) probandwise, but no concordant dizygotic pairs were identified. A questionnaire on 80 items possibly related to disease cause was administered to 70 twin pairs, 135 sporadic patients, and 135 healthy volunteers. Variables positively (7) or negatively (2) associated with predisposition and concordance in twins largely overlapped and were mainly linked to infection. If compared with previous studies, our data demonstrate that penetrance in twins appears to correlate with MS prevalence. They highlight the relevance of nonheritable variables in Mediterranean areas. The apparent underrepresentation of MS among Italian twins draws attention to protective factors, shared by twins, that may influence susceptibility.

Cohort Studies↗

PubMed2006

Associations among postpartum depression, eating disorders, and perfectionism in a population-based sample of adult women.

OBJECTIVE: The current study investigated associations among eating disorders, depressive symptoms during pregnancy and postpartum, and perfectionism in a population-based sample of women. METHOD: Females who reported > or = 1 pregnancy (N = 1,119) completed questionnaires assessing perfectionism, eating disorder symptomatology, and depression during pregnancy and postpartum. Information regarding participants' history of major depressive disorder (MDD) was also available from structured psychiatric interviews completed during a previous wave of data collection. RESULTS: Depressive symptoms during pregnancy and postpartum were high among women with a history of eating disorders. Both binge eating disorder (BED) and bulimia nervosa (BN) were positively associated with symptoms of postpartum depression (PPD), even when lifetime MDD was controlled. However, logistic regression indicated that women with a history of BN and BED are at particular risk of developing PPD symptomatology. Linear regression analyses conducted with the subset of the sample who endorsed a PPD screening item suggested that the severity of PPD symptomatology may be attributable to Concern Over Mistakes, a specific aspect of perfectionism. CONCLUSION: These results highlight the importance of assessing specific features of perfectionism. In addition, they suggest that women with BN, BED, or high Concern over Mistakes may be at particular risk of developing PPD symptoms, and could benefit from prenatal screening.

Adult↗

PubMed2006

A pediatric twin study of brain morphometry.

BACKGROUND: Longitudinal pediatric neuroimaging studies have demonstrated increasing volumes of white matter and regionally-specific inverted U shaped developmental trajectories of gray matter volumes during childhood and adolescence. Studies of monozygotic and dyzygotic twins during this developmental period allow exploration of genetic and non-genetic influences on these developmental trajectories. METHOD: Magnetic resonance imaging brain scans were acquired on a pediatric sample of 90 monozygotic twin pairs, 38 same-sex dyzygotic twin pairs, and 158 unrelated typically developing singletons. Structural equation modeling was used to estimate the additive genetic, common environment, and unique environment effects, as well as age by heritability interactions, on measures of brain volumes from these images. RESULTS: Consistent with previous adult studies, additive genetic effects accounted for a substantial portion of variability in nearly all brain regions with the notable exception of the cerebellum. Significant age by heritability interactions were observed with gray matter volumes showing a reduction in heritability with increasing age, while white matter volume heritability increased with greater age. CONCLUSION: Understanding the relative contributions of genetic and nongenetic factors on developmental brain trajectories may have implications for better understanding brain-based disorders and typical cognitive development.

Adolescent↗

PubMed2006

Identification of susceptibility loci for alcohol-related traits in the Irish Affected Sib Pair Study of Alcohol Dependence.

BACKGROUND: Alcoholism is a phenotypically and probably genetically heterogeneous condition. Thus, one strategy for finding genes influencing liability to alcoholism is to study the components of alcoholism, which may be more directly related to the underlying pathophysiology than is clinical diagnosis. The goal of this study was to identify genomic regions containing susceptibility loci for alcohol-related traits. METHODS: A 4-cM dense whole-genome linkage study was conducted in the Irish Affected Sib Pair Study of Alcohol Dependence. Probands, affected siblings, and parents were evaluated by structured interview. Variance component linkage analysis was applied to data from 485 families for 5 measures: initial sensitivity and tolerance (based on scales from the self-report of the effects of ethanol; maximum drinks within 24 hours, an empirically derived factor score based on withdrawal symptoms, and age at onset of alcohol dependence. RESULTS: Evidence for linkage (p<0.005) was found on 9 chromosomes. For age at onset, 2 regions were found on chromosome 9 (highest Lod=2.3, p=0.0005). For initial level of response to alcohol, suggestive regions were on chromosomes 1 and 11 (highest Lod=2.9, p=0.0001 on chromosome 11), while those for tolerance signals were on chromosomes 1, 6, and 22. Maximum drinking was associated with regions on chromosomes 12 and 18. For withdrawal symptoms, the highest peak was on chromosome 2 (Lod=2.2, p=0.0007). CONCLUSIONS: Using quantitative measures of components of alcohol dependence, we identified several regions of the genome that may contain susceptibility loci for specific alcohol-related traits and merit additional study.

Adult↗

PubMed2006

A joint genomewide linkage analysis of symptoms of alcohol dependence and conduct disorder.

BACKGROUND: A large linkage peak for alcohol dependence (AD) was detected on chromosome 4q in the Irish Affected Sib Pair Study of Alcohol Dependence (IASPSAD). Are the susceptibility genes underlying this peak specific for AD or do they increase risk for externalizing disorders more generally? Can we, in the IASPSAD, replicate prior evidence for linkage to conduct disorder (CD)? METHODS: The 733 all possible sibling pairs in IASPSAD were typed for 1,020 short-tandem-repeat genetic markers. Univariate and bivariate linkage analyses were conducted by the program sequential oligogenic linkage analysis routines (SOLAR), for both the raw and the transformed number of symptoms of AD (ADsx) and number of symptoms of CD (CDsx). In the bivariate analyses, specificity was assessed by the ratio of the variance accounted for in ADsx and CDsx by the quantitative trait locus. RESULTS: In the univariate linkage analyses, no evidence for linkage to CDsx was found under the 4q peak for ADsx and the largest peaks for CDsx were seen on chromosomes 1q (LOD=3.16) and 14p (LOD=2.36). In the bivariate linkage analysis, the 4q peak had high specificity for AD (AD/CD ratio of 39.9). Several smaller peaks, on chromosomes 1, 7, and 10, had moderate specificity for CD but also impacted on risk for AD, with AD/CD ratios of 0.18 to 0.32. CONCLUSIONS: Genes under the 4q linkage peak for AD in the IASPSAD impact specifically on risk for AD rather than more broadly on risk for externalizing syndromes. Suggestive linkages were found in several locations for CD, 2 of which broadly replicate prior findings. The bivariate analyses identified genomic locations containing susceptibility loci that impacted on risk for both CDsx and ADsx.

Alcohol-Related Disorders↗

PubMed2006

A population-based twin study of the relationship between neuroticism and internalizing disorders.

OBJECTIVE: The anxiety and depressive disorders exhibit high levels of lifetime comorbidity with one another. The authors examined how genetic and environmental factors shared by the personality trait neuroticism and seven internalizing disorders may help explain this comorbidity. METHOD: Lifetime major depression, generalized anxiety disorder, panic disorder, agoraphobia, social phobia, animal phobia, situational phobia, and neuroticism were assessed in over 9,000 twins from male-male, female-female, and opposite-sex pairs through structured diagnostic interviews. Multivariate structural equation models were used to decompose the correlations between these phenotypes into genetic and environmental components, allowing for sex-specific factors. RESULTS: Genetic factors shared with neuroticism accounted for between one-third and one-half of the genetic risk across the internalizing disorders. When nonsignificant gender differences were removed from the models, the genetic correlations between neuroticism and each disorder were high, while individual-specific environmental correlations were substantially lower. In addition, the authors could identify a neuroticism-independent genetic factor that significantly increased risk for major depression, generalized anxiety disorder, and panic disorder. CONCLUSIONS: There is substantial, but not complete, overlap between the genetic factors that influence individual variation in neuroticism and those that increase liability across the internalizing disorders, helping to explain the high rates of comorbidity among the latter. This may have important implications for identifying the susceptibility genes for these conditions.

Adult↗

PubMed2006

Detecting genotype-environment interaction in monozygotic twin data: comparing the Jinks and Fulker test and a new test based on Marginal Maximum Likelihood estimation.

This article is concerned with the power to detect the presence of genotype by environment interaction (G x E) in the case that both genes and environment feature as latent (i.e., unmeasured) variables. The power of the test proposed by Jinks and Fulker (1970), which is based on regressing the absolute difference between the scores of monozygotic twins on the sums of these scores, is compared to the power of an alternative test, which is based on Marginal Maximum Likelihood (MML). Simulation studies showed that generally the power of the MML-based test was greater than the power of the Jinks and Fulker test in detecting linear and curvilinear G x E interaction, regardless of whether the distribution of the data deviated significantly from normality. However, after a normalizing transformation, the Jinks and Fulker test performed slightly better. Some possible future extensions of the MML-based test are briefly discussed.

Biometry↗

PubMed2006

A finite mixture model for genotype and environment interactions: detecting latent population heterogeneity.

Approaches such as DeFries-Fulker extremes regression (LaBuda et al., 1986) are commonly used in genetically informative studies to assess whether familial resemblance varies as a function of the scores of pairs of twins. While useful for detecting such effects, formal modeling of differences in variance components as a function of pairs' trait scores is rarely attempted. We therefore present a finite mixture model which specifies that the population consists of latent groups which may differ in (i) their means, and (ii) the relative impact of genetic and environmental factors on within-group variation and covariation. This model may be considered as a special case of a factor mixture model, which combines the features of a latent class model with those of a latent trait model. Various models for the class membership of twin pairs may be employed, including additive genetic, common environment, specific environment or major locus (QTL) factors. Simulation results based on variance components derived from Turkheimer and colleagues (2003), illustrate the impact of factors such as the difference in group means and variance components on the feasibility of correctly estimating the parameters of the mixture model. Model-fitting analyses estimated group heritability as .49, which is significantly greater than heritability for the rest of the population in early childhood. These results suggest that factor mixture modeling is sufficiently robust for detecting heterogeneous populations even when group mean differences are modest.

Biometry↗

PubMed2006

Multivariate genetic analysis of sex limitation and G x E interaction.

Sex-limited expression of genetic or environmental factors occurs in two basic forms. First, the effects of a factor may be larger on one sex than on another, which is known as scalar sex limitation. Second, some factors may have an effect on one sex but not on the other, which is called nonscalar sex limitation. In the classical twin study, scalar sex-limited effects cause same-sex male and same-sex female twin correlations to differ. Nonscalar sex-limited effects would cause the correlations between opposite-sex pairs of relatives to be lower than would be expected from the correlations between relatives of the same sex. One approach to modeling such effects is to allow the genetic correlation between opposite-sex dizygotic twins to be less than one-half; another is to allow the common environment correlation for opposite-sex pairs to be less than unity. Extension of this approach to the multivariate case is not straightforward. Direct extension of the Cholesky decomposition such that each Cholesky factor is allowed to correlate less than one-half in opposite-sex pairs yields a model where the order of the variables can change the goodness-of-fit of the model. It is shown that similar problems exist with a variety of multivariate and longitudinal models, and in a variety of models of genotype x environment interaction. Several solutions to these problems are described.

Female↗