Showing papers by "Michael C. Neale published in 2011"

OpenMx: An Open Source Extended Structural Equation Modeling Framework

Abstract: OpenMx is free, full-featured, open source, structural equation modeling (SEM) software. OpenMx runs within the R statistical programming environment on Windows, Mac OS–X, and Linux computers. The rationale for developing OpenMx is discussed along with the philosophy behind the user interface. The OpenMx data structures are introduced—these novel structures define the user interface framework and provide new opportunities for model specification. Two short example scripts for the specification and fitting of a confirmatory factor model are next presented. We end with an abbreviated list of modeling applications available in OpenMx 1.0 and a discussion of directions for future development.

The Structure of Genetic and Environmental Risk Factors for Syndromal and Subsyndromal Common DSM-IV Axis I and All Axis II Disorders

Abstract: Objective:The authors sought to clarify the structure of the genetic and environmental risk factors for 22 DSM-IV disorders: 12 common axis I disorders and all 10 axis II disorders. Method:The authors examined syndromal and subsyndromal axis I diagnoses and five categories reflecting number of endorsed criteria for axis II disorders in 2,111 personally interviewed young adult members of the Norwegian Institute of Public Health Twin Panel. Results:Four correlated genetic factors were identified: axis I internalizing, axis II internalizing, axis I externalizing, and axis II externalizing. Factors 1 and 2 and factors 3 and 4 were moderately correlated, supporting the importance of the internalizing-externalizing distinction. Five disorders had substantial loadings on two factors: borderline personality disorder (factors 3 and 4), somatoform disorder (factors 1 and 2), paranoid and dependent personality disorders (factors 2 and 4), and eating disorders (factors 1 and 4). Three correlated environmental factors...

The joint structure of DSM-IV Axis I and Axis II disorders.

Abstract: The Diagnostic and Statistical Manual (4th ed. [DSM-IV]; American Psychiatric Association, 1994) distinction between clinical disorders on Axis I and personality disorders on Axis II has become increasingly controversial. Although substantial comorbidity between axes has been demonstrated, the structure of the liability factors underlying these two groups of disorders is poorly understood. The aim of this study was to determine the latent factor structure of a broad set of common Axis I disorders and all Axis II personality disorders and thereby to identify clusters of disorders and account for comorbidity within and between axes. Data were collected in Norway, through a population-based interview study (N = 2,794 young adult twins). Axis I and Axis II disorders were assessed with the Composite International Diagnostic Interview (CIDI) and the Structured Interview for DSM-IV Personality (SIDP-IV), respectively. Exploratory and confirmatory factor analyses were used to investigate the underlying structure of 25 disorders. A four-factor model fit the data well, suggesting a distinction between clinical and personality disorders as well as a distinction between broad groups of internalizing and externalizing disorders. The location of some disorders was not consistent with the DSM-IV classification; antisocial personality disorder belonged primarily to the Axis I externalizing spectrum, dysthymia appeared as a personality disorder, and borderline personality disorder appeared in an interspectral position. The findings have implications for a meta-structure for the DSM.

Blue Again: Perturbational Effects of Antidepressants Suggest Monoaminergic Homeostasis in Major Depression

Abstract: Some evolutionary researchers have argued that current diagnostic criteria for major depressive disorder (MDD) may not accurately distinguish true instances of disorder from a normal, adaptive stress response. According to disorder advocates, neurochemicals like the monoamine neurotransmitters (serotonin, norepinephrine, and dopamine) are dysregulated in major depression. Monoamines are normally under homeostatic control, so the monoamine disorder hypothesis implies a breakdown in homeostatic mechanisms. In contrast, adaptationist hypotheses propose that homeostatic mechanisms are properly functioning in most patients meeting current criteria for MDD. If the homeostatic mechanisms regulating monoamines are functioning properly in these patients, then oppositional tolerance should develop with prolonged antidepressant medication (ADM) therapy. Oppositional tolerance refers to the forces that develop when a homeostatic mechanism has been subject to prolonged pharmacological perturbation that attempt to bring the system back to equilibrium. When pharmacological intervention is discontinued, the oppositional forces cause monoamine levels to overshoot their equilibrium levels. Since depressive symptoms are under monoaminergic control, this overshoot should cause a resurgence of depressive symptoms that is proportional to the perturbational effect of the ADM. We test this prediction by conducting a meta-analysis of ADM discontinuation studies. We find that the risk of relapse after ADM discontinuation is positively associated with the degree to which ADMs enhance serotonin and norepinephrine in prefrontal cortex, after controlling for covariates. The results are consistent with oppositional tolerance, and provide no evidence of malfunction in the monoaminergic regulatory mechanisms in patients meeting current diagnostic criteria for MDD. We discuss the evolutionary and clinical implications of our findings.

Genetic and Environmental Contributions to Regional Cortical Surface Area in Humans: A Magnetic Resonance Imaging Twin Study

Abstract: Cortical surface area measures appear to be functionally relevant and distinct in etiology, development, and behavioral correlates compared with other size characteristics, such as cortical thickness. Little is known about genetic and environmental influences on individual differences in regional surface area in humans. Using a large sample of adult twins, we determined relative contributions of genes and environment on variations in regional cortical surface area as measured by magnetic resonance imaging before and after adjustment for genetic and environmental influences shared with total cortical surface area. We found high heritability for total surface area and, before adjustment, moderate heritability for regional surface areas. Compared with other lobes, heritability was higher for frontal lobe and lower for medial temporal lobe. After adjustment for total surface area, regionally specific genetic influences were substantially reduced, although still significant in most regions. Unlike other lobes, left frontal heritability remained high after adjustment. Thus, global and regionally specific genetic factors both influence cortical surface areas. These findings are broadly consistent with results from animal studies regarding the evolution and development of cortical patterning and may guide future research into specific environmental and genetic determinants of variation among humans in the surface area of particular regions.

Presence of ApoE ε4 allele associated with thinner frontal cortex in middle age.

Abstract: The presence of an ApoE e4 allele (e4+) increases the risk of developing Alzheimer's disease (AD). Previous studies support an adverse relationship between e4+ status and brain structure and function in mild cognitive impairment and AD; in contrast, the presence of an e2 allele may be protective. Whether these findings reflect disease-related effects or pre-existing endophenotypes, however, remains unclear. The present study examined the influence of ApoE allele status on brain structure solely during middle-age in a large, national sample. Participants were 482 men, ages 51-59, from the Vietnam Era Twin Study of Aging (VETSA). T1-weighted images were used in volumetric segmentation and cortical surface reconstruction methods to measure regional volume and thickness. Primary linear mixed effects models predicted structural measures with ApoE status (e3/3, e2/3, e3/4) and control variables for effects of site, non-independence of twin data, age, and average cranial vault or cortical thickness. Relative to the e3/3 group, the e3/4 group demonstrated significantly thinner cortex in superior frontal and left rostral and right caudal midfrontal regions; there were no significant effects of e4 status on any temporal lobe measures. The e2/3 group demonstrated significantly thicker right parahippocampal cortex relative to the e3/3 group. The ApoE e4 allele may influence cortical thickness in frontal areas, which are later developing regions thought to be more susceptible to the natural aging process. Previous conflicting findings for mesial temporal regions may be driven by the inclusion of older individuals, who may evidence preclinical manifestations of disease, and by unexamined moderators of e4-related effects. The presence of the e2 allele was related to thicker cortex, supporting a protective role. Ongoing follow-up of the VETSA sample may shed light on the potential for age- and disease-related mediation of the influence of ApoE allele status.

Genetic patterns of correlation among subcortical volumes in humans: results from a magnetic resonance imaging twin study.

Abstract: Little is known about genetic influences on the volume of subcortical brain structures in adult humans, particularly whether there is regional specificity of genetic effects. Understanding patterns of genetic covariation among volumes of subcortical structures may provide insight into the development of individual differences that have consequences for cognitive and emotional behavior and neuropsychiatric disease liability. We measured the volume of 19 subcortical structures (including brain and ventricular regions) in 404 twins (110 monozygotic and 92 dizygotic pairs) from the Vietnam Era Twin Study of Aging and calculated the degree of genetic correlation among these volumes. We then examined the patterns of genetic correlation through hierarchical cluster analysis and by principal components analysis. We found that a model with four genetic factors best fit the data: a Basal Ganglia/Thalamus factor; a Ventricular factor; a Limbic factor; and a Nucleus Accumbens factor. Homologous regions from each hemisphere loaded on the same factors. The observed patterns of genetic correlation suggest the influence of multiple genetic influences. There is a genetic organization among structures which distinguishes between brain and cerebrospinal fluid spaces and between different subcortical regions. Further study is needed to understand this genetic patterning and whether it reflects influences on early development, functionally dependent patterns of growth or pruning, or regionally specific losses due to genes involved in aging, stress response, or disease.

Generalized anxiety disorder and anorexia nervosa: evidence of shared genetic variation

Abstract: Background: Previous studies have indicated a high prevalence of generalized anxiety disorder (GAD) in women with anorexia nervosa (AN). However, the shared genetic and environmental components of these disorders have not been explored. This study seeks to elucidate the shared genetic and environmental components between GAD and AN. Method: Using 2,083 women from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders, structural equation modeling was used to obtain maximum likelihood estimates of the environmental genetic, shared and unique environmental components in 496 women with GAD, 47 women with AN, 43 women with GAD + AN, and 1,497 women without GAD or AN. Results: Results show that the heritability of GAD was 0.32 and AN was 0.31, and the genetic correlation between the two disorders was 0.20, indicating a modest genetic contribution to their comorbidity. Unique environment estimate was 0.68 for GAD and 0.69 for AN, with a unique environmental correlation of 0.18. All common environmental parameters were estimated at zero. Conclusions: The modest shared genetic and unique environmental liability to both disorders may help explain the high prevalence of GAD in women with AN. This knowledge could help in the treatment and prevention of comorbid disorders. Depression and Anxiety, 2011. © 2011 Wiley-Liss, Inc.

Age moderates non‐genetic influences on the initiation of cannabis use: a twin‐sibling study in Dutch adolescents and young adults

Abstract: Aims To examine the heritability of cannabis initiation, the influence of a possible twin-specific environment and the influence of age on the effects of genes and environment in Dutch adolescents and young adults. Design Genetic structural equation modelling was used to partition the variance in the liability to cannabis initiation into genetic and environmental components. Setting All participants were registered with the Netherlands Twin Register. Partici- pants Atotalof 6208twins(age13-20)and1545siblings(age11-25)from3503familiesparticipatedinthisstudy. Measurements Self-reportedcannabisusewasassessedprospectivelywiththeDutchHealthBehaviorQuestionnaire. Findings At the median age of the sample (16.5), genetic factors explained 40% of the individual differences in liability to cannabis initiation.Twins resembled each other more than non-twin siblings, which could not be attributed to the age difference between non-twin siblings. Environmental influences increased with age.This increase applied to environmental factors shared by twins (47% of the variance), environmental factors shared by twins and siblings (24%) and environmental factors unique to an individual (13%). Conclusion The heritability of the liability for cannabis initiation is higher in adolescents than in young adults due to a larger contribution of environmental factors in young adults. This is due mainly to environmental factors only shared by twins and those shared by all offspring growing up in the same family, but the contribution of environmental factors specific to individuals is also larger in young adults.

A twin association study of nicotine dependence with markers in the CHRNA3 and CHRNA5 genes.

Abstract: Twin and family studies have provided overwhelming evidence for the genetic basis of individual differences in tobacco initiation (TI), regular smoking (RS) and nicotine dependence (ND). However, only a few genes have been reliably associated with ND. We used a finite mixture distribution model to examine the significance and effect size of the association of previously identified and replicated specific variants in the CHRNA5 and CHRNA3 receptor genes with ND, against the background of genetic and environmental risk factors for ND. We hypothesize that additional phenotypic information in relatives who have not been genotyped can be used to increase the power of detecting the genetic variant. The nicotine measures were assessed by personal interview in female, male and opposite sex twin pairs (N = 4,153) from the population-based Virginia Twin Registry. Three SNPs in the CHRNA5 and CHRNA3 receptor genes, previously shown to be significantly associated with ND in this sample, were replicated in the augmented analyses; they accounted for less than one percent of the genetic variance in liability to ND, which is estimated to be over 50% of the phenotypic variance. The significance of these effects was increased by adding twins with phenotype but without genotype data, but gains are limited and variable. The SNPs associated with ND did not show a significant association with either TI or RS and appear to be specific to the addictive stage of ND, characterized by current smoking and smoking a large amount of cigarettes per day. Furthermore, these SNPs did not appear to be associated with the remaining items comprising the FTND scale. This study confirmed a significant contribution of the CHRNA receptor on different forms of tobacco dependence. However, the genetic variant only accounted for little of the total genetic variance for liability to ND. Including phenotypic data on ungenotyped relatives can improve the statistical power to detect the effects of genetic variants when they contribute to individual differences in the phenotype.

An Investigation of Weight Suppression in a Population-Based Sample of Female Twins

Abstract: Weight suppression (WS), defined as the discrepancy between one’s highest adult and current weight, is a relatively understudied concept in the area of eating disorders. It was first highlighted in Lowe’s [1] three-factor model of dieting behavior, which included frequency of dieting and overeating, current dieting, and WS. To date, this construct has been investigated primarily among clinical samples, and evidence suggests that WS negatively impacts the course and treatment of eating disorders [e.g., 2]. However, given the rapid increases in rates of overweight and obesity in the U.S. [3–4], it is possible that the ability to maintain weight loss could be advantageous among subsamples of the general population. The following sections briefly review studies of WS and eating-and weight-related constructs among eating disordered and non-eating disordered samples. Restraint theory posits that dietary restraint leads to subsequent overeating [5–6]. However, some have argued that restraint theory does not distinguish between chronic and acute dieting [1]. That is, while acute dieting may increase risk for overeating (including binge eating), chronic dieting may be advantageous for sustaining healthy weight loss. Data suggest that individuals who successfully maintain weight loss in the long term are able to consciously control their dietary intake. For example, participants in the National Weight Control Registry, who have lost an average of 33 kg and maintained this weight loss for more than five years, report fairly high levels of cognitive restraint [7]. Notably, these levels are lower than those of eating disorder patients [7]. Experimental studies suggest that individuals who have lost weight successfully and maintained that loss (i.e., weight suppressors) have adapted their appetitive reactions in a way that facilitates their ability to control weight (e.g., reduced preference for sweets [8]). Thus, the construct of WS may behave differently among individuals with and without eating disorders. Most investigations have demonstrated the negative effects of WS on eating disorders and related constructs. In addition, it has been hypothesized that WS might be particularly relevant to bulimia nervosa (BN), as individuals with this disorder often enter treatment at weights substantially below their highest adult weights. Specifically, in two samples of BN patients in a low-normal weight range, Garner and Fairburn [9] found that one-third and one-half, respectively, had previously been at least 15% overweight. Further, WS was found to be a significant predictor of weight gain among individuals receiving inpatient treatment for BN [10]. WS was also positively associated with binge eating frequency in a sample of women with BN [11]. Evidence further suggests that WS can impact the course of this disorder [2, 11]. For example, Butryn et al. [2] found that WS predicted attrition from BN treatment as well as poor outcomes (i.e., inability to achieve abstinence from bingeing and purging) among treatment completers. Taken together, these results suggest that WS may contribute to the development and maintenance of eating disorders, particularly BN. In addition to these investigations of WS in samples of patients with eating disorders [2, 10, 11], one recent study included non-treatment seeking college freshmen [12]. Lowe, Annunziato et al. [12] found that WS and a history of dieting for weight loss predicted weight gain. However, restraint, disinhibition, and emotional eating were not associated with weight gain in this sample. The authors noted that these results provided further support for WS and restraint as distinct constructs; further, they argued that WS appears to be a robust predictor of future weight gain. These studies provide important information regarding the WS construct; however results from treatment-seeking and college samples may not be applicable to the general population of adults. Although WS has been associated with eating disorder-related traits and weight gain among these groups, eating disordered and college samples might be particularly vulnerable to both more severe eating disorder symptomatology as well as greater weight gain than the general population [12]. Thus, the current study investigated associations among WS and eating disorder-related variables in a population-based sample of female twins, to determine whether these relationships differ for individuals reporting binge eating and loss of control (BE+LOC) vs. those reporting no binge eating (NBE). We chose to examine this form of disordered eating in our population-based sample, as evidence suggests that individuals manifesting subthreshold levels of binge eating report levels of distress comparable to those with binge eating disorder (e.g., [13]). The current study also estimated genetic and environmental influences on WS. Twin samples are useful for such analyses, as including both monozygotic (MZ) and dizygotic (DZ) twins in a structural equation model allows the variance of a given trait to be partitioned into additive genetic (A), common environmental (i.e., that which is shared among twin pairs; C), and unique environmental (i.e., that which is not shared among twin pairs; E) influences [14]. There are several reasons why twin research could provide insight into WS and related constructs. First, body mass index (BMI) is strongly influenced by genetic factors (e.g., approximately 50–90% of variance in BMI is attributable to additive genetic effects [15]). Second, twin studies of eating disorders have found that AN, BN, and related behaviors (e.g., binge eating and vomiting) are moderately heritable (for a review, see Bulik, et al. [16]). However, twin studies have also indicated that specific disordered eating related behaviors and attitudes are differentially influenced by genetic and environmental factors. For example, Neale et al. [17] found that disinhibited eating was most strongly influenced by additive genetic factors. However, restraint was more strongly influenced by common environmental factors. Similarly, the undue influence of weight on self-evaluation has been found to be more strongly influenced by environmental, rather than genetic, factors [18]. Thus, it is unclear to what degree genetic and environmental factors might influence liability to the specific construct of WS. In sum, the current study investigated WS among NBE and BE+LOC women in two ways. Regression models investigating relations between WS and eating disorder-related constructs (body dissatisfaction, drive for thinness, Restraint, Disinhibition, Hunger, and time spent dieting before and after age 18) were conducted separately in these two subsamples. We hypothesized that the associations among these variables and WS might differ for women reporting BE+LOC, relative to NBE participants, such that WS would be associated with more pathological behaviors among the BE+LOC group. Second, the genetic and environmental sources of variance were estimated in each subsample. We hypothesized that genetic influences on WS would be stronger in the BE+LOC group, relative to the NBE group, based on results of prior twin studies in the area of eating disorders.

Differential age and sex effects in the assessment of major depression: a population-based twin item analysis of the DSM criteria.

Abstract: A twin item factor analytic model was developed to test for the presence of noninvariant age, sex, and age by sex interaction effects on the individual DSM-III-R criteria for major depression (MD). Based on 1-year reports, six of the nine MD criteria and duration requirement were found to have covariate factor loading and/or threshold effects that significantly deviated from their corresponding factor level expectations. A significant age effect was found for the binary duration variable factor loading. The ‘loss of interest’, ‘weight problems’ and ‘psychomotor problems’ criteria all displayed forms of threshold only effects. ‘Depressed mood’, ‘fatigue’, and ‘feeling worthless’ had more complex patterns that included both factor loading and threshold effects. A significant factor age by sex interaction effect indicating an increasing female mean difference with age was found to be largely associated with the presence of differential threshold covariate effects. Disagreement between estimated factor scores and DSM-derived affected vs. unaffected classification was ~ 1.3%. Status on the duration requirement was found to be the one feature common to all discrepancies. The MD criteria set provided maximum information for calibrating MD factor scores in the scale region where discrepancies occurred. The dimensional modeling results are discussed in the broader context of epidemiological research and clinical assessment of major depression.