Showing papers by "Michael C. Neale published in 1995"

Stressful life events, genetic liability, and onset of an episode of major depression in women.

Abstract: Objective This study was undertaken to clarify how genetic liability and stressful life events interact in the etiology of major depression. Method Information about stressful life events and onset of major depressive episodes in the past year was collected in a population-based sample of female-female twin pairs including 2,164 individuals, 53,215 person-months of observation, and 492 onsets of depression. Results Nine "personal" and three aggregate "network" stressful events significantly predicted onset of major depression in the month of occurrence, four of which predicted onset with an odds ratio of > 10 and were termed "severe": death of a close relative, assault, serious marital problems, and divorce/breakup. Genetic liability also had a significant impact on risk of onset of depression. For severe stressful events, as well as for 10 of the 12 individual stressful events, the best-fitting model for the joint effect of stressful events and genetic liability on onset of major depression suggested genetic control of sensitivity to the depression-inducing effects of stressful life events. In individuals at lowest genetic risk (monozygotic twin, co-twin unaffected), the probability of onset of major depression per month was predicted to be 0.5% and 6.2%, respectively, for those unexposed and exposed to a severe event. In those at highest genetic risk (monozygotic twin, co-twin affected), these probabilities were 1.1% and 14.6%, respectively. Linear regression analysis indicated significant Genotype by Environment interaction in the prediction of onset of major depression. Conclusions Genetic factors influence the risk of onset of major depression in part by altering the sensitivity of individuals to the depression-inducing effect of stressful life events.

The structure of the genetic and environmental risk factors for six major psychiatric disorders in women. Phobia, generalized anxiety disorder, panic disorder, bulimia, major depression, and alcoholism.

Abstract: Background: Although prior family and twin studies have examined the relationship between the genetic and environmental risk factors for pairs of psychiatric disorders, the interrelationship between these classes of risk factors for a broad range of psychiatric disorders remains largely unknown. Methods: An epidemiologic sample of 1030 femalefemale twin pairs with known zygosity, ascertained from the Virginia Twin Registry, were evaluated by a personal interview conducted by mental health professionals, assessing lifetime history of phobia, generalized anxiety disorder, panic disorder, bulimia nervosa, major depression, and alcoholism. Results: A multivariate twin analysis suggested the following: First, genetic, familial-environmental, and individual-specific environmental risk factors each cause a unique pattern of comorbidity among the six disorders. Second, genetic influences on these disorders are best explained by two factors, the first of which loads heavily on phobia, panic disorder, and bulimia nervosa and the second, on major depression and generalized anxiety disorder. Third, unlike other disorders, genetic influences on alcoholism are largely disorder specific. Fourth, familialenvironmental influences on these disorders are best explained by a single factor that substantially influenced liability to bulimia nervosa only. Fifth, individual-specific environmental influences on the risk for these psychiatric disorders are best explained by a single factor, with highest loadings on generalized anxiety disorder and major depression and with large-disorder—specific loadings, especially on phobias, panic disorder, and alcoholism. Conclusions: These results support the following hypotheses: First, each major risk factor domain (genes, family environment, and individual-specific environment) influences comorbidity between these disorders in a distinct manner. Second, genetic influences on these six disorders are neither highly specific nor highly nonspecific. Neither a model that contains a discrete set of genetic factors for each disorder nor a model in which all six disorders results from a single set of genes is well supported. Third, the anxiety disorders are not, from a genetic perspective, etiologically homogeneous. Fourth, most of the genetic factors that influence vulnerability to alcoholism in women do not alter the risk for development of other common psychiatric disorders. These results should be interpreted in the context of both the strengths and limitations of multivariate twin analysis.

Models of comorbidity for multifactorial disorders.

Abstract: We develop several formal models for comorbidity between multifactorial disorders. Based on the work of D. N. Klein and L. P. Riso, the models include (i) alternate forms, where the two disorders have the same underlying continuum of liability; (ii) random multiformity, in which affection status on one disorder abruptly increases risk for the second; (iii) extreme multiformity, where only extreme cases have an abruptly increased risk for the second disorder; (iv) three independent disorders, in which excess comorbid cases are due to a separate, third disorder; (v) correlated liabilities, where the risk factors for the two disorders correlate; and (vi) direct causal models, where the liability for one disorder is a cause of the other disorder. These models are used to make quantitative predictions about the relative proportions of pairs of relatives who are classified according to whether each relative has neither disorder, disorder A but not B, disorder B but not A, or both A and B. For illustration, we analyze data on major depression (MD) and generalized anxiety disorder (GAD) assessed in adult female MZ and DZ twins, which enable estimation of the relative impact of genetic and environmental factors. Several models are rejected--that comorbid cases are due to chance; multiformity of GAD; a third independent disorder; and GAD being a cause of MD. Of the models that fit the data, correlated liabilities, MD causes GAD, and reciprocal causation seem best. MD appears to be a source of liability for GAD. Possible extensions to the models are discussed.

A twin study of generalized anxiety disorder and major depression

Abstract: Previous analyses with a sample of female twins sampled from the general population in Virginia have suggested that generalized anxiety disorder (GAD) and major depression (MD) share their genetic determinants but have partly different environmental determinants. The goal of this report is to examine whether these findings apply to samples that include male as well as female twins and contain high proportions of subjects who had been hospitalized for MD. The subjects were ascertained through two different sources: (i) index probands were ascertained through the Swedish Psychiatric Twin Registry for a diagnosis of unipolar or bipolar affective illness; (ii) control twin probands were ascertained through the Swedish Twin Registry. Subjects were sent questionnaires for the assessment of lifetime history of GAD and MD. Positing multinormal distribution of the liability for GAD and MD, we fitted bivariate models to examine the sources of comorbidity. The full model included additive genetic effects, shared environment and individual-specific environment, as well as scalar and non-scalar sex limitations and different thresholds across genders. The best-fitting model included: (i) a genetic correlation of unity; (ii) no common environment; (iii) an individual-specific environmental correlation of 0.28; (iv) different thresholds across genders, but neither scalar nor non-scalar sex-limitations. A model that included additive and dominant genetic effects and individual-specific environment, with correlation of unity for both additive and dominant genetic effects, provided an equivalent fit. These analyses confirm that GAD and MD share the same genetic factors but that their environmental determinants are mostly distinct. Moreover, the present report supports the feasibility of combining clinical ascertained and general-population samples into a single bivariate analysis.

Evaluating the Spectrum Concept of Schizophrenia in the Roscommon Family Study

Abstract: Objective: The authors sought to evaluate whether the pattern ofschizophrenia and related disorders in probands and their relatives can be explained by a single underlying continuum ofliability to the “schizophrenia spectrum. “ Method: In the epidemiologically based Roscommon Family Study, the authors separately examined-in siblings, parents, and relatives of index and comparison probands-the familial aggregation and coaggregation offive hierarchically defined disorders: schizophrenia, schizoaffective disorder, schizotypal/paranoid personality disorder, other nonaffective psychoses, and psychotic affective illness. A multiple threshold model was fitted to these contingency tables by maximum likelihood. Results: The multiple threshold model that constrained resemblance to be the same in siblings and parents fit the data well and estimated the correlation in liability to schizophrenia spectrum disorders between probands and first-degree relatives at 0.36. Parents, however, required higher levels of liability to manifest schizophrenia spectrum disorders than siblings. While schizophrenia and psychotic affective illness could be clearly assigned to the two extremes ofthe schizophrenia spectrum, the proper ordering ofschizoaffective disorder, schizotypal/paranoid personality disorder, and other nonaffective psychoses could not be unambiguously determined. Conclusions: These results are consistent with the existence of a schizophrenia spectrum in which these five disorders are manifestations, of varying severity, of the same underlying vulnerability. This vulnerability is strongly transmitted within families. (Am J Psychiatry 1995; 152:749-754)

Physical similarity and the equal-environment assumption in twin studies of psychiatric disorders.

Abstract: The equal-environment assumption (EEA), upon which twin methodology is based, was examined for the impact of physical similarity on phenotypic resemblance in five common psychiatric disorders: major depression, generalized anxiety disorder, phobia, alcoholism, and bulimia. A population-based sample of 882 female-female twin pairs of known zygosity was rated for similarity of appearance by color photographs. Psychiatric diagnoses were made by clinical assessment of personal interviews of the twins. Structural equation modeling of the data using physical similarity as a form of specified common environment provided no evidence for a significant effect of physical resemblance on concordance for major depression, generalized anxiety disorder, phobia, and alcoholism, thereby supporting the validity of the EEA in twin studies of these disorders. Results for bulimia, on the other hand, suggest, within the limitations of this study, that physical similarity may significantly influence twin resemblance for this disorder.

A pilot Swedish twin study of affective illness including hospital- and population-ascertained subsamples: results of model fitting.

Abstract: We investigated the heritability of liability to affective illness (AI) in twins ascertained through psychiatric hospitalization for AI from the Swedish Psychiatric Twin Registry and from the general population Swedish Twin Registry. Lifetime diagnoses were assessed by mailed questionnaire containing, in self-report format, DSM-III-R criteria for mania and major depression (MD). Jointly analyzing both subsamples using Mx, and assuming a multifactorial threshold model, the best-fitting twin model using narrow diagnostic criteria suggested that the liability to AI could be explained by additive genetic effects, with an estimated heritability of liability of 64%, and individual-specific environment. Using broad criteria, results were similar except that the estimated broad heritability of liability was higher (83%) and due largely to dominance genetic effects. Fitting sex-dependent models suggested that the same genetic and environmental factors influenced liability to AI in men and women to the same degree, although women had a lower threshold of manifestation. These results suggested that in Sweden, AI is a highly heritable syndrome and family resemblance is due largely or entirely to genetic factors.

Genetic Covariance Structure of Incisor Crown Size in Twins

Abstract: Previous studies of tooth size in twins and their families have suggested a high degree of genetic control, although there have been difficulties separating the various genetic and environmental effects. A genetic analysis of variation in crown size of the permanent incisors of South Australian twins was carried out, with structural equation modeling used to determine the relative contributions of genetic and environmental factors. Maximum mesiodistal crown dimensions of maxillary and mandibular permanent incisors were recorded from dental models of 298 pairs of twins, including 149 monozygous (MZ) and 149 dizygous (DZ) pairs. The analysis revealed that: (i) an adequate fit required additive genetic and unique environmental components; (ii) augmenting the model with non-additive genetic variation did not lead to a significant improvement in fit; (iii) there was evidence of shared environmental influences in the upper central incisors of males; (iv) the additive genetic component constituted a general factor loading on all eight teeth, with group factors loading on antimeric pairs of teeth; (v) unique environmental effects were mostly variable-specific; (vi) most factor loadings on antimeric tooth pairs could be constrained to be equal, indicating a symmetry of genetic and environmental influences between left and right sides; and (vii) estimated heritability of the incisor mesiodistal dimensions varied from 0.81 to 0.91.

The genetic epidemiology of self-esteem.

Abstract: BACKGROUND Previous studies on self-esteem have focused exclusively on its psychosocial determinants. The goal of the present study is to clarify genetic v. environmental determinants of self-esteem. METHOD Participants were Caucasian women sampled from the Virginia Twin Register: 363 pairs of MZ and 238 pairs of DZ twins were available from the first wave of the study, and 430 pairs of MZ and 308 pairs of DZ twins from the second. Self-esteem was assessed with the Rosenberg's Self-Esteem Scale. RESULTS Using univariate twin analyses of self-esteem and a repeated measurement twin model, we found that self-esteem is a moderately heritable trait (heritability = 52% in the repeated measurement model); environmental influences are also very important, and are probably mostly not shared by members of a twin pair. CONCLUSIONS Aetiological models of self-esteem which examine only psychosocial factors are incomplete; genetic factors need to be integrated.

A twin-family study of self-report symptoms of panic-phobia and somatization.

Abstract: Self-report symptoms of anxiety are widely used in mental health and social science research as an index of current psychiatric state. Previous twin studies have suggested that genetic factors account for a significant proportion of the variance in these symptoms. To replicate and extend these findings, we examined self-report symptoms of panic-phobia and somatization in the "Virginia 30,000" twin-family sample. Model fitting applied to 80 unique relationships in the twin-family pedigree produced the following major results: (i) genetic effects were significant for both symptom factors, accounting for between 25 and 49% of the total variance, with the exception of symptoms of panic-phobia in females, where they accounted for 15-16% of the variance; (ii) familial environmental effects were absent for symptoms of somatization, while for symptoms of panic-phobia they accounted for a very small proportion of variance in males (< or = 1.2%) and a modest proportion in females (6-17%); (iii) spousal correlations were present for both factors, ranging from +0.05 to +0.20; (iv) genetic factors which influenced symptoms were generally the same in males and females, although their effect was greater in males; (v) heritability estimates were lower in the population-based than in the volunteer sample; and (vi) when test-retest reliability was included in the model, results suggest that genetic factors account for at least half of the stable variance for all symptom factors, except panic-phobia in females. Our results support the validity of previous twin studies of self-report symptoms of anxiety and suggest that genetic factors significantly influence these symptoms but familial-environmental factors play little or no etiologic role.

Multiple raters of disruptive child behavior: using a genetic strategy to examine shared views and bias.

Abstract: Most research on child behavior incorporates information from different individuals. While agreement between informants is generally only modest, there is little understanding of the processes underlying disagreement. In twin studies, differential agreement among raters for MZ and DZ twins is of particular concern. The processes underlying differences among mother, father, and child ratings of oppositional and conduct disorder symptoms are explored. Evidence in favor of a shared parental view of behavior is presented. Parental ratings give higher intrapair correlations, which could be due to either parents rating their twins more similarly or twins contrasting themselves. Rater bias and situational specificity are among the possible explanations of differential ratings. The effects of incorporating multiple raters of behavior on estimates of genetic and environmental effects are explored. These suggest that genetic influences are greater for the shared (multiple-rater) phenotype than for individual ratings; reduction in measurement error is only a partial explanation.

Genetic, environmental, and phenotypic links between body mass index and blood pressure among women.

Abstract: Greater relative weight is associated with higher blood pressure, but the reasons are unknown. The inability of current technology to induce sustained weight loss among overweight persons precludes experimental tests of whether this association is causal. We evaluated the degree to which the covariation between body mass index (BMI; kg/m2) and blood pressure (BP) among women is due to pleiotropic genetic factors, environmental factors, or phenotypic causation. The sample included 75 monozygotic (MZ) and 39 dizygotic (DZ) pairs of adult female twins. “BP” was calculated as the unitweighted mean of systolic and diastolic. Data were analyzed through structural equation modeling. A model was specified stipulating that additive genetic effects (A) and unique environmental effects (E) each contributed to the covariance between BMI and BP, thus allowing for both pleiotropic and unique environmental influences on the covariance between BMI and BP. Dropping the pleiotropic influences significantly worsened the model (χ2 = 4.62, df = 1, P = .032), suggesting significant pleiotropic effects. Dropping the environmental influences on the cross-phenotype covariance did not significantly worsen the model (χ2 = 1.42, df = 1, P =.233). This indicates no significant effect of the environment on the covariance between BMI and BP. Finally, a model of phenotypic causation in which BMI directly influenced BP was fitted. This model provided the best single parameter explanation of the BP-BMI covariation. These data suggest that, among women, regardless of the source of variation, chaanges in BMI should lead to long-standing changes in BP. © 1995 Wiley-Liss, Inc.

Research Design and Methods to Study the Genetic Epidemiology of Obesity

Abstract: As discussed elsewhere in this volume, obesity is associated with increased risk of cardiovascular disease. Besides its apparent health consequences, obesity can be a source of psychosocial stress. The overweight may worry about their future health, and may be subject to direct or indirect social pressures to be thin. To understand the causes of individual differences in body composition is therefore an important scientific objective.