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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.

Objective: Self-reported symptoms of depression are commonly used in mental health research to assess current psychiatric state, yet wide variation in these symptoms among individuals has been found in both clinical and epidemiologic populations. The authors sought to understand, from a genetic-epidemiologic perspective, the sources of individual differences in depressive symptoms. Method: Self-reported symptoms of depression were assessed in two samples of twins and their spouses, parents, siblings, and offspring: one sample contained volunteer twins recruited through the American Association of Retired Persons and their relatives (N=19,203 individuals) and the other contained twins from a population-based twin registry in Virginia and their relatives (N=11,242 individuals). Model fitting by an iterative, diagonal, weighted least squares method was applied to the 80 different family relationships in the extended twin-family design. Results: Independent analyses of the two samples revealed that the level of depressive symptoms was modestly familial, and familial resemblance could be explained solely by genetic factors and spousal resemblance. The estimated heritability of depressive symptoms was between 30% and 37%. There was no evidence that the liability to depressive symptoms was environmentally transmitted from parents to offspring or was influenced by environmental factors shared either generally among siblings or specifically between twins. With correction for unreliability of measurement, genetic factors accounted for half of the stable variance in depressive symptoms. Conclusions: Depressive symptoms in adulthood partly reflect enduring characteristics of temperament that are substantially influenced by hereditary factors but little, or not at all, by shared environmental experiences in the family of origin.

Objective: The authors seek to understand in general the sources of familial resemblance for alcoholism and in particular how parents transmit the vulnerability to alcoholism to their daughters. Method: The authors interviewed 1,030 pairs of female same-sex twins of known zygosity from the population-based Virginia Twin Registry and 1,468 of their parents. They examined a narrow definition of alcoholism, requiring tolerance or dependence, and a threshold approach that classified individuals either as unaffected or as suffering from one of three levels of severity of alcohol-related problems. Twin-family structural equation models were fitted to the observed tetrachoric or polychoric correlation matrices by using asymptotic weighted least squares. Results: In the best-fitting model from both diagnostic approaches, 1) the familial resemblance for alcoholism was due to genetic factors, with the heritability of liability estimated at 51% to 59%; 2) genetic vulnerability to alcoholism was equally transmitted to daughters from their fathers and from their mothers; and 3) alcoholism in parents was not environmentally transmitted to their children. Assortative mating for alcoholism was found only for the broader definitions of illness. Genetic factors that influenced the liability to alcoholism were the same in the parental and twin generation for the narrow definition of alcoholism. When broader definitions were used, these factors, while substantially correlated, were not identical. Conclusions: The transmission of the vulnerability to alcoholism from parents to their daughters is due largely or entirely to genetic factors.

Objective: The authors develop an exploratory, integrated etiologic model for the prediction of episodes of major depression in an epidemiologic sample of women. Method: Both members of 680 female-female twin pairs of known zygosity from a population-based register were assessed three times at greater than 1-year intervals. The last two assessments included a structured interview evaluation for presence of episodes of major depression, defined by DSM-III-R, in the preceding year. The final structural equation model contained nine predictor variables: genetic factors, parental warmth, childhood parental loss, lifetime traumas, neuroticism, social support, past depressive episodes, recent difficulties, and recent stressful life events. Results: The best-fitting model predicted 50.1% of the variance in the liability to major depression. The strongest predictors of this liability were, in descending order, 1) stressful life events, 2) genetic factors, 3) previous history of major depression, and 4) neuroticism. While 60% of the effect of genetic factors on the liability to major depression was direct, the remaining 40% was indirect and mediated largely by a history of prior depressive episodes, stressful life events, lifetime traumas, and neuroticism. The model suggested that at least four major and interacting risk factor domains are needed to understand the etiology of major depression: traumatic experiences, genetic factors, temperament, and interpersonal relations. Conclusions: Major depression is a multifactorial disorder, and understanding its etiology will require the rigorous integration of genetic, temperamental, and environmental risk factors.

Psychiatric patients are usually asked to note any psychiatric disorders affecting their relatives, especially their first-order relatives. This family history is useful in both psychiatric research and in evaluating the patient, but it must be accurate to be useful. Few studies have examined the characteristics of the person that gives the family history (the informant) which relate to the accuracy of the history. To examine whether a person with a certain psychiatric disorder is more likely to report a family history of the disorder, both twins of 1,033 pairs and one member of 97 pairs were interviewed to find sets of twins in which one twin suffered from either major depression, anxiety disorder, or alcoholism, while the other twin was normal. The discordant twin pairs were then asked whether either their mother or father had the same illness that afflicted one of the twins. Twins that suffered from either major depression or anxiety disorder were significantly more likely to report that one or both parents also had the disorder than were their unafflicted twin siblings. Twins who were alcoholic, on the other hand, were not more likely to report alcoholism among their parents than were their nonalcoholic siblings. These results indicate that psychiatric patients' reports of a family history of their own illness - at least concerning depression or anxiety disorders - should be interpreted cautiously and that other family members may need to be interviewed in order to obtain a more accurate family history. (Consumer Summary produced by Reliance Medical Information, Inc.)

Left ventricular (LV) hypertrophy in adults is a recognized risk factor for the subsequent development of cardiovascular morbidity. To make informed preventive health decisions it is important to understand the interaction of genes and environment on LV mass. In both children and adults, weight is a strong correlate of LV mass. We hypothesized that genetic influences common to both of these variables could in part explain the strong relation between weight and LV mass in children. In a population of 341 twins (11 years old), these questions were asked: (1) How much of the total variance of LV mass is under genetic control? (2) After accounting for weight and weight adjusted for sexual maturity, how much of the remaining variance is genetic? (3) Of the total genetic variance, what proportion is specific for LV mass and what proportion is common to both weight and LV mass? (4) How much of the correlation between these 2 variables is explained by genes common to both LV mass and weight? Univariate genetic analyses documented that genes operating at different magnitudes in boys (63%) and girls (71%) explain a significant proportion of the variance of LV mass. After removing the effect of weight and sexual maturity by regression methods, genes remain an important influence. Bivariate genetic analyses confirmed that genes common to LV mass and weight significantly influence the covariation of these variables and that >90% of the correlation of LV mass and weight is due to common genes. (Am J Cardiol 1991;68:661-668), Left ventricular hypertrophy (enlargement) is generally caused by hypertension, and is a good indication that coronary artery disease will develop. Left ventricular (LV) size increases as body weight increases among adults. In order to make effective recommendations about methods for reducing LV mass, it is necessary to understand the mechanisms regulating it. Because of the association between weight and LV mass, it is likely that genetic factors influence both, but the effects of genetics and the environment are difficult to isolate. A total of 341 pubertal (11-year-old) twins were studied to assess the factors affecting LV mass. The children whose blood pressure was in the upper quintile for their sex and age had greater LV mass. Children in the middle and lower quintiles had normal LV mass. In an earlier study of black twins, the differences in LV mass were greater between dizygotic (fraternal) twins than between monozygotic (identical) twins, and it was concluded that both genetic and environmental factors determined LV mass in black children. In this study univariate genetic analyses demonstrated that genetic influences were responsible for 63 percent of the variance in LV mass in boys and 71 percent in girls. After weight and sexual maturity were removed, genetic factors remained significant. Over 90 percent of the strength of the relation between LV mass and weight was explained by genetic influences. (Consumer Summary produced by Reliance Medical Information, Inc.)

Background: Clinicians and researchers could benefit from a greater understanding of the role of genetic and environmental factors in human eating behavior. Objective: Our aim was to estimate the relative influence of genetic and environmental factors on habitual eating patterns in middle-aged and elderly men and women. Design: Male and female twins (n = 4640) aged [is greater than or equal to] 50 y completed a mailed version of the National Cancer Institute food-frequency questionnaire. Factor analysis was performed to identify eating patterns among respondents. Estimates of genetic, common environmental (shared by family members), and specific environmental (unique to an individual) influences were obtained for food use, serving size, and consumption frequency by comparing monozygotic and dizygotic twin-pair groups with structural equation analysis. Results: Two independent eating patterns were identified: the first consisted of items high in fat, salt, and sugar, and the second reflected healthful eating habits. Although the influence of environmental factors was larger, between 15% and 38% of the total variation in pattern 1 and between 33% and 40% in pattern 2 were explained by genetic influences. Models accounting for sex differences in genetic and environmental estimates fit the data significantly better for food use and serving size of foods in eating pattern 1 and for food use in eating pattern 2. Conclusion: Although 60-85% of the variability in eating patterns was associated with environmental factors, genetic influences were also apparent and there was some evidence of sex specificity. These findings may be important in crafting dietary interventions and predicting adherence to these interventions. Am J Clin Nutr 1999;70:456-65.

Some studies have shown that genetics plays a role in blood pressure and that high-normal infant blood pressure may be the forerunner of adult hypertension. The effects of genetics and environment on blood pressure and heart rate were studied in 251 11-year-old twin pairs. In both sexes, genetic influence could be observed to affect systolic blood pressure, the pressure exerted against the walls of the blood vessels during a heart contraction. Although the amounts of variation of sex-specific genetic effects were the same between the sexes with respect to systolic blood pressure, diastolic pressure (the pressure in between contractions) had a variance of 64 percent among the boys, compared with 51 percent in girls. There were no differences between the sexes with respect to heart rates. There is no firm evidence that a difference in blood pressures exists between boys and girls. No shared environmental effects were noted. (Consumer Summary produced by Reliance Medical Information, Inc.)

To determine prevalence and heritability of insomnia during middle/late childhood and adolescence; examine longitudinal associations in insomnia over time; and assess the extent to which genetic and environmental factors on insomnia remain stable, or whether new factors come into play, across this developmental period.

Insomnia is a highly prevalent sleep disorder yet little is known about the role of genetic factors in its pathophysiology. The aim of this study was to examine the relative contributions of genetic and environmental factors in explaining variability in insomnia symptoms.

The reported interaction between the length polymorphism 5HTTLPR in the serotonin transporter gene SLC6A4 and stressful life events on depression has led to many attempts to replicate but with inconsistent results. This inconsistency may reflect, in part, small sample size and the unknown contribution of the long allele SNP, rs25531. Using a large twin sample of 3,243 individuals from 2,230 families aged 18–95 years mean  32.3, SD  13.6 we investigate the interaction between 5HTTLPR subtyped with SNP rs25531 and stressful events on risk of depression and suicidality using both ordinal regressions and item response theory analyses. Participants reported via mailed questionnaire 82 response rate both stressful events in the preceeding 12 months and symptoms of depression. Stressful events were defined as “personal” affecting the individual, or “network” affecting close family or friends. One to 10 years later mean  4.2 years, participants completed a comprehensive clinical psychiatric telephone interview 83 response rate which assessed DSMIV major depression and ideation of suicidality. Selfreports of depression and an increase in depressionsuicidality assessed by clinical interview are significantly associated with prior personal events P < 0.001 after controlling for age and sex. However, they are inconsistently associated with prior network events ranging, ns to P < 0.01 and are not significantly associated with any of the genotype main effects 5HTTLPR, 5HTTLPR  rs25531 or interactions stress × genotype. We find no evidence to support the hypothesis of any 5HTTLPR genotype by stress interaction. © 2009 WileyLiss, Inc.

AbstractRecent studies have claimed to detect interaction between candidate genes and specific environmental factors (Genotype ? Environment interaction, G ? E) in susceptibility to psychiatric disorder. The objective of the present study was to examine possible artifacts that could explain widely publicized findings. The additive effects of candidate genes and measured environment on liability to disorder were simulated under a model that allowed for mixture of distributions in liability conditional on genotype and environment. Simulated liabilities were dichotomized at a threshold value to reflect diagnosis of disorder. Multiple blocks of simulated data were analyzed by standard statistical methods to test for the main effects and interactions of genes and environment on outcome. The main outcome of this study was simulated liabilities and diagnoses of major depression and antisocial behavior. Analysis of the dichotomized data by logistic regression frequently detected significant G ? E interaction even though none was present for liability. There is therefore reason to question the biological significance of published findings.

AbstractThe children of twins (COT) design has been proposed as an alternative to the adoption study to resolve the direct effects of parental treatment from secondary parent?child association due to genetic factors. The basic analytical approach compares the parent?offspring correlation with the correlation between children and the monozygotic (MZ) twins of their parents. We show that a significant difference between these correlations does not imply direct environmental causality when the measured parental treatment in question is dyadic, that is, influenced by both parents even when mating is random. Nongenetic causal effects yield very similar patterns of correlation to secondary genetic effects on dyadic treatment variables. The fact that many candidate environments, such as parental divorce, are dyadic gives reason to question the interpretation of their correlations with behavior in the children of twins.

AbstractThree dimensions of temperament ? difficult temperament, unadaptablility and unsociability ? were assessed in the first year of life by maternal interview in twins born in Puerto Rico during 2001 and 2002. Eight hundred and sixty-five eligible mothers (80%) were traced and interviewed. Model- fitting results showed that additive genetic factors and the individual specific environment contributed to variation in all three dimensions. In addition, the pattern of variances and correlations suggested that sibling contrast effects influence ratings of difficult temperament. Moderate effects of the shared environment contributed to ratings of adaptability and sociability. There was a significant genetic correlation between difficult temperament and unadaptability. Genetic and environmental effects do not differ significantly between boys and girls. The study is the first population-based study of Puerto Rican twins and one of few to attempt the assessment of behavior in the first year. Preliminary results for difficult temperament and sociability were consistent with those in other populations and ages. In contrast, a significant effect of the shared environment on the temperamental trait of unadaptability has not been reported previously.

AbstractAll etiological studies of complex human traits focus on analyzing the causes of variation. Given this complexity, there is a premium on studying those processes that mediate between gene products and cellular or organismal phenotypes. Studies of levels of gene expression could offer insight into these processes and are likely to be especially useful to the extent that the major sources of their variation are known in normal tissues. The classical study of monozygotic (MZ) and dizygotic (DZ) twins was employed to partition the genetic and environmental influences in gene expression for over 6500 human genes measured using microarrays from lymphoblastoid cell lines. Our results indicate that mean expression levels are correlated about .3 in monozygotic (MZ) and .0 in dizygotic (DZ) twins suggesting an overall epistatic regulation of gene expression. Furthermore, the functions of several of the genes whose expression was most affected by environmental effects, after correction for measurement error, were consistent with their known role in mediating sensitivity to environmental influences.

AbstractSeveral studies report apparent sibling contrast effects in analyses of twin resemblance. In the presence of genetic differences, contrast effects reduce the dizygotic (DZ) twin correlation relative to that in monozygotic (MZ) twins and produce higher DZ than MZ variance. Explanations of contrast effects are typically cast in terms of direct social interaction between twins or an artifact of the process of rating children by their parents. We outline a model for sibling imitation and contrast effects that depends on social interaction between parents and children. In addition to predicting the observed pattern of twin variances and covariances, the parental mediation of child imitation and contrast effects leads to differences in the variance of parents of MZ and DZ twins and differences between the correlations of parents with their MZ and DZ children.

AbstractThe objective was to investigate the genetic epidemiology of figural stimuli. Standard figural stimuli were available from 5,325 complete twin pairs: 1,751 (32.9%) were monozygotic females, 1,068 (20.1%) were dizygotic females, 752 (14.1%) were monozygotic males, 495 (9.3%) were dizygotic males, and 1,259 (23.6%) were dizygotic male-female pairs. Univariate twin analyses were used to examine the influences on the individual variation in current body size and ideal body size. These data were analysed separately for men and women in each of five age groups. A factorial analysis of variance, with polychoric correlations between twin pairs as the dependent variable, and age, sex, zygosity, and the three interaction terms (age x sex, age x zygosity, sex x zygosity) as independent variables, was used to examine trends across the whole data set. Results showed genetic influences had the largest impact on the individual variation in current body size measures, whereas non-shared environmental influences were associated with the majority of individual variation in ideal body size. There was a significant main effect of zygosity (heritability) in predicting polychoric correlations for current body size and body dissatisfaction. There was a significant main effect of gender and zygosity in predicting ideal body size, with a gender x zygosity interaction. In common with BMI, heritability is important in influencing the estimation of current body size. Selection of desired body size for both men and women is more strongly influenced by environmental factors.

We examined longitudinally the psychometric properties of the Twin Inventory of Relationships and Experiences (TIRE), an instrument designed to assess non‐shared and shared environmental experiences in twins and siblings. A community sample of 1,117 pairs of like‐sex monozygotic and dizygotic twins, aged eight to 16, and their parents, was used. Results indicated that the TIRE provided constructs that are consistent across informants, gender and time. These dimensions showed good longitudinal stability within raters, and low to moderate inter‐rater agreement; the results are consistent with those of other studies using different instruments to assess family environment. It is concluded that the TIRE may be used to assess dimensions of the non‐shared environment of twins and siblings and their influence on children's development. Copyright © 2001 Whurr Publishers Ltd.

AbstractNon-linear epigenetic processes are a potential underlying source of phenotypic differences in development. Simulation studies of twin pairs using simple non-linear development models characterised by chaotic or near-chaotic behavior are presented. The effect of chaotic processes on correlations is to lower them from their initial values, but high initial correlations are affected much less by chaotic and near-chaotic processes than intermediate correlations. Therefore, we would predict that traits affected by chaotic processes would have high MZ and low DZ twin correlations and this is reminiscent of certain traits such as EEG spectra. However the much more frequent observation of MZ correlations close to twice their DZ counterparts would suggest that the role of chaos in development is quite limited.

AbstractReligious attendance has been shown to correlate negatively with alcohol use. We investigated whether this relationship is driven by genetic or environmental factors. Data on frequency of church attendance and frequency of alcohol use were obtained from twins and their families in the Virginia 30 000 study. A comprehensive bivariate model of family resemblance was fitted to the data using Mx. This model is described in detail. Results indicate that genetic factors primarily account for the relationship between alcohol and church attendance in males, whilst shared environmental factors, including cultural transmission and genotype-environment covariance, are stronger determinants of this association in females.

AbstractMeasures of self-transcendence, physical health and psychological well-being were included in a self-report Health and Lifestyle questionnaire administered to Australian twins aged over 50 between 1993 and 1995. Self-transcendence appears to be higher among older Australian women than men, and was significantly associated with religious affiliation, marital status (in women) and age (in men). No strong correlations were observed between self-transcendence and any measure of psychological or physical health. Additive genetic effects were found to be important in influencing self-transcendence, with heritability estimates of 0.37 and 0.41 for men and women respectively, whilst shared environment effects were not found to be significant. Multivariate modelling of self-transcendence scores and self-reported church attendance behavior indicated substantially different etiologies for these variables, with implications for methods of investigation of religiosity and spirituality.

AbstractResearch has consistently shown that religiousness is associated with lower levels of alcohol and drug use, but little is known about the nature of adolescent religiousness or the mechanisms through which it influences problem behavior in this age group. This paper presents preliminary results from the Mid-Atlantic School Age Twin Study, a prospective, population-based study of 6?18-year-old twins and their mothers. Factor analysis of a scale developed to characterize adolescent religiousness, the Religious Attitudes and Practices Inventory (RAPI), revealed three factors: theism, religious/spiritual practices, and peer religiousness. Twin correlations and univariate behavior-genetic models for these factors and a measure of belief that drug use is sinful reveal in 357 twin pairs that common environmental factors significantly influence these traits, but a minor influence of genetic factors could not be discounted. Correlations between the multiple factors of adolescent religiousness and substance use, comorbid problem behavior, mood disorders, and selected risk factors for substance involvement are also presented. Structural equation modeling illustrates that specific religious beliefs about the sinfulness of drugs and level of peer religiousness mediate the relationship between theistic beliefs and religious/spiritual practices on substance use. Limitations and future analyses are discussed.

This study reports the results of a biometrical genetical analysis of scores on a personality inventory (The Eysenck Personality Questionnaire, or EPQ), which purports to measure psychoticism, neuroticism, extraversion and dissimulation (Lie Scale). The subjects were 544 pairs of twins, from the Maudsley Twin Register. The purpose of the study was to test the applicability of various genotype-environmental models concerning the causation of Pscores.

BACKGROUND: Depression, a clinically heterogeneous syndrome, may also be etiologically heterogeneous. Using a prospective, epidemiologic, and genetically informative sample of adult female twins, we identify and validate a typology of depressive syndromes. METHODS: Latent class analysis was applied to 14 disaggregated DSM-III-R symptoms for major depression reported over the last year by members of 1029 female-female twin pairs. RESULTS: Seven classes were identified, of which 3 represented clinically significant depressive syndromes: (1) mild typical depression, (2) atypical depression, and (3) severe typical depression. Severe typical depression was characterized by comorbid anxiety and panic, long episodes, impairment, and help seeking. Atypical depression was similar in severity to mild typical depression, but was characterized by increased eating, hypersomnia, frequent, relatively short episodes, and a proclivity to obesity. Individuals with recurrent episodes tended to have the same syndrome on each occasion. The members of twin pairs concordant for depression had the same depressive syndrome more often than expected by chance and this resemblance was greater in monozygotic than in dizygotic pairs. CONCLUSION: In an epidemiologic sample of female twins, depression is not etiologically homogeneous, but is instead made up of several syndromes that are at least partially distinct from a clinical, longitudinal, and familial/genetic perspective.

BACKGROUND: Studies of adult antisocial behavior or criminality usually find genetic factors to be more important than the family environment, whereas studies of delinquency find the family environment to be more important. We compared DSM-III-R antisocial personality disorder symptoms before vs after the age of 15 years within a sample of twins, rather than comparing across studies. METHODS: We administered the Diagnostic Interview Schedule Version III—revised by telephone to 3226 pairs of male twins from the Vietnam Era Twin Registry. Biometrical modeling was applied to each symptom of antisocial personality disorder and summary measures of juvenile and adult symptoms. RESULTS: Five juvenile symptoms were significantly heritable, and five were significantly influenced by the shared environment. Eight adult symptoms were significantly heritable, and one was significantly influenced by the shared environment. The shared environment explained about six times more variance in juvenile antisocial traits than in adult traits. Shared environmental influences on adult antisocial traits overlapped entirely with those on juvenile traits. Additive genetic factors explained about six times more variance in adult vs juvenile traits. The juvenile genetic determinants overlapped completely with genetic influences on adult traits. The unique environment (plus measurement error) explained the largest proportion of variance in both juvenile and adult antisocial traits. CONCLUSIONS: Characteristics of the shared or family environment that promote antisocial behavior during childhood and early adolescence also promote later antisocial behavior, but to a much lesser extent. Genetic causal factors are much more prominent for adult than for juvenile antisocial traits.

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.

• We examined the etiologic role of genetic and environmental factors in 14 symptoms of anxiety and depression reported by 3,798 pairs of adult twins from the Australian National Health and Medical Research Council Twin Register. Multifactorlal multiple-threshold models fit the individual symptom scores well. For a substantial majority of the symptoms, the variance in liability was best explained by only genetic factors and environmental influences specific to the individual, where 33% to 46% of the variance was due to genetic factors. For four symptoms, it was not possible to choose definitively between models that, in addition to specific environment, included genetic vs familial environmental effects. These results provide strong evidence for the role of genetic factors in the etiology of symptoms of anxiety and depression as reported in a general population. Evidence for an etiologic role of familial environmental factors was much weaker. If familial environmental factors play any role in the production of these symptoms, they are more important in symptoms of depression than of anxiety, and the factors that predispose to these symptoms are only modestly correlated in males and females.

We investigated the relative contributions of genetic, individual environmental, and shared environmental effects on 2,3-diphosphoglycerate (DPG) regulation in preadolescent children. In a population of 165 early pubescent boy and girl twin pairs (11.4 y old), of whom 63 were passive smokers, we asked: 1) Are there differences in the control of DPG levels between early pubertal boys and girls? 2) If present, are these differences influenced by exposure to passive cigarette smoke? Non-passive-smoking boys and girls had similar DPG levels. With exposure to passive smoke, DPG levels increased in boys (p = 0.02) but not in girls. Analysis of variance on DPG demonstrated a parental smoking effect (p = 0.008) and suggested an interactive effect between parental smoking and sex of the child (p = 0.08). Univariate genetic analyses suggested that genes operated at different magnitudes in boys (9) and girls (39) in explaining a significant portion of the variance in DPG. The magnitude of shared environmental influences was greater in boys (62) than in girls (34), whereas individual environmental effects were similar in boys (29) and girls (26). Early pubertal boys differ from girls in their regulation of DPG. Environmental stres-sors such as passive cigarette smoke may elicit different responses in males and females, even at an early age. The use of path analysis may provide important insights into the mechanisms and interactions of genetic and environmental effects that underly the childhood antecedents of atherosclerotic heart disease.

We have conducted a cross-sectional analysis of the genetic and environmental contributions to the variance of anthropometric measurements in children during early adolescence. Univariate path analysis was used to estimate the relative contributions of genes, individual environment, and family environment to measures of childhood obesity in 259 11-y-old Caucasian twin pairs. Triceps, subscapular, and suprailiac skinfold thicknesses, as well as waist circumferences, ht, and wt were measured in a standardized protocol. In this sample, a parsimonious model that included only additive genetic effects and environmental factors unique to the individual provided an adequate explanation for the variation in ht, wt, quetelet index, and subscapular and triceps skinfolds. In this largely preadolescent population, different magnitudes of genetic effects were seen in males and females for waist circumference, biiliac diameter, and suprailiac skinfold.

We explore the power of the twin study to resolve sources of familial resemblance when the data are measured at the binary or ordinal level. Four components of variance were examined: additive genetic, nonadditive genetic, and common and specific environment. Curves are presented to compare the power of the continuous case with those of threshold models corresponding to different prevalences in the population: 1, 5, 10, 25, and 50%. Approximately three times the sample size is needed for equivalent power to the continuous case when the threshold is at the optimal 50%, and this ratio increases to about 10 times when 10% are above threshold. Some power may be recovered by subdividing those above threshold to form three or more ordered classes, but power is determined largely by the lowest threshold. Non-random ascertainment of twins (i) through affected twins and examining their cotwins or (ii) through ascertainment of all pairs in which at least one twin is affected increases power. In most cases, strategy i is more efficient than strategy ii. Though powerful for the rarer disorders, these methods suffer the disadvantage that they rely on prior knowledge of the population prevalence. Furthermore, sampling from hospital cases may introduce biases, reducing their value. A useful approach may be to assess the population with a screening instrument; the power calculations indicate that sampling all concordant and half of the discordant pairs would be efficient, as along as the cost of screening is not too high.

If pairs of relatives correlate in their liability to participate in a research project, it is possible to test for the effects of volunteering on the criterion variable of interest. Much of the information for this test comes from a difference in criterion variable mean between individuals with and those without a cooperative relative. Also, if data are available from more than one class of relative, it may be possible to discriminate between (i) volunteering that occurs as a consequence of the criterion variable and (ii) volunteering as a cause of the criterion. Likelihood formulae are presented that permit quantification and significance testing of volunteer bias. If data are collected from a genetically informative design such as a twin study, it is possible to estimate genetic and environmental parameters independent of the contaminating effects of such bias. We describe some methods of reducing the computational burden of multidimensional integration to allow extension to multivariate data. Implications for research design and management are discussed.

A model based on the latent class model is developed for the effects of genes and environment on multivariate categorical data in twins. The model captures many essential features of dimensional and categorical conceptions of complex behavioral phenotypes and can include, as special cases, a variety of major locus models including those that allow for etiological heterogeneity, differential sensitivity of latent classes to measured covariates, and genotype × environment interaction (G×E). Many features of the model are illustrated by an application to ratings on eight items relating to conduct disorder selected from the Rutter Parent Questionnaire (RPQ). Mothers rated their 8-to 16-year-old male twin offspring [174 monozygotic (MZ) and 164 dizygotic (DZ) pairs]. The impact of age on the frequency of reported symptoms was relatively slight. Preliminary latent class analysis suggests that four classes are required to explain the reported behavioral profiles of the individual twins. A more detailed analysis of the pairwise response profiles reveals a significant association between twins for membership of latent classes and that the association is greater in MZ than DZ twins, suggesting that genetic factors played a significant role in class membership. Further analysis shows that the frequencies of MZ pairs discordant for membership of some latent classes are close to zero, while others are definitely not zero. One possible explanation of this finding is that the items reflect underlying etiological heterogeneity, with some response profiles reflecting genetic categories and others revealing a latent environmental risk factor. We explore two “four-class” models for etiological heterogeneity which make different assumptions about the way in which genes and environment interact to produce complex disease phenotypes. The first model allows for genetic heterogeneity that is expressed only in individuals exposed to a high-risk (“predisposing”) environment. The second model allows the environment to differentiate two forms of the disorder in individuals of high genetic risk. The first model fits better than the second, but neither fits as well as the general model for four latent classes associated in twins. The results suggest that a single-locus/two-allele model cannot fit the data on these eight items even when we allow for etiological heterogeneity. The pattern of endorsement probabilities associated with each of the four classes precludes a simple “unidimensional” model for the latent process underlying variation in symptom profile in this population. The extension of the approach to larger pedigrees and to linkage analysis is briefly considered.

An 18 month prospective study of personality traits (as assessed by Cattell's Children's Personality Questionnaire and Sixteen Personality Factor Questionnaire) was conducted on twin pairs and their parents. The primary personality trait scores for both the adults and children had relatively low stability over the 18 month interval; in addition, in some cases, the inter-factor stability coefficients exceeded the intra-factor coefficients. This finding, coupled with the lack of parent/offspring similarity for the primary personality traits, places in question the predictive power of Cattell's personality questionnaires. A factor analysis on the original items indicated that 5 oblique factors for the children and 6 oblique factors for the adults need be retained. These factors were not only more stable than the primary trait scores, but they also did not have such high inter-factor stability coefficients. Except for Neuroticism and IQ, the adult and juvenile factors do not show structural similarities.

The traditional twin method is predicated on the equal-environment assumption (EEA)—that monozygotic (MZ) and dizygotic (DZ) twins are equally correlated in their exposure to environmental events of etiologic importance for the trait under study. In 1968, Scarr proposed a test of the EEA which examines the impact of phenotypic similarity in twins of perceived versus true zygosity. We apply this test for the EEA to five common psychiatric disorders (major depression, generalized anxiety disorder, phobia, bulimia, and alcoholism), as assessed by personal interview, in 1030 female-female twin pairs from the Virginia Twin Registry with known zygosity. We use a newly developed model-fitting approach which treats perceived zygosity as a form of specified familial environment. In 158 of the 1030 pairs (15.3%), one or both twins disagreed with the project-assigned zygosity. Model fitting provided no evidence for a significant influence of perceived zygosity on twin resemblance for any of the five disorders. Although limited in power, these results support the validity of the EEA in twin studies of psychiatric disorders.

Comparative ratings between pairs of siblings or other relatives are commonly used to refine measures of intrafamily variation. A simple model, based on signal detection theory, is proposed which shows how comparative ratings can be used to estimate within-pair variances of true scores, which can, in turn, be modeled with any of the conventional approaches to partitioning genetic and environmental variance within families.

AbstractDepression scores (DSSI) were available for 1232 MZ and 751 DZ female twin pairs who completed a mailed questionnaire. Pairs were divided into those concordant for being in a marriage-like state, concordant for having no partners, and those discordant. The pattern of twin correlations differed according to marital status. Our results suggest that having a marriage-like relationship acts as a protective factor in reducing the impact of inherited liability to symptoms of depression in the general population.

AbstractNew large-sample data show that non-additive genetic effects, probably epistatic interactions between loci, and sex-limited gene expression are significant features of the genetic architecture of human personality as measured by questionnaire scales of extraversion and neuroticism. Three large data sets ? new data on large samples (n = 20 554) of US twins, their spouses, parents, siblings and children, correlations for Australian twins (n = 7 532), and previously published twin data from Finland (n = 14 288) ? are subjected to an integrated analysis to test alternative hypotheses about the genetic causes of family resemblance in personality. When allowance is made for differences in reliability of the scales, the combined data are consistent with the same model for variation. There are significant amounts of genetic non-additivity for both dimensions of personality. The evidence favours additive ? additive epistatic interactions rather than dominance. In the case of neuroticism, there is especially strong evidence of sex differences in genetic architecture favouring a greater relative contribution of non-additive genetic effects in males. The data confirm previous claims to find no major contribution of the shared environment of twins and siblings to these dimensions of personality. Correlations between spouses are zero, and the correlations for very large samples of siblings and non-identical twins do not differ significantly.

BACKGROUND: In epidemiologie samples, the assessment of lifetime history (LTH) of major depression (MD) is not highly reliable. In female twins, we previously found that LTH of MD, as assessed at a single personal interview, was moderately heritable (approximately 40%). In that analysis, errors of measurement could not be discriminated from true environmental effects. METHODS: In 1721 female twins from a populationbased register, including both members of 742 pairs, LTH of MD, covering approximately the same time period, was obtained twice, once by self-administered questionnaire and once at personal interview. RESULTS: Reliability of LTH of MD was modest (×= + .34, tetrachoric r= + .56) and was predicted by the number of depressive symptoms, treatment seeking, number of episodes, and degree of impairment. Deriving an "index of caseness" from these predictors, the estimated heritability of LTH of MD was greater for more restrictive definitions. Incorporating error of measurement into a structural equation model including both occasions of measurement, the estimated heritability of the liability to LTH of MD increased substantially (approximately 70%). More than half of what was considered environmental effects when LTH of MD was analyzed on the basis of one assessment appeared, when two assessments were used, to reflect measurement error. CONCLUSIONS: Major depression, as assessed over the lifetime, may be a rather highly heritable disorder of moderate reliability rather than a moderately heritable disorder of high reliability.

OBJECTIVE: To elucidate the nature of the etiologic relationship between personality and major depression in women. DESIGN: A longitudinal twin design in which twins completed a time 1 questionnaire and, 15 months later, were personally interviewed for the occurrence of major depression during the last year and completed a time 2 questionnaire. Both questionnaires contained short forms assessing neuroticism and extraversion. PARTICIPANTS: 1733 twins from female-female pairs ascertained from the population-based Virginia Twin Registry. RESULTS: Extraversion was unrelated to lifetime or 1-year prevalence of major depression. Neuroticism was strongly related to lifetime prevalence of major depression and robustly predicted the prospective 1-year prevalence of major depression in those who, at time 1, denied previous depressive episodes. However, controlling for levels of neuroticism at time 1, levels of neuroticism at time 2 were moderately elevated in those who had had an episode of major depression between times 1 and 2 ("scar" effect) and substantially elevated in those experiencing an episode of major depression at time 2 ("state" effect). In those who developed major depression, levels of neuroticism did not predict time to onset. In the best-fit longitudinal twin model, the proportion of the observed correlation between neuroticism and the liability to major depression that is due to shared genetic risk factors was estimated at around 70%, that due to shared environmental risk factors at around 20%, and that due to a direct causal effect of major depression on neuroticism (via both "scar" and "state" effects) at around 10%. Approximately 55% of the genetic liability of major depression appeared to be shared with neuroticism, while 45% was unique to major depression. CONCLUSION: In women, the relationship between neuroticism and the liability to major depression is substantial and largely the result of genetic factors that predispose to both neuroticism and major depression.

OBJECTIVES: This study seeks to clarify the etiologic importance and temporal stability of the genetic and environmental risk factors for 1-year prevalence of major depression (1YP-MD) in women. DESIGN: One-year prevalence of major depression was personally assessed, using DSM-III-R criteria, at two time points a minimum of 1 year apart. PARTICIPANTS: Both members of 938 adult femalefemale twin pairs ascertained from the population-based Virginia Twin Registry. RESULTS: The correlation in liability to 1YP-MD was much greater in monozygotic (MZ) than in dizygotic (DZ) twins at time 1 alone, time 2 alone, or at either time 1 or time 2. Model fitting suggested that the liability to 1YP-MD was due to additive genes and individual specific envi- ronment with a heritability of 41% to 46% and was not biased by violations of the equal environment assumption. Jointly analyzing both times of assessment using a longitudinal twin model suggested that, over a 1-year period, genetic effects on the liability to 1YP-MD were entirely stable, while environmental effects were entirely occasion specific. CONCLUSIONS: These results suggest that (1) genetic factors play a moderate etiologic role in the 1YP-MD, (2) the temporal stability of the liability to major depression in adult women is largely or entirely genetic in origin, and (3) environmental factors play a significant role in the etiology of major depression, but their effects are generally transitory and do not result in enduring changes in the liability to illness.

BACKGROUND: Although major depression (MD) and alcoholism co-occur in clinical and epidemiologic samples of women more often than expected by chance, the magnitude and causes of this comorbidity are uncertain. METHODS: Personal interviews were conducted with 2163 female twins from a population-based twin registry. Bivariate twin analysis was performed using two definitions of MD and three definitions of alcoholism of varying diagnostic breadth. RESULTS: Odds ratios ranged from 2.7 to 6.0 and were consistently higher using narrower diagnostic criteria for either disorder. Twin analyses found (1) no evidence for familial environmental factors for either MD or alcoholism; (2) significant genetic correlations, ranging from +.4 to +.6, between MD and alcoholism, which were higher using narrower criteria for alcoholism; (3) significant in- dividual-specific environmental correlations, ranging from +.2 to +.4, for all but one of the diagnostic combinations, which were higher using narrower criteria for MD. CONCLUSIONS: Comorbidity between MD and alcoholism in women is substantial and appears to result largely from genetic factors that influence the risk to both disorders, but common environmental risk factors also contribute. However, genetic factors exist that influence the liability to MD without influencing the risk for alcoholism and vice versa. Narrowing the diagnostic criteria for MD or alcoholism increases comorbidity, but for different reasons narrow diagnostic criteria for MD increase the environmental sources of comorbidity while narrow diagnostic criteria for alcoholism increase the genetic sources of comorbidity.

• Among 1566 personally evaluated female twins from a population-based register, average lifetime daily cigarette consumption was strongly related to lifetime prevalence and to prospectively assessed 1-year prevalence of major depression (MD). Using the cotwin control method, we evaluated whether the association between smoking and lifetime MD was causal or noncausal. While the relative risk (95% confidence interval) for ever smoking given a lifetime history of MD was 1.48 (1.30 to 1.65) in the entire sample, it was 1.18 (0.88 to 1.47) and 0.98 (0.71 to 1.26), respectively, in dizygotic and monozygotic twin pairs discordant for a history of MD. The relative risk for a history of MD given ever smoking was 1.60 (1.39 to 1.83) in the entire sample, while in dizygotic and monozygotic twins discordant for smoking, it was 1.29 (0.87 to 1.74) and 0.96 (0.59 to 1.42), respectively. Controlling for personal smoking history, family history of smoking predicted risk for MD; controlling for the personal history of MD, family history of MD predicted smoking. The best-fitting bivariate twin model suggested that the relationship between lifetime smoking and lifetime MD resulted solely from genes that predispose to both conditions. These results suggest that the association between smoking and MD in women is not a causal one but arises largely from familial factors, which are probably genetic, that predispose to both smoking and MD.

• Bivariate twin analysis can determine the extent to which two disorders share common genetic, familial environmental, or individual-specific environmental risk factors. We applied this method to lifetime diagnoses of major depression and generalized anxiety disorder as assessed at personal interview in a population-based sample of 1033 pairs of female same-sex twins. Three definitions of generalized anxiety disorder were used that varied in minimum duration (1 vs 6 months) and in the presence or absence of a diagnostic hierarchy. For all definitions of generalized anxiety disorder, the best-fitting twin model was the same. Familial environment played no role in the etiology of either condition. Genetic factors were important for both major depression and generalized anxiety disorder and were completely shared between the two disorders. A modest proportion of the nonfamilial environmental risk factors were shared between major depression and generalized anxiety disorder. Within the limits of our statistical power, our findings suggest that in women, the liability to major depression and generalized anxiety disorder is influenced by the same genetic factors, so that whether a vulnerable woman develops major depression or generalized anxiety disorder is a result of her environmental experiences.

• Little is known about the role of familial and genetic factors in the etiology of generalized anxiety disorder (GAD), a new disorder first proposed in DSM-III. We examine this question in 1033 female-female twin pairs from a population-based registry. Both members in each twin pair were "blindly" assessed by structured psychiatric interview. Our results suggest the following: (1) GAD is a moderately familial disorder; (2) the tendency for GAD to run in families seems to be due largely or entirely to genetic factors shared between relatives rather than to the effects of the familial environment; (3) the heritability of GAD, estimated at around 30%, is modest, with the remainder of the variance in liability resulting from environmental factors not shared by adult twins; (4) the heritability of GAD cannot be explained solely by the occurrence of GAD only during episodes of major depression or panic disorder; and (5) the etiologic role of genetic factors is probably similar in GAD with a 1- vs a 6-month minimum duration of illness.

• In 2163 personally interviewed female twins from a population-based registry, the pattern of age at onset and comorbidity of the simple phobias (animal and situational) — early onset and low rates of comorbidity—differed significantly from that of agoraphobia—later onset and high rates of comorbidity. Consistent with an inherited "phobia proneness" but not a "social learning" model of phobias, the familial aggregation of any phobia, agoraphobia, social phobia, and animal phobia appeared to result from genetic and not from familial-environmental factors, with estimates of heritability of liability ranging from 30% to 40%. The bestfitting multivariate genetic model indicated the existence of genetic and individual-specific environmental etiologic factors common to all four phobia subtypes and others specific for each of the individual subtypes. This model suggested that (1) environmental experiences that predisposed to all phobias were most important for agoraphobia and social phobia and relatively unimportant for the simple phobias, (2) environmental experiences that uniquely predisposed to only one phobia subtype had a major impact on simple phobias, had a modest impact on social phobia, and were unimportant for agoraphobia, and (3) genetic factors that predisposed to all phobias were most important for animal Phobia and least important for agoraphobia. Simple phobias appear to arise from the joint effect of a modest genetic vulnerability and phobia-specific traumatic events in childhood, while agoraphobia and, to a somewhat lesser extent, social phobia result from the combined effect of a slightly stronger genetic influence and nonspecific environmental experiences.

• Although depression aggregates in families, the degree to which this aggregation results from genetic vs environmental factors remains uncertain. We examined this question in 1033 female-female twin pairs from a population-based registry. Both members of each twin pair were "blindly" assessed by structured psychiatric interview. Nine commonly used definitions of major depression, which produced lifetime prevalence rates ranging from 12% to 33%, were examined. For all definitions, the results of model fitting to twin correlations suggested that the liability to depression results from genetic factors and environmental experiences unique to the individual. For seven of the definitions, the estimated heritability of liability was similar, ranging from 33% to 45%. For the two definitions that included only primary cases of depression, the heritability was lower (21% to 24%). The results document that in women (1) genetic factors play a substantial, but not overwhelming, role in the cause of depression; (2) the tendency for depression to aggregate in families results largely from shared genetic and not from shared environmental factors, (3) except for definitions that exclude secondary cases, the magnitude of genetic influence is similar in broadly and narrowly defined forms of major depression, and (4) most environmental experiences of causative importance for depression are those not shared by members of an adult twin pair.

• We examine the relationship between parental loss prior to age 17 years and adult psychopathology in 1018 pairs of female twins from a population-based registry. The relationship between loss and adult psychopathology varied as a function of the kind of loss (death vs separation), the parent involved, and the form of psychopathology. Increased risk for major depression and generalized anxiety disorder was associated with parental separation but not parental death and with separation from either mother or father. Panic disorder was associated with parental death and maternal, but not paternal, separation. Increased risk for phobia was associated with parental death and not parental separation. Risk for eating disorder was unrelated to the experience of parental loss. A model that includes parental loss as a form of "specified" family environment shows that, if it is truly an environmental risk factor for adult psychopatholgic conditions, it can account for between 1.5% and 5.1% of the total variance in liability to these disorders and is responsible for between 7.0% and 20.5% of the tendency for these disorders to aggregate in siblings.

• While traditional multivariate statistical methods can describe patterns of psychiatric symptoms, they cannot provide insight into why certain symptoms tend to co-occur in a population. However, this can be achieved using recently developed methods of multivariate genetic analysis. Examining self-report symptoms in a clinically unselected twin sample (3798 pairs), traditional factor analysis indicates that symptoms of depression and anxiety tend to form separate symptom clusters. Multivariate genetic analysis shows that genes act largely in a nonspecific way to influence the overall level of psychiatric symptoms. No evidence could be found for genes that specifically affect symptoms of depression without also strongly influencing symptoms of anxiety. By contrast, the environment seems to have specific effects, ie, certain features of the environment strongly influence symptoms of anxiety while having little impact on symptoms of depression. These results, which are replicated across sexes, suggest that the separable anxiety and depression symptom clusters in the general population are largely the result of environmental factors.

Self-report data on smoking initiation (whether the respondent admitted ever having smoked) were obtained from three large adult twin samples (Australia, N= 3,808 pairs; Virginia, N= 2,145 pairs; AARP, N= 3,620 pairs). Data were broken down into birth cohorts, and genetic models were fitted to test whether the decline, in more recent birth cohorts, in the percentage of individuals becoming smokers has led to a change in the relative contributions of genes and environment to risk of becoming a smoker. Despite a marked change in the proportion of male respondents who reported ever having smoked, we found no evidence for cohort differences in genetic and environmental effects (no Genotype × Cohort interaction). Significant differences in genetic and environmental parameters were found between sexes, and between the Australian and the two U.S. samples. In the U.S. samples, estimates of the genetic contribution to risk of becoming a smoker were 60% in men, 51% in women. In the Australian sample, heritability estimates were 33% in men, but 67% in women. Significant shared environmental effects on smoking initiation also were found, accounting for 23% of the variance in U.S. men, 28% of the variance in U.S. women, 39% of the variance in Australian men, and 15% of the variance in Australian women. In models that allowed for the environmental impact of cotwin smoking on a twin's risk of smoking initiation, estimates of the direct genetic contribution to risk of smoking initiation were comparable or higher (49–58% in U.S. women and 71% in Australian women; 58–61% in U.S. men, and 37% in Australian men).

Oral contraceptive (ORC)-related depression and irritability are among the most commonly reported drug-induced psychiatric symptoms. To investigate the etiological role of genetic factors in ORC-related symptoms, we studied questionnaire responses in 715 monozygotic and 416 dizygotic volunteer twin pairs concordant for ORC usage. Biometrical genetic analysis indicated that the liability to ORC-related depression was clearly influenced by genetic but not familial-environmental factors. Similar, but less definitive, results were found for ORC-related irritability. Multivariate genetic analysis indicated that both the genetic and the individual-specific environmental factors that influenced the liability to ORC-related depression and irritability were largely distinct from those that influence baseline levels of psychiatric symptoms. Genes play an important etiological role in ORC-related psychiatric side effects. The genes that influence liability to these side effects appear to differ from those that are etiologically important in baseline psychiatric symptomatology.