A direct test of the diathesis-stress model for depression.

The diathesis-stress theory for depression states that the effects of stress on the depression risk are dependent on the diathesis or vulnerability, implying multiplicative interactive effects on the liability scale. We used polygenic risk scores for major depressive disorder (MDD) calculated from the results of the most recent analysis from the Psychiatric Genomics Consortium as a direct measure of the vulnerability for depression in a sample of 5221 individuals from 3083 families. In the same we also had measures of stressful life events and social support and a depression symptom score, as well as DSM-IV MDD diagnoses for most individuals. In order to estimate the variance in depression explained by the genetic vulnerability, the stressors and their interactions, we fitted linear mixed models controlling for relatedness for the whole sample as well as stratified by sex. We show a significant interaction of the polygenic risk scores with personal life events (0.12% of variance explained, P-value=0.0076) contributing positively to the risk of depression. Additionally, our results suggest possible differences in the aetiology of depression between women and men. In conclusion, our findings point to an extra risk for individuals with combined vulnerability and high number of reported personal life events beyond what would be expected from the additive contributions of these factors to the liability for depression, supporting the multiplicative diathesis-stress model for this disease.

Evidence for polygenic epistatic interactions in man?

Studies of multifactorial inheritance in man have ignored nonadditive gene action or attributed it entirely to dominance. Reanalyses of dermatoglyphic data on monozygotic and dizygotic twins, siblings and parents and offspring suggest that a substantial proportion of variation in total finger pattern intensity is due to epistatic interactions between additive genetic deviations, not dominance. Bootstrapping and power simulations support this interpretation of the data. We believe this is the strongest evidence so far for polygenic epistasis in man.

Analysis of the covariance structure of digital ridge counts in the offspring of monozygotic twins.

Improved methods for analysis of covariance structures now permit the rigorous testing of multivariate genetic hypotheses. Using Jöreskog's Lisrel IV computer program we have conducted a confirmatory factor analysis of dermal ridge counts on the individual fingers of 509 offspring of 107 monozygotic twin pairs. Prior to the initiation of the model-fitting procedure, the sex-adjusted ridge counts for the offspring of male and female twins were partitioned by a multivariate nested analysis of variance yielding five 10 X 10 variance-covariance matrices containing a total of 275 distinctly observed parameters with which to estimate latent sources of genetic and environmental variation and test hypotheses about the factor structure of those latent causes. To provide an adequate explanation for the observed patterns of covariation, it was necessary to include additive genetic, random environmental, epistatic and maternal effects in the model and a structure for the additive genetic effects which included a general factor and allowed for hand asymmetry and finger symmetry. The results illustrate the value of these methods for the analysis of interrelated metric traits.

Symptoms of anxiety and depression in a volunteer twin population. The etiologic role of genetic and environmental factors.

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. Multifactorial 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.

Symptoms of anxiety and symptoms of depression. Same genes, different environments?

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.

Alcoholism and major depression in women. A twin study of the causes of comorbidity.

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 individual-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.

Major depression and generalized anxiety disorder. Same genes, (partly) different environments?

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.

Childhood parental loss and adult psychopathology in women. A twin study perspective.

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 psychopathologic 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.

A population-based twin study of major depression in women. The impact of varying definitions of illness.

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 life-time 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.

Generalized anxiety disorder in women. A population-based twin study.

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.

The genetic epidemiology of phobias in women. The interrelationship of agoraphobia, social phobia, situational phobia, and simple phobia.

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 best-fitting 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.

A longitudinal twin study of personality and major depression in women.

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.

A longitudinal twin study of 1-year prevalence of major depression in women.

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 female-female 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 environment 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.

The lifetime history of major depression in women. Reliability of diagnosis and heritability.

BACKGROUND: In epidemiologic 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 population-based 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 (kappa = +.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.

Genetic case-control association studies in neuropsychiatry.

Case-control association studies use genetic markers as putative etiologic risk factors. The approach is controversial and has tended to produce associations in neuropsychiatry that do not stand the test of time. We studied the processes that can bias the outcomes away from a true representation of the relationship between a genetic marker and a neuropsychiatric disorder. If conducted with care and mindfulness of the potential pitfalls, case-control association studies can be an important tool for psychiatric genetic research.

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.

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 female-female 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, familial-environmental 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.

The identification and validation of distinct depressive syndromes in a population-based sample of female twins.

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.

Smoking and major depression. A causal analysis.

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.

The Virginia Twin Study of Adolescent Behavioral Development. Influences of age, sex, and impairment on rates of disorder.

BACKGROUND: The Virginia Twin Study of Adolescent Behavioral Development is a cohort-longitudinal epidemiological study that uses the genetic twin design to study the development and maintenance of child psychiatric disorders. We determined the rates of DSM-III-R disorders, disorders with impairment, and age, sex, and comorbidity effects. METHODS: Families of 2762 white twins aged 8 to 16 years participated. Twins and their parents were asked systematically about risk factors and current psychiatric symptoms by means of investigator-based psychiatric interviews and questionnaires. The DSM-III-R diagnoses were made for major depressive disorder, separation anxiety, overanxious disorder, simple phobia, social phobia, agoraphobia, oppositional defiant disorder, conduct disorder, and attention deficit hyperactivity disorder. RESULTS: The 3-month point prevalence for any DSM-III-R disorders was 413 per 1000, and that for disorders with associated impairment was 142 per 1000. Emotional disorders with impairment occurred in 89 per 1000, with girls being more commonly affected; behavioral disorders had a prevalence of 71 per 1000, with boys being more frequently affected. The proportion with disorder who also had functional impairment varied across disorders; anxiety and phobic disorders were particularly likely not to be accompanied by impairment. Rates of emotional and behavioral disorders increased over the age range. There was extensive comorbidity among disorders. CONCLUSIONS: The prevalence rates and patterns of findings from this study of twins are consistent with those of other epidemiological studies, supporting previous findings of few differences in rates of psychiatric disorder between twins and singletons. The importance of including measures of functional impairment is evident by its effect on rates of disorder and patterns of comorbidity.

Differential heritability of adult and juvenile antisocial traits.

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 anti-social 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.