CONTEXT The strong association between lower IQ and risk for psychosis has led to the suggestion that the search for genes influencing cognition may provide a useful strategy for examining the genetic origins of psychosis. However, research in this area has generally used designs in which twin pairs are selected by case status and with assessment of IQ after the onset of psychosis rather than longitudinal population-based samples. OBJECTIVE To examine the relationship and shared genetic origin between premorbid IQ and psychotic disorders in a longitudinal population-based cohort. DESIGN Genetically informative longitudinal study. SETTING Population-based cohort in Sweden. PARTICIPANTS Individuals were identified from the population-based Swedish Multi-Generation Register and consisted of male sibling (n = 369 960), monozygotic twin (n = 1986), and dizygotic twin (n = 2253) pairs born between January 1951 and December 1976. Their IQs were measured during compulsory military conscription. MAIN OUTCOME MEASURE Individuals having a subsequent diagnosis of psychosis were identified via the Swedish National Hospital Discharge Register. RESULTS Heritability estimates for IQ and psychosis were similar to previous estimates, approximately 69% and 56%, respectively. However, the phenotypic correlation between IQ and psychosis was only -0.11, of which 91% was due to shared genetic influences. The proportion of genetic variance for psychosis shared with that for IQ was approximately 7%. CONCLUSIONS Using IQ as a phenotype to identify genes that have an important role in the genetic origin of schizophrenia is unlikely to be a successful strategy. The low correlation seen in this study between premorbid IQ and psychosis vs the higher correlations reported in the literature with postmorbid IQ suggests the correlation between these phenotypes has more to do with the influence that the onset of psychosis has on cognitive functioning than with shared genetic origin.

BACKGROUND The contribution of hereditary factors to the causation of sporadic cancer is unclear. Studies of twins make it possible to estimate the overall contribution of inherited genes to the development of malignant diseases. METHODS We combined data on 44,788 pairs of twins listed in the Swedish, Danish, and Finnish twin registries in order to assess the risks of cancer at 28 anatomical sites for the twins of persons with cancer. Statistical modeling was used to estimate the relative importance of heritable and environmental factors in causing cancer at 11 of those sites. RESULTS At least one cancer occurred in 10,803 persons among 9512 pairs of twins. An increased risk was found among the twins of affected persons for stomach, colorectal, lung, breast, and prostate cancer. Statistically significant effects of heritable factors were observed for prostate cancer (42 percent; 95 percent confidence interval, 29 to 50 percent), colorectal cancer (35 percent; 95 percent confidence interval, 10 to 48 percent), and breast cancer (27 percent; 95 percent confidence interval, 4 to 41 percent). CONCLUSIONS Inherited genetic factors make a minor contribution to susceptibility to most types of neoplasms. This finding indicates that the environment has the principal role in causing sporadic cancer. The relatively large effect of heritability in cancer at a few sites suggests major gaps in our knowledge of the genetics of cancer.

BACKGROUND Patterns of comorbidity suggest that the common psychiatric and substance use syndromes may be divisible into 2 broad groups of internalizing and externalizing disorders. We do not know how genetic and environmental risk factors contribute to this pattern of comorbidity or whether the etiologic structure of these groups differ in men and women. METHODS Lifetime diagnoses for 10 psychiatric syndromes were obtained at a personal interview in more than 5600 members of male-male and female-female twin pairs ascertained from a population-based registry. Multivariate twin modeling was performed using the program Mx. RESULTS We first fit models to the following 7 syndromes: major depression, generalized anxiety disorder, phobia, alcohol dependence, drug abuse/dependence, adult antisocial behavior, and conduct disorder. The full model, which could be constrained to equality in male and female subjects, identified 2 genetic factors. The first had strongest loadings on alcohol dependence, drug abuse/dependence, adult antisocial behavior, and conduct disorder; the second, on major depression, generalized anxiety disorder, and phobia. Alcohol dependence and drug abuse/dependence had substantial disorder-specific genetic risk factors. Shared environmental factors were most pronounced for conduct disorder and adult antisocial behavior. No clear internalizing/externalizing structure was seen for the unique environmental common factors. We then fit models to 5 internalizing syndromes. The full model, which could also be constrained to equality in men and women, revealed one genetic factor loading most heavily on major depression and generalized anxiety disorder and another loading most strongly on animal and situational phobia. CONCLUSIONS The underlying structure of the genetic and environmental risk factors for the common psychiatric and drug abuse disorders in men and women is very similar. Genetic risk factors predispose to 2 broad groups of internalizing and externalizing disorders. Within the internalizing disorders, 2 genetic factors are seen that predispose to disorders dominated by anxious-misery and fear. Substance use disorders have disorder-specific genetic risks. The externalizing disorders of conduct disorder and adult antisocial behavior are significantly influenced by the shared environment. The pattern of lifetime comorbidity of common psychiatric and substance use disorders results largely from the effects of genetic risk factors.

BACKGROUND A family history of premature coronary heart disease has long been thought to be a risk factor for coronary heart disease. Using data from 26 years of follow-up of 21,004 Swedish twins born between 1886 and 1925, we investigated this issue further by assessing the risk of death from coronary heart disease in pairs of monozygotic and dizygotic twins. METHODS The study population consisted of 3298 monozygotic and 5964 dizygotic male twins and 4012 monozygotic and 7730 dizygotic female twins. The age at which one twin died of coronary heart disease was used as the primary independent variable to predict the risk of death from coronary heart disease in the other twin. Information about other risk factors was obtained from questionnaires administered in 1961 and 1963. Actuarial life-table analysis was used to estimate the cumulative probability of death from coronary heart disease. Relative-hazard estimates were obtained from a multivariate survival analysis. RESULTS Among the men, the relative hazard of death from coronary heart disease when one's twin died of coronary heart disease before the age of 55 years, as compared with the hazard when one's twin did not die before 55, was 8.1 (95 percent confidence interval, 2.7 to 24.5) for monozygotic twins and 3.8 (1.4 to 10.5) for dizygotic twins. Among the women, when one's twin died of coronary heart disease before the age of 65 years, the relative hazard was 15.0 (95 percent confidence interval, 7.1 to 31.9) for monozygotic twins and 2.6 (1.0 to 7.1) for dizygotic twins. Among both the men and the women, whether monozygotic or dizygotic twins, the magnitude of the relative hazard decreased as the age at which one's twin died of coronary heart disease increased. The ratio of the relative-hazard estimate for the monozygotic twins to the estimate for the dizygotic twins approached 1 with increasing age. These relative hazards were little influenced by other risk factors for coronary heart disease. CONCLUSIONS Our findings suggest that at younger ages, death from coronary heart disease is influenced by genetic factors in both women and men. The results also imply that the genetic effect decreases at older ages.

OBJECTIVE In a 1989 article, the authors provided a hypothesis for the neuroanatomical basis of panic disorder that attempted to explain why both medication and cognitive behavioral psychotherapy are effective treatments. Here they revise that hypothesis to consider developments in the preclinical understanding of the neurobiology of fear and avoidance. METHOD The authors review recent literature on the phenomenology, neurobiology, and treatment of panic disorder and impressive developments in documenting the neuroanatomy of conditioned fear in animals. RESULTS There appears to be a remarkable similarity between the physiological and behavioral consequences of response to a conditioned fear stimulus and a panic attack. In animals, these responses are mediated by a "fear network" in the brain that is centered in the amygdala and involves its interaction with the hippocampus and medial prefrontal cortex. Projections from the amygdala to hypothalamic and brainstem sites explain many of the observed signs of conditioned fear responses. It is speculated that a similar network is involved in panic disorder. A convergence of evidence suggests that both heritable factors and stressful life events, particularly in early childhood, are responsible for the onset of panic disorder. CONCLUSIONS Medications, particularly those that influence the serotonin system, are hypothesized to desensitize the fear network from the level of the amygdala through its projects to the hypothalamus and the brainstem. Effective psychosocial treatments may also reduce contextual fear and cognitive misattributions at the level of the prefrontal cortex and hippocampus. Neuroimaging studies should help clarify whether these hypotheses are correct.

OBJECTIVE Stressful life events are associated with the onset of episodes of major depression. However, exposure to stressful life events is influenced by genetic factors, and these factors are correlated with those that predispose to major depression. The aim of this study was to clarify the degree to which stressful life events cause major depression. METHOD The authors assessed the occurrence of 15 classes of stressful life events and the onset of DSM-III-R major depression over a 1-year period in female twins ascertained from a population-based registry. The sample contained 24,648 person-months and 316 onsets of major depression. Stressful life events were individually rated on contextual threat and dependence (the degree to which the stressful life event could have resulted from the respondent's behavior). The nature of the relationship between stressful life events and major depression was tested by 1) discrete-time survival analysis examining the relationship between dependence and the depressogenic effect of stressful life events and 2) a co-twin control analysis. RESULTS While independent stressful life events were significantly associated with onsets of depression, when level of threat was controlled, the association was significantly stronger for dependent events. The odds ratio for onset of major depression in the month of a stressful life event was 5.64 in all subjects, 4.52 within dizygotic pairs, and 3.58 within monozygotic pairs. CONCLUSIONS Stressful life events have a substantial causal relationship with the onset of episodes of major depression. However, about one-third of the association between stressful life events and onsets of depression is noncausal, since individuals predisposed to major depression select themselves into high-risk environments.

We review the literature on the familial resemblance of body mass index (BMI) and other adiposity measures and find strikingly convergent results for a variety of relationships. Results from twin studies suggest that genetic factors explain 50 to 90% of the variance in BMI. Family studies generally report estimates of parent-offspring and sibling correlations in agreement with heritabilities of 20 to 80%. Data from adoption studies are consistent with genetic factors accounting for 20 to 60% of the variation in BMI. Based on data from more than 25,000 twin pairs and 50,000 biological and adoptive family members, the weighted mean correlations are .74 for MZ twins,.32 for DZ twins,.25 for siblings,.19 for parent-offspring pairs,.06 for adoptive relatives, and .12 for spouses. Advantages and disadvantages of twin, family, and adoption studies are reviewed. Data from the Virginia 30,000, including twins and their parents, siblings, spouses, and children, were analyzed using a structural equation model (Stealth) which estimates additive and dominance genetic variance, cultural transmission, assortative mating, nonparental shared environment, and special twin and MZ twin environmental variance. Genetic factors explained 67% of the variance in males and females, of which half is due to dominance. A small proportion of the genetic variance was attributed to the consequences of assortative mating. The remainder of the variance is accounted for by unique environmental factors, of which 7% is correlated across twins. No evidence was found for a special MZ twin environment, thereby supporting the equal environment assumption. These results are consistent with other studies in suggesting that genetic factors play a significant role in the causes of individual differences in relative body weight and human adiposity.

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.

BACKGROUND: Genetic influences on alcoholism risk are well-documented in men, but uncertain in women. We tested for gender differences in genetic influences on, and risk-factors for, DSM-III-R alcohol dependence (AD). METHOD: Diagnostic follow-up interviews were conducted in 1992-3 by telephone with twins from an Australian twin panel first surveyed in 1980-82 (N = 5889 respondents). Data were analysed using logistic regression models. RESULTS: Significantly higher twin pair concordances were observed in MZ compared to DZ same-sex twin pairs in women and men, even when data were weighted to adjust for over-representation of well-educated respondents, and for selective attrition. AD risk was increased in younger birth cohorts, in Catholic males or women reporting no religious affiliation, in those reporting a history of conduct disorder or major depression and in those with high Neuroticism, Social Non-conformity, Toughmindedness, Novelty-Seeking or (in women only) Extraversion scores; and decreased in 'Other Protestants', weekly church attenders, and university-educated males. Controlling for these variables, however, did not remove the significant association with having an alcoholic MZ co-twin, implying that much of the genetic influence on AD risk remained unexplained. No significant gender difference in the genetic variance in AD was found (64% heritability, 95% confidence interval 32-73%). CONCLUSIONS: Genetic risk-factors play as important a role in determining AD risk in women as in men. With the exception of certain sociocultural variables such as religious affiliation, the same personality, sociodemographic and axis I correlates of alcoholism risk are observed in women and men.

Myotonic dystrophy (DM), the most common form of muscular dystrophy in adults, can be caused by a mutation on either chromosome 19q13 (DM1) or 3q21 (DM2/PROMM). DM1 is caused by a CTG expansion in the 3' untranslated region of the dystrophia myotonica-protein kinase gene (DMPK). Several mechanisms have been invoked to explain how this mutation, which does not alter the protein-coding portion of a gene, causes the specific constellation of clinical features characteristic of DM. We now report that DM2 is caused by a CCTG expansion (mean approximately 5000 repeats) located in intron 1 of the zinc finger protein 9 (ZNF9) gene. Parallels between these mutations indicate that microsatellite expansions in RNA can be pathogenic and cause the multisystemic features of DM1 and DM2.

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.