The structure of psychosis: latent class analysis of probands from the Roscommon Family Study.

BACKGROUND: The nosologic structure of psychotic illness, still influenced as much by historical as empirical perspectives, remains controversial. METHODS: Latent class analysis was applied to detailed symptomatic and outcome assessments of probands (n=343) with broadly defined schizophrenia and affective illness ascertained from a population-based psychiatric registry in Roscommon County, Ireland. First-degree relatives (n=942) were assessed by personal interview and/or review of hospital record. RESULTS: Six classes were found, all of which bore substantial resemblance to current or historical nosologic constructs. In order of decreasing frequency, they were (1) classic schizophrenia, (2) major depression, (3) schizophreniform disorder, (4) bipolar-schizomania, (5) schizodepression, and (6) hebephrenia. These classes differed on many historical and clinical variables not used in the latent class analysis. Compared with relatives of controls, significantly increased rates of major depression were seen in relatives of depressed and schizodepressed probands. Significantly increased rates of bipolar illness were restricted to relatives of bipolar-schizomanic probands. The risks for schizophrenia and schizophrenia spectrum disorders were significantly increased in relatives of all proband classes except major depression. This increase was moderate for bipolar-schizomanic probands, substantial for schizophrenic, schizophreniform, and schizodepressed probands, and marked for hebephrenic probands. CONCLUSIONS: These results suggest a relatively complex typology of psychotic syndromes consistent neither with a unitary model nor with a Kraepelinian dichotomy. The familial vulnerability to psychosis extends across several syndromes, being most pronounced in those with schizophrenialike symptoms. The familial vulnerability to depressive and manic affective illness is somewhat more specific.

Illicit psychoactive substance use, heavy use, abuse, and dependence in a US population-based sample of male twins.

BACKGROUND: In order to develop informed approaches to prevention and treatment of illicit psychoactive substance use, abuse, and dependence, we need to understand the sources of individual differences in risk. METHODS: In personal interviews with 1198 male-male twin pairs (708 monozygotic and 490 dizygotic) ascertained from a population-based registry, we assessed lifetime use, heavy use, and abuse of and dependence on cannabis, sedatives, stimulants, cocaine, opiates, and hallucinogens. Twin resemblance was assessed by probandwise concordance, odds ratio, tetrachoric correlations, and biometrical model fitting. RESULTS: Twin resemblance for substance use, heavy use, abuse, and dependence was substantial, and consistently greater in monozygotic than in dizygotic twins. For any drug use and for cannabis and hallucinogen use, model fitting suggested that twin resemblance was due to both genetic and familial-environmental factors. Twin resemblance for sedative, stimulant, cocaine, and opiate use, however, was caused solely by genetic factors. With 2 exceptions (cocaine abuse and stimulant dependence), twin resemblance for heavy use, abuse, and dependence resulted from only genetic factors, with heritability of liability usually ranging from 60% to 80%. No consistent evidence was found for violations of the equal environment assumption. CONCLUSIONS: In accord with prior results in studies of women, the family environment plays a role in twin resemblance for some forms of substance use in men. However, twin resemblance for heavy use, abuse, and dependence in men is largely caused by genetic factors, and heritability estimates are high.

Causal relationship between stressful life events and the onset of major depression.

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.

Longitudinal population-based twin study of retrospectively reported premenstrual symptoms and lifetime major depression.

OBJECTIVE: While family and twin studies suggest that retrospectively reported premenstrual symptoms are heritable, these studies have not accounted for the unreliability of such measures. In addition, we know little about the relationship of the familial risk factors for premenstrual symptoms and major depression. METHOD: Lifetime major depression and premenstrual-related tiredness, sadness, and irritability were assessed twice over 6 years in 1,312 menstruating female twins ascertained from a population-based twin register. A twin-measurement model--which permits estimation of the etiologic roles of genetic and environmental factors with correction for errors of measurement or short-term temporal fluctuations--was applied to these data. RESULTS: A single premenstrual symptom factor was found that was moderately stable over time. The best-fitting twin-measurement model estimated the heritability of the stable component of premenstrual symptoms at 56% and showed no impact of family-environmental factors. A bivariate twin-measurement model estimated that the genetic and environmental risk factors for lifetime major depression contributed only modestly to the etiology of premenstrual syndrome. No evidence was found for significant biases in the twin method. CONCLUSIONS: Retrospectively reported premenstrual-related symptoms of depression and anxiety are moderately stable over time and, when correction is made for this level of stability, substantially heritable. The genetic and environmental risk factors for these premenstrual symptoms and lifetime major depression are not closely related.

Sibling correlation of deficit syndrome in the Irish study of high-density schizophrenia families.

OBJECTIVE: The deficit syndrome is a subtype of schizophrenia characterized by primary and enduring negative features of psychopathology. It appears to reflect a distinct subtype within the syndrome of schizophrenia. Little is known about the familial or genetic aspects of the deficit syndrome. The purpose of this study was to determine whether deficit versus nondeficit subtypes are correlated in sibling pairs affected with schizophrenia. METHOD: The present study was based on the Irish Study of High-Density Schizophrenia Families. From the earlier study the authors selected a subset of patients who were members of sibling pairs in which both siblings had been diagnosed with "core" schizophrenia, which included schizophrenia, simple schizophrenia, and schizoaffective disorder with poor outcome. The Schedule for the Deficit Syndrome was used to make deficit versus nondeficit diagnoses, which were based on chart examinations by reviewers blind to sibling status. This method resulted in 65 patients being diagnosed with the deficit syndrome and 401 patients diagnosed as nondeficit (prevalence=13.9%). This group included 347 full sibling pairs, which were analyzed for resemblance with respect to deficit versus nondeficit subtype by means of logistic regression. RESULTS: Deficit versus nondeficit subtypes were significantly correlated in sibling pairs concordant for core schizophrenia. CONCLUSIONS: Familial factors contribute significantly to whether a person has the deficit subtype of schizophrenia. This familial contribution could be genetic or environmental.

Differences in locomotor activity across the lifespan of Drosophila melanogaster.

The identification of differential patterns of change across the lifespan in quantitative traits is of abiding interest in the biological and gerontological research communities. These differential phenotypic patterns in complex systems illuminate developmental processes and form the foundation for the identification of putative biomarkers of aging. The goal of the present study was to explore changes in locomotor activity through the lifespan of Drosophila melanogaster. A replicated serial cross-sectional sampling design was used to test activity in five genetically independent inbred strains at 7, 14, 21, 28, 35, and 42 days of age. Differences were observed in activity level across ages and strains, suggesting that patterns of activity throughout the lifespan of D. melanogaster are influenced by genetic factors. Observed sex differences in change in activity level indicate that the aging processes may proceed differently in males and females.

Multivariate assessment of factors influencing illicit substance use in twins from female-female pairs.

Although familial factors have been shown to influence drug use, abuse, and dependence, little is known about the common and specific factors that influence polysubstance use and misuse. Our objective was to assess whether there are genetic and environmental factors specific to each substance or whether there are factors that predispose an individual to use of illicit substances in general. Twins from female-female pairs from the Virginia Twin Registry were interviewed by phone to assess lifetime nonmedical use of cannabis, sedatives, stimulants, cocaine, opiates, and hallucinogens. Multivariate, biometrical model-fitting was applied to the data using the Mx computer package. In the best-fitting model, use of all classes of drugs was influenced by a single general genetic factor (common to all substances) and a general familial environmental factor. The magnitude of influence of the general genetic factor ranged from 3% of the variance for opiates to 59% of the variance for cannabis. Some differences were seen from the univariate results, indicating some of the parameter estimates were unstable due to small numbers of concordant pairs. However, generalizations could be made. In women, the substances examined share genetic and familial environmental factors which contribute to the vulnerability to use. Degree of influence of the factors differs for the substances examined. However, no specific genetic or familial environmental factors were found to contribute significantly to use of any of the illicit substances.

An examination of the genetic relationship between bipolar and unipolar illness in an epidemiological sample.

In an epidemiologic sample of female-female twin pairs, we previously reported analyses of lifetime major depression. Because lifetime mania was not assessed, we could not differentiate unipolar from bipolar illness. Having completed such an evaluation in this sample, we now examine three questions: (i) does removing bipolar cases from our cohort substantially alter estimates for the heritability of major depression?; (ii) does our epidemiologic data support a familial relationship between major depression and mania?; and (iii) do our results for major depression and mania suggest that the two disorders are caused by the same underlying liability? We find that (i) the heritability of major depression declines only trivially if cases with a history of mania are removed; (ii) mania in one twin predicts major depression in her cotwin-suggesting a familial/genetic relationship between major depression and mania; and (iii) a multiple threshold model fits our data well, consistent with the hypothesis that unipolar and bipolar disorders are points on a continuum of a single liability of illness. The validity of these results are tempered by the small number of bipolar cases detected, as expected from the low base rate of mania in general population samples.

Genetic selection disrupts stability of mouse brain weight development.

Fuller Brain Weight Selection lines are well differentiated for 42-day brain weight and a high degree of genetic homogeneity for trait-relevant genes is indicated. Using these lines, random bred descendants of the foundation population and an inbred line, biometrical analysis of brain growth from birth to 23 days was attempted. While strain means differ as expected, within and between litter variances for genetically heterogeneous mice were typically no greater than for more genetically homogeneous selected lines. Possible explanations involving gestational age, intra-uterine and postnatal competition and ontogenetic buffering are discussed.

Stressful life events and major depression: risk period, long-term contextual threat, and diagnostic specificity.

Although stressful life events (SLEs) play a major role in many etiologic theories of major depression (MD), important questions remain about the nature of their association with the onset of depressive episodes. We assessed over the last year, in female twins ascertained from a population based registry, the occurrence of 15 classes of SLEs and the onset of DSM-III-R MD and 2-week generalized anxiety disorder (GAD). The sample contained 24,648 person-months, 316 onsets of MD, and 239 onsets of GAD. SLEs were rated on long-term contextual threat and dependence. Discrete time-survival analyses were employed. The association between SLEs and depressive onsets was usually strongest in the month of occurrence but extended for "difficulty-like" events for up to 6 months. The depressogenic effect of SLEs was strongly predicted by contextual threat level, although some low threat events significantly increased risk for MD. The risk for a depressive onset given the number of reported SLEs within one month was: no event, 0.9%; one, 3.4%; two, 6.8%; and three, 23.8%. Although a few events were relatively specifically depressogenic or anxiogenic, most SLEs increased risk for both MD and GAD. The risk period produced by SLEs range from short-lived to relatively prolonged. High threat events encompass most but not all of the depressogenic effects of SLEs. Multiple SLEs in the same month substantially increase the risk for a depressive onset. The specificity of most SLEs for depressive versus anxiety syndromes is modest.

The assessment of dependence in the study of stressful life events: validation using a twin design.

BACKGROUND: In the assessment of stressful life events (SLEs), researchers have often tried to evaluate whether individual events are dependent or independent of the respondent's behaviour. We sought to validate this evaluation using a twin methodology. We predicted that dependent SLEs would be more heritable than independent SLEs. METHODS: We explored, by twin modelling, the resemblance in two pairs of past-year personal and network SLEs rated individually, by trained interviewers, on a four-point dependence-independence scale. We examined results from two waves of interviews with 785 female-female twin pairs ascertained from a population based registry. RESULTS: Twin model-fitting found no evidence for genetic effects on personal or network independent SLEs. However, familial-environmental factors played an important role in the aetiology of network independent SLEs. For personal and network dependent SLEs, by contrast, three of four analyses suggested a significant aetiological role for genetic factors with estimated heritabilities ranging from 19 to 51%. CONCLUSIONS: Our results support the validity of interviewer assessments of dependence versus independence of SLEs. As predicted, these assessments were relatively successful at distinguishing SLEs that were influenced by genetic factors from those that were not.

Fears and phobias: reliability and heritability.

BACKGROUND: Familial factors, which are partly genetic, influence risk for phobias. Prior family and twin studies, however, were based on a single lifetime assessment, which may be only moderately reliable. METHODS: We obtained, 8 years apart, two assessments of lifetime history of five unreasonable fears and phobias (agoraphobia and social, situational, animal and blood-injury phobia) from face-to-face and telephone interviews from 1708 individual female twins from a population-based registry. We also obtained, 1 month apart, test retest reliability on 192 twins. We fitted, using the program Mx, a measurement model that estimates the role of genetic and environmental risk factors correcting for measurement error. RESULTS: Short-term reliability of the five phobias was modest (mean kappa = 0.46), but higher than long-term stability (mean kappa = 0.30). Unreliability occurred both for subject recall of unreasonable fears and for interviewer assessment of which fears constituted phobias. Examining fears and phobias together, in a multiple threshold model, results suggested that twin resemblance was due solely to genetic factors, with estimated total heritabilities, corrected for unreliability, of: any 43%, agoraphobia 67%, animal 47%, blood/injury 59%, situational 46% and social 51%. With the exception of animal phobia, similar results were obtained analysing phobias alone. CONCLUSIONS: Lifetime histories of unreasonable fears and phobias assessed at personal interview have substantial unreliability. Correcting for unreliability, the liability to fears and their associated phobias is moderately heritable. Individual-specific environmental experiences play an important role in the development of phobias, while familial-environmental factors appear to be of little aetiological significance.

Latent class analysis of temperance board registrations in Swedish male-male twin pairs born 1902 to 1949: searching for subtypes of alcoholism.

BACKGROUND: Alcoholism is clinically heterogeneous. We have attempted to identify and validate subtypes of broadly defined alcoholism. METHODS: Latent class analysis (LCA) was applied to data on the number, age at onset and reasons for temperance board registration (TBR) in all male-male twin pairs of known zygosity born in Sweden from 1902-1949. RESULTS: Of the five classes identified, two were relatively common: single-cause registrant-drunk (SCR-D); and early-onset multiple-cause registrant (EO-MCR). In contrast to the SCR-D class, the EO-MCR class was characterized by: (i) earlier age at first TBR; (ii) higher number of TBRs; (iii) TBRs for drunk driving and alcohol-related crimes; (iv) much higher risk for alcohol-related imprisonment and hospitalization; (v) higher levels of neuroticism and novelty-seeking; and (vi) much greater risk for TBR in co-twins. In twin pairs concordant for TBR, concordance for LCA-derived class assignment far exceeded chance expectation, more so in monozygotic than in dizygotic pairs. CONCLUSIONS: Alcoholism is aetiologically as well as clinically heterogeneous. The two most common subtypes identified in these analyses bear substantial but imperfect resemblance to previously proposed typologies.

Multivariate genetic analysis of the causes of temperance board registrations. In all Swedish male-male [correction of male-female] twin pairs born 1926-1949.

BACKGROUND: The Temperance Boards in Sweden registered individuals for three reasons: public drunkenness, driving under the influence of alcohol and committing a crime in connection with alcohol. We wanted to ascertain whether these three forms of alcohol-related problems result from similar or different genetic and environmental risk factors. METHOD: We conducted a trivariate twin analysis of these three causes of registration in all male-male [corrected] twin pairs of known zygosity born in Sweden, 1926-1949 (n = 5177 twin pairs). RESULTS: Prevalences of registration for public drunkenness, drink-driving and alcohol-related crime were, respectively, 9.0, 3.6 and 4.0%. The best-fitting model had one general genetic and one general familial-environmental factor with specific genetic risk factors for drink-driving and specific familial-environmental risk factors for alcohol-related crime. CONCLUSIONS: The three causes for alcohol registration in Sweden largely reflect the same genetic and environmental risk factors. Estimated heritabilities were similar for the three forms of registration. However, specific genetic risk factors exist for drink-driving and specific familial-environmental risk factors for alcohol-related crime. Genetic factors are somewhat less important and familial-environmental factors more important for public drunkenness than for drink-driving and alcohol related crime.

Genetic and environmental risk factors in the aetiology of illicit drug initiation and subsequent misuse in women.

BACKGROUND: Subsequent to initial exposure to the use of a psychoactive substance, psychoactive substance use disorder (PSUD) may or may not develop. AIMS: To investigate the relationship between the risk factors for initiation and the subsequent misuse of psychoactive substances. METHOD: The lifetime history of illicit substance use and misuse was obtained by telephone interview with 1934 members of female-female twin pairs. We apply a novel model, which estimates the role of genetic and environmental risk factors that influence initiation and those specific to misuse, to three classes of illicit psychoactive substances. RESULTS: The individual-specific environment and family environment influenced the probability of initiation, but only individual-specific environment had an impact on the probability of subsequent misuse. Genetic factors which influence the risk of initiation and of misuse were identified. CONCLUSIONS: Aetiological factors that influence drug initiation and subsequent misuse are correlated but not identical. Family environment is an important determinant of risk for drug experimentation. Two classes of genetic risk factors act on the liability to PSUD: those that influence the probability of initiation and those that influence the risk of misuse.