Showing papers by "Michael C. Neale published in 1992"

Methodology for Genetic Studies of Twins and Families

Abstract: Preface. List of Figures. List of Tables. 1. The Scope of Genetic Analyses. 2. Data Summary. 3. Biometrical Genetics. 4. Matrix Algebra. 5. Path Analysis and Structural Equations. 6. LISREL Models and Methods. 7. Model Fitting Functions and Optimization. 8. Univariate Analysis. 9. Power and Sample Size. 10. Social Interaction. 11. Sex Limitation and GE Interaction. 12. Multivariate Analysis. 13. Direction of Causation. 14. Repeated Measures. 15. Longitudinal Mean Trends. 16. Observer Ratings. 17. Assortment and Cultural Transmission. 18. Future Directions. Appendices: A. List of Participants. B. The Greek Alphabet. C. LISREL Scripts for Univariate Models. D. LISREL Script for Power Calculation. E. LISREL Scripts for Multivariate Models. F. LISREL Script for Sibling Interaction Model. G. LISREL Scripts for Sex and GE Interaction. H. LISREL Script for Rater Bias Model. I. LISREL Scripts for Direction of Causation. J. LISREL Script and Data for Simplex Model. K. LISREL Scripts for Assortment Models. Bibliography. Index.

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

Abstract: • 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.

The Genetic Epidemiology of Phobias in Women: The Interrelationship of Agoraphobia, Social Phobia, Situational Phobia, and Simple Phobia

Abstract: • 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

A population-based twin study of alcoholism in women

Abstract: Objective. —To clarify the role of genetic factors in the etiology of alcoholism in women. Design and Setting. —Personal structured psychiatric interviews conducted by researchers "blinded" to the status of the co-twin in an epidemiologic sample of 1030 female-female twin pairs of known zygosity from the population-based Virginia Twin Registry. Measures. —Three definitions of lifetime prevalence of alcoholism based on Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised criteria: (1) alcoholism with tolerance or dependence; (2) alcoholism with or without tolerance-dependence; and (3) alcoholism with or without tolerance-dependence or problem drinking. Results. —Using narrow, intermediate, or broad definitions, the probandwise concordance for alcoholism was consistently higher in monozygotic than in dizygotic twin pairs. Multifactorial threshold models suggested that the heritability of liability to alcoholism in women is in the range of 50% to 60%. Conclusions. —The results support the hypothesis that genetic factors play a major role in the etiology of alcoholism in women. Women should be well represented in the efforts currently under way to elucidate the molecular basis of the genetic susceptibility to alcoholism. ( JAMA . 1992;268:1877-1882)

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

Abstract: 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.

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

Abstract: 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.

Generalized Anxiety Disorder in Women: A Population-Based Twin Study

Abstract: • 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

Social support, depressed mood, and adjustment to stress: a genetic epidemiologic investigation.

Abstract: A survey of 821 same-sex female twin pairs from a population-based registry assessed 8 dimensions of social support and social integration. Twin analyses documented significant common environmental influences on 5 of these 8 measures and significant genetic influences on 5 of the 8. A decomposition of the multiplicative association between support and a measure of stressful life experiences in predicting depressed mood—an association typically interpreted as providing evidence for a stress-buffering effect of social support—shows clearly that it is the environmental and genetic factors that cause support, rather than support itself, that buffer the effects of stress on mood in most cases. We discuss the implications of this result for future research on the relationship between social support and psychopathology. Although there is now overwhelming evidence that social support is associated with reduced risk of psychopathology (for reviews, see Cohen & Wills, 1985; House, Landis, & Umberson, 1988; House, Umberson, & Landis, 1988; Kessler & McLeod, 1985), very little is known about the processes underlying this association. The most common view is that support promotes adjustment to stress by providing assistance with appraisal and coping processes (Thoits, 1986). Numerous social support interventions are based on this view (Gottlieb, 1988). Yet there is other research that suggests that the association between support and adjustment to stress may be spurious. Heller (1979) and Heller and Swindle (1983), for example, have suggested that the relationship between support and adjustment to stress may be due to differences in social competence rather than to stressbuffering effects of supports, and Henderson, Byrne, and Duncan-Jones (1981) have argued that the putative effects of support are due to neuroticism. Attempts to isolate variables that clearly explain the effects of support have focused almost exclusively on personality factors. These attempts have been largely unsuccessful up to now (Cohen, Sherrod, & Clark, 1986). The major exception is the work of Henderson et al. (1981), who found that the effects of support

The analysis of parental ratings of children's behavior using LISREL

Abstract: A common procedure for assessing children's behavior is to obtain parental ratings of the child. Since the ratings obtained are a function of both parent and child, disentangling the child's phenotype from that of the rater becomes an important methodological problem. For the analysis of genetic and environmental contributions to children's behavior, solutions to this are available when multiple raters, e.g., two parents, rate multiple children, e.g., twins. This paper describes and illustrates simple LISREL models for the analysis of parental ratings of children's behavior. We show how the assumption that mothers and fathers are rating the same behavior in children can be contrasted with the weaker alternative that parents are rating correlated behaviors. Given the stronger assumption, which appears adequate for ratings of children's internalizing behavior problems, the contribution of rater bias and unreliability may be separated from the shared and nonshared environmental components of variation in a behavior genetic analysis.

Evidence for genetic influences on personality from self-reports and informant ratings.

Abstract: Self-report data on Extraversion (E) and Neuroticism (N), together with ratings by the co-twin, were obtained from a sample of 826 adult female twin pairs ascertained through a population-based twin register. Data were analyzed using a model that allowed for the contributions to personality ratings of the rater's personality (rater bias) as well as of the personality of the person being rated. For E, but not for N, significant rater bias was found, with extraverted respondents tending to underestimate, and introverted respondents tending to overestimate, the Extraversion of their co-twins. Good agreement between self-reports and ratings by the respondent's co-twin was found for both E and N. Substantial genetic influences were found for both personality traits, confirming findings from genetic studies of personality that have relief only on self-reports of respondents.

Genetic and environmental factors in the aetiology of menstrual, premenstrual and neurotic symptoms: a population-based twin study.

Abstract: Symptoms during the premenstrual and menstrual phases of the female reproductive cycle were assessed in 827 pairs of female same-sex twins from a population-based registry. By conventional factor analysis, premenstrual and menstrual symptoms were relatively independent of one another and of baseline ‘neurotic’ symptoms (i.e. anxiety, depression and somatization). Familial resemblance for menstrual and premenstrual symptoms was due solely to genetic factors with heritability estimates of 39·2% and 35·1%, respectively. Multivariate genetic analysis revealed distinct genetic and environmental factors for menstrual, premenstrual and neurotic symptoms. The genes and individual-specific experiences that predispose to premenstrual symptoms appear to be largely distinct from those which predispose either to menstrual or to neurotic symptoms. The generalizability of these results may be limited because only a modest number of premenstrual and menstrual symptoms were assessed, all by retrospective self-report.

Bulimia nervosa and major depression: a study of common genetic and environmental factors.

Abstract: A genetic analysis of the co-occurrence of bulimia and major depression (MD) was performed on 1033 female twin pairs obtained from a population based register. Personal interviews were conducted and clinical diagnoses made according to DSM-III-R criteria. Additive genes, but not family environment, are found to play an important aetiological role in both bulimia and MD. The genetic liabilities of the two disorders are correlated 0.456. While unique environmental factors account for around half of the variation in liability to both bulimia and MD, these risk factors appear to be unrelated, i.e., each disorder has its own set of unique environmental risk factors. Thus, the genetic liability of bulimia and MD is neither highly specific nor entirely non-specific. There is some genetic correlation between the two disorders as well as some genetic and environmental risk factors unique to each disorder. Limitations and directions for future research are discussed.

Genetic and environmental contributions to the variance of body height in a sample of first and second degree relatives.

Abstract: Height was measured in a health screening of the population in Nord-Trondelag, Norway. Correlations were computed for 24,281 pairs of spouses, 43,613 pairs of parents and offspring, 19,168 pairs of siblings, 1,318 pairs of grandparents and grandchildren, 1,218 cognate avuncular pairs, 849 noncognate avuncular pairs, 175 pairs of same-sexed twins, and smaller groups of other types of relatives. Fitting of structural equation models showed proportions of additive genetic variance of approximately 0.8 for both sexes and small sex-specific effects that probably reflect genetic dominance or environmental sibling effects. The correlations between parents and offspring were significantly lower in old than young cohorts, seeming to imply some kind of interaction effect between genes and environment. © 1992 Wiley-Liss, Inc.

Familial influences on the clinical characteristics of major depression: a twin study.

Abstract: We sought in this study to clarify the role that familial factors play in influencing the clinical presentation of major depression (MD). We examined the similarity of the historical and symptomatic features of MD in 176 pairs of female-female monozygotic (MZ) and dizygotic (DZ) twins from a population-based registry, where both members reported a history of MD defined by DSM-III-R criteria. The age at onset and treatment-seeking were significantly correlated in all twin pairs and the correlation in concordant DZ pairs was actually somewhat higher than in concordant MZ twins. The degree of impairment was modestly correlated in all twin pairs with substantially higher correlations in MZ vs DZ twins. No twin resemblance was observed for number of episodes or longest duration of an episode. Twin resemblance for the clinical features of MD was modest, but so was their consistency for the same individual over successive 1-year periods. However, in 5 of the 6 neurovegetative symptoms involving changes in appetite, weight and sleep, MZ twins were significantly correlated and correlations were significantly greater in concordant MZ vs DZ twins. Although the familial factors that cause twin resemblance for the age at onset and treatment seeking appear to be largely environmental, twin resemblance for the degree of impairment and neurovegetative symptoms are probably due largely to genetic factors. Our results suggest that familial factors influence the predisposition to some clinical features of MD.

Genetic and environmental effects on blood pressure in a Norwegian sample

Abstract: Systolic (SBP) and diastolic (DBP) blood pressures were measured in a health screening of the adult population in Nord-Trondelag, Norway. Correlations were computed for 23,936 pairs of spouses, 43,586 pairs of parent and offspring, 19,151 pairs of siblings, 1,251 pairs of grandparents-grandchildren, 1,146 pairs of biological uncles/aunts-nephews/nieces (avuncular), 801 non-biological avuncular pairs, 169 pairs of same-sex twins, and smaller groups of other types of relationships. Spouse correlations of 0.08 and 0.09 were approximately constant or slightly decreasing with marital duration. The correlation values for SBP and DBP were approximately 0.16 for parents-offspring, 0.19 to 0.23 for same-sex siblings with similar values for DZ twins, 0.19 and 0.16 for opposite-sex siblings, 0.52 and 0.43 for MZ twins, and close to zero for most of the second-order relationships. Genetic additive variance was estimated at 0.29 and genetic dominance variance at 0.18 with the best model for SBP. The corresponding estimates from the best models for DBP were 0.29 or lower and 0.22 or lower, the sum not exceeding 0.35. There was evidence of a moderate effect of environmental factors shared by same-sex siblings and twins (for DBP), but no cultural transmission, and whether or not adult relatives live together does not affect familial resemblance for BP. The data did not permit a very precise resolution of the relative magnitude of genetic dominance and sibling effects. The correlation structure did not show sex-specific genetic effects.

Aphidicolin-inducible common fragile-site expression: results from a population survey of twins.

Abstract: Common chromosomal fragile sites appear to be ubiquitous in humans and other mammals, and, although the molecular basis and function of these sites remain an enigma, it has been speculated that they may be a cytogenetic expression of gene activity. A population survey of 28 twin pairs was conducted to assess the heritability of common fragile-site expression. Our data yielded a heritability estimate of .88 for total site expression, suggesting that these sites may result from some common process that is under relatively stringent genetic control. An analysis of the expression of individual autosomal sites revealed that expression on both homologues in the same cell occurred more frequently than expected.

The relationship between age at first drug use and teenage drug use liability.

Abstract: Our analyses of Carey's (1992) simulated data set of substance abuse in a cohort of adolescent twins were aimed at answering the question What is the relationship between age at first drug use andEVER having used drugs (i.e., teenage drug use liability)? Three analytic methods were used to determine whether age at first drug use was (1) a “perfect” index of drug use liability, (2) correlated in relatives but conditionally independent of drug use liability, or (3) causally influenced by drug use liability and by factors independent of liability. The analytic methods included nonmetric multidimensional scaling, multifactorial threshold model-fitting to contingency tables, and pedigree-based likelihood formulations for the raw data. All approaches indicated that age at first drug use was a perfect index of drug use liability. Further, model-fitting results indicated that only shared environmental factors accounted for twin similarity in the onset and timing of drug use. We discuss the limitations of each of the analytic methods and integrate our findings with the true model used in Carey's simulation.

The Scope of Genetic Analyses

Abstract: This book has its origin in a week-long intensive course on methods of twin data analysis taught on several occasions over the last few years at the Katholieke Universiteit of Leuven in Belgium and the Institute for Behavioral Genetics, Boulder, in Colorado. Our principal aim here is to help those interested in the genetic analysis of individual differences to realize that there are more challenging questions than simply “Is trait X genetic?” or “What is the heritability of X?” and that there are more flexible and informative methods than those that have been popular for more than half a century. We shall achieve this goal primarily by considering those analyses of data on twins that can be conducted with the LISREL program. There are two main reasons for this restriction: 1) the basic structure and logic of the twin design is simple and yet can illustrate many of the conceptual and practical issues that need to be addressed in any genetic study of individual differences; 2) the LISREL program is well-documented, commercially available for personal computers and can be used to apply most of the basic ideas we shall discuss. These limitations not withstanding, however, we believe that the material to be presented will open many new horizons to investigators in a wide range of disciplines and provide them with the tools to begin to explore their own data more fruitfully.

Direction of Causation

Abstract: The past 15 years have seen a broadening of the focus of studies in behavioral genetics and genetic epidemiology. Rather than concentrating exclusively on a single behavioral domain (e.g., IQ or personality or psychiatric disorder or a behavioral risk-factor for major chronic disease), researchers have attempted to assess numerous behavioral domains and environmental risk-factors in a single study. There has been a corresponding growth of interest in identifying ‘intervening’ or ‘mediating’ variables in the causal pathway pathway from genotype and environment to outcome. In alcoholism research, for example, the hypothesis has been advanced (e.g., Tartar et al., 1985; Cloninger, 1987) that the genetic influence on risk of alcoholism (Heath et al., 1990) is in part explained by the inheritance of temperamental or personality factors which in turn influence an individual’s risk of becoming alcoholic. The growing interest in genotype-environment correlation, particularly the extent to which an individual’s genotype shapes the environment to which she or he is exposed (Eaves et al., 1977; Plomin et al., 1977; Scarr and McCartney, 1983; Plomin and Bergeman, 1991), has led to the formulation of competing hypotheses about how inherited differences in personality, temperament, or other behavioral variables might influence the environment to which an individual exposes herself (e.g., adverse life-events). These environmental agents in turn may increase the risk of psychiatric disorder (e.g., depression: Kendler et al., 1992d). In such cases we need to go beyond merely demonstrating that an outcome variable is influenced by genetic factors, in tests of univariate genetic models (Chapter 8), or merely demonstrating that this variable loads on the same genetic factor(s) as measures of temperament and personality or measures of environmental exposure, in a multivariate genetic analysis (Chapter 12).

Sex-limitation and G × E Interaction

Abstract: As described in Chapter 8, the basic univariate ACE model allows us to estimate genetic and environmental components of phenotypic variance from like-sex MZ and DZ twin data. When data are available from both male and female twin pairs, an investigator may be interested in asking whether the variance profile of a trait is similar across the sexes or whether the magnitude of genetic and environmental influences are sex-dependent. To address this issue, the ACE model may be fitted independently to data from male and female twins, and the parameter estimates compared by inspection. This approach, however, has three severe limitations: (1) it does not test whether the heterogeneity observed across the sexes is significant; (2) it does not attempt to explain the sex differences by fitting a particular sex-limitation model; and (3) it discards potentially useful information by excluding dizygotic opposite-sex twin pairs from the analysis. In the first part of this chapter (section 11.2), we outline three models for exploring sex differences in genetic and environmental effects (i.e., models for sex-limitation) and provide an example of each by analyzing twin data on body mass index (BMI).

Path Analysis and Structural Equations

Abstract: Path analysis was invented by the geneticist Sewall Wright (1921a, 1934, 1960, 1968), and has been widely applied to problems in genetics and the behavioral sciences. It is a technique which allows us to represent, in diagrammatic form, linear ‘structural’ models and hence derive predictions for the variances and covariances (the covariance structure) of our variables under that model. The books by Kenny (1979), Li (1975), or Wright (1968) supply good introductory treatments of path analysis, and general descriptions of structural equation modeling can be found in Bollen (1989) and Loehlin (1987). In this chapter we provide only the basic background necessary to understand models used in the genetic analyses presented in this text.

Model Fitting Functions and Optimization

Abstract: In the previous chapter we described the LISREL model and outlined the functions therein that may be used to fit a model to data. We now describe these fitting functions in greater detail, and with special emphasis on the genetic analysis of twin data. We also discuss how the fitting functions are used to generate optimal estimates of genetic parameters in the twin design. Again, understanding of these issues is not essential for the use of LISREL to fit models to data; we provide this Chapter for those readers wishing to further their knowledge of how LISREL does what it does, and the statistical theory behind the choice of fit functions for particular types of data.

Power and Sample Size

Abstract: In this chapter we discuss the power of the twin study to detect variance components in behavioral characters. Our discussion is not in any way intended to be an exhaustive description of the power of the twin study under all possible combinations of causal factors and model parameters. Such a description is in large part available for the continuous case (Martin et al.,1978) and there is an extensive comparison of the power of various designs to detect cultural transmission (Heath et al., 1985). As we move out of the framework of the univariate classical twin study to consider multivariate hypotheses and data from additional classes of relatives, a comprehensive treatment rapidly becomes unmanageably large. Fortunately, it seems rather unnecessary because the prospective researcher usually has certain specific aims of a study in mind, and often has a reasonable idea about the values of some of the parameters in the model. This information can be used to prune the prodigious tree of possible scenarios to manageable proportions. All that is required is an understanding of the principles involved, which we aim to provide in Section 9.2. We illustrate these methods with a limited range of examples for continuous and categorical twin data.

LISREL Models and Methods

Abstract: In this Chapter we develop the LISREL model formally, and assume some knowledge of elementary statistics. While understanding the model will prove useful in the long run, it is not strictly prerequisite for the LISREL applications in this book. It provides a valuable reference section and guide to the statistical theory behind applied model-fitting, especially in conjunction with our first application of the package in Section 8.4. The less mathematically-minded reader may wish to skim this Chapter for now, and return to it when they feel more comfortable with the practical use of LISREL for simple models.