Carol A. Prescott

A population-based twin study in women of smoking initiation and nicotine dependence

BACKGROUND The development of drug dependence requires prior initiation. What is the relationship between the risk factors for initiation and dependence? METHODS Using smoking as a model addiction, we assessed smoking initiation (SI) and nicotine dependence (ND) by personal interview in 1898 female twins from the population-based Virginia Twin Registry. We developed a twin structural equation model that estimates the correlation between the liability to SI and the liability to ND, given SI. RESULTS The liabilities to SI and ND were substantially correlated but not identical. Heritable factors played an important aetiological role in SI and in ND. While the majority of genetic risk factors for ND were shared with SI, a distinct set of familial factors, which were probably partly genetic, solely influenced the risk for ND. SI was associated with low levels of education and religiosity, high levels of neuroticism and extroversion and a history of a wide range of psychiatric disorders. ND was associated with low levels of education, extroversion, mastery, and self-esteem, high levels of neuroticism and dependency and a history of mood and alcohol use disorders. CONCLUSIONS The aetiological factors that influence SI and ND, while overlapping, are not perfectly correlated. One set of genetic factors plays a significant aetiological role in both SI and ND, while another set of familial factors, probably in part genetic, solely influences ND. Some risk factors for SI and ND impact similarly on both stages, some act at only one stage and others impact differently and even in opposite directions at the two stages. The pathway to substance dependence is complex and involves multiple genetic and environmental risk factors.

Genetic risk factors for major depression in men and women: similar or different heritabilities and same or partly distinct genes?

BACKGROUND Although women are at consistently greater risk for major depression (MD) than men, it is unclear whether sex modifies the aetiological impact of genetic factors on MD. Is the heritability of MD different in men and women? Do the same genetic risk factors predispose to MD in the two sexes? METHODS We obtained a lifetime history of MD by personal interview on two occasions from 6672 individual twins and 2974 complete twin pairs. Three diagnostic criteria of increasing narrowness were employed: DSM-III-R, DSM-III-R plus impairment and Washington University. To increase power by controlling for unreliability of assessment, we evaluated sex differences on genetic risk for MD using a structural equation measurement model. RESULTS Using DSM-III-R criteria, but not the two narrower definitions, heritability of MD was significantly greater in women than in men. In the three diagnostic systems, the genetic correlation in liability to MD in men and women was estimated at between +0.50 and +0.65. These estimates differed significantly from unity for the two broader definitions. CONCLUSION Using broad but not narrower definitions of illness, genetic factors play a greater role in the aetiology of MD in women than in men. The genes that influence risk for MD in the two sexes are correlated but are probably not entirely the same. These results raise the possibility that, in linkage and association studies, the impact of some loci on risk for MD will differ in men and women.

A twin study of genetic and environmental influences on tobacco initiation, regular tobacco use and nicotine dependence

BACKGROUND Numerous twin studies have reported significant genetic contributions to the variability of tobacco initiation (TI), while fewer studies have shown similar results for the persistence of smoking behavior, or nicotine dependence (ND). As the development of ND requires regular tobacco use (RTU) which in turn requires TI, a conditional approach is necessary. METHOD We used structural equation modeling of multi-step conditional processes to examine the relationship between genetic and environmental risk factors for TI, RTU and ND. The tobacco variables were assessed by personal interview in female, male and opposite-sex twin pairs from the population-based Virginia Twin Registry. RESULTS The results suggested that the liabilities to TI, RTU and ND were correlated. Over 80 % of the variance in liability to TI and RTU were shared, and a smaller proportion was shared between RTU and ND. The heritabilities were estimated at 75 %, 80 % and 60 % respectively for TI, RTU and ND. The variance specific to liability to RTU was entirely accounted for by additive genetic factors. Only a modest part of the heritability in liability of ND was due to genetic factors specific to ND. Shared environmental factors were not significant. No sex differences were found for the sources of variation or causal paths, but prevalences were significantly greater in males versus females. CONCLUSIONS This study showed significant overlap in the contribution of genetic factors to individual differences in TI, RTU and ND. Furthermore, there was evidence for significant additional genetic factors specific to RTU and ND.

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.

Childhood parental loss and risk for first-onset of major depression and alcohol dependence: the time-decay of risk and sex differences

BACKGROUND Whereas a number of studies have suggested that parental loss is associated with increased risk for major depression (MD), much less is known about possible gender differences, diagnostic specificity and the time course of the impact of loss. METHOD First-onsets for MD and alcohol dependence (AD) were assessed at personal interviews in 5070 twins from same-sex (SS) and 2118 from opposite-sex (OS) twin pairs ascertained from a population-based registry. Cox Proportional Hazard (PH) and Non-Proportional Hazard (NPH) models, examining first onsets of MD and AD, were used with twins from SS pairs and conditional logistic regression for OS pairs. Parent-child separations prior to age 17 were divided into death and separation from other causes. RESULTS The PH assumptions of constant increased risk were rejected for the impact of loss on risk for MD but not for AD. NPH models found significantly increased risk for MD after both death and separation with the risk lasting much longer for separations. For AD, the PH model found significantly increased risk after parental separation but not death. In both SS and OS twin pairs, no sex differences were seen in the impact of parental loss on risk for MD whereas the association between separation and risk for AD was significantly stronger in females than in males. CONCLUSION Consistent sex differences in the association with parental loss were seen for AD but not MD. The analysis of the time-course of increased risk after loss suggests three different patterns which may reflect different relationships: parental death and MD (return to baseline within approximately 12 years), separation and MD (return to baseline within approximately 30 years) and separation and AD (no change in risk over time).

A twin study of early cannabis use and subsequent use and abuse/dependence of other illicit drugs

INTRODUCTION Cannabis use is strongly associated with the use and abuse/dependence of other illicit drugs. Gateway and common liabilities models have been employed to explain this relationship. We sought to examine this association using a combination of the discordant twin design and modeling methods. METHOD We assess the relationship between early cannabis use and the subsequent use and abuse/ dependence of other illicit drugs in a population-based sample of male and female twin pairs using four analyses: (i) analysis of the association between early cannabis use and other illicit drug use and abuse/dependence in the entire sample of twins, (ii) assessment of the influence of early cannabis use in twin 1 on twin 2s use or abuse/dependence of other illicit drugs, (iii) use of twin pairs discordant for early cannabis use in a discordant twin design and (iv) a model-fitting procedure. RESULTS We found: (i) a strong association between early cannabis use and use and abuse/dependence of other illicit drugs in the sample, (ii) twin 1s early cannabis use is significantly associated with the twin 2s other illicit drug use, (iii) the role of correlated genetic factors with some evidence for a causal influence, and (iv) the correlated liabilities model fits the data well. CONCLUSIONS Early cannabis use is strongly associated with other illicit drug use and abuse/dependence. The relationship arises largely due to correlated genetic and environmental influences with persisting evidence for some causal influences.

Obsessive and compulsive symptoms in a general population sample of female twins

Obsessive-compulsive disorder (OCD) and obsessive-compulsive symptoms (OCS) exhibit a familial pattern of transmission. The different components of these conditions and the extent to which these components are inherited have not been studied well. A sample of 1,054 female twins, including both members of 527 pairs, from the Virginia Twin Registry returned questionnaires that included 20 items from the Padua Inventory of obsessive-compulsiveness. Their responses were used to estimate the heritability of the different factors of OCS in this population. Principal components analysis suggested two meaningful factors corresponding roughly to obsessions and compulsions. The best-fit model suggested heritabilities of 33 and 26%, respectively. The correlation between additive genetic effects on compulsiveness and obsessiveness was found to be +0.53. Self-report symptoms of obsessions and compulsions in women from the general population are moderately heritable and due, in part, to the same genetic risk factors. An understanding of the etiology of these symptoms is relevant to the study of OCD. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:791-796, 2000.

Sex differences in the genetic and environmental influences on the development of antisocial behavior

The present study uses a population-based sample of 6.806 adult twins from same-sex and opposite-sex twin pairs to examine sex differences in the underlying genetic and environmental architecture of the development of antisocial behavior (AB). Retrospective reports of AB during three different developmental periods were obtained: prior to age 15 years (childhood), age 15-17 years (adolescent), and age 18 years and older (adult). Structural equation modeling analyses revealed that there was no evidence for sex-specific genetic or sex-specific shared family environmental influences on the development of AB; that is, the types of genetic and environmental influence were similar for males and females. For both sexes, a model that allowed for genetic influences on adolescent and adult AB that were not shared with childhood AB fit better than a model with a single genetic factor. In contrast, shared environmental influences on adolescent and adult AB overlapped entirely with shared environmental influences on childhood AB. Genetic factors played a larger role in variation in childhood AB among females, whereas shared environmental factors played a larger role among males. However, heritability of AB increased from childhood to adolescence and adulthood for both sexes, and the magnitude of genetic and environmental influences on adolescent and adult AB was approximately equal across sex. We speculate that sex differences in timing of puberty may account for the earlier presence of genetic effects among 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.

Parenting and adult mood, anxiety and substance use disorders in female twins: an epidemiological, multi-informant, retrospective study

BACKGROUND Although parenting has long been considered an important risk factor for subsequent psychopathology, most investigations of this question have studied a single informant, clinical populations, one or a few disorders and did not consider relevant covariates. METHODS Three dimensions of parenting (coldness, protectiveness and authoritarianism) were measured by combining the retrospective reports from adult female twins, their co-twins, and their mothers and fathers. We assessed by personal interview, lifetime history in the twins of eight common psychiatric and substance abuse disorders and a range of predictors of parenting. Analyses were performed using logistic regression. RESULTS Examined individually, high levels of coldness and authoritarianism were modestly but significantly associated with increased risk for nearly all disorders, while the impact of protectiveness was more variable. These associations declined modestly when putative predictors of parenting were added as covariates. Maternal and paternal parenting were equally associated with outcomes in adult daughters. When coldness, protectiveness and authoritarianism were examined together, nearly all significant associations were seen solely with coldness. Few significant interactions were found between maternal and paternal parenting or between coldness, protectiveness and authoritarianism. The shared experience of these three dimensions of parenting predicts a quite small correlation in liability to these disorders in dizygotic twin pairs (e.g. r < 0.04). CONCLUSION In women, parenting behaviour, especially levels of coldness, is probably causally related to risk for a broad range of adult psychiatric disorders. The impact of parenting on substance use disorders may be largely mediated through their co-morbidity with major depression, phobias and generalized anxiety disorder. In general population samples, the association of poor parenting with psychiatric illness is modest, largely non-specific and explains little of the observed aggregation of these disorders in families.