 |
|
The Structure of Genetic and Environmental Risk Factors for Common Psychiatric and Substance Use Disorders in Men and Women
Kenneth S. Kendler, MD;
Carol A. Prescott, PhD;
John Myers, MS;
Michael C. Neale, PhD
Arch Gen Psychiatry. 2003;60:929-937.
ABSTRACT
| |
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.
INTRODUCTION
HIGH LEVELS of comorbidity are consistently seen for psychiatric and substance use disorders.1-2 Such a pattern suggests that many risk factors for psychopathology are not disorder specific, a contention supported by numerous studies.3-5 This observed pattern of comorbidity indicates that the broad array of common psychiatric disorders may be explained more parsimoniously by a small number of underlying factors. Recently, 3 large epidemiological studies have suggested that the most important of these factors reflect the broad groupings of internalizing and externalizing disorders6-8 (although 2 of these studies7-8 suggest that the internalizing factor might itself be divisible into subfactors).
These important studies, however, were observational and did not address the risk factors responsible for this pattern of comorbidity. By contrast, multivariate studies of genetically informative designs can decompose patterns of comorbidity into those due to genetic vs environmental risk factors. Furthermore, such studies can clarify the level of diagnostic specificity of major genetic and environmental risk factors.
Many such studies have now been published that include 2 or 3 diverse disorders9-11 or multiple disorders within 1 diagnostic class.12-14 These studies have demonstrated substantial sharing of genetic and, to a lesser extent, environmental risk factors across disorders. We are, however, aware of only 2 reports that have applied such methods to a wide array of psychiatric and drug abuse disorders.15-16 Both studies found evidence of broad genetic/familial factors that predisposed to a range of disorders. One of these studies was restricted to women and included only a single externalizing disorder (alcohol dependence).15 The other examined only nuclear families and could not discriminate genetic from shared environmental effects.16
Most psychiatric and drug abuse disorders show substantial sex differences in prevalence.17-18 Less is known about similarities or differences in patterns of comorbidity.7, 19 We are unaware of any systematic examination of the similarities in the underlying genetic and environmental risk factors for common psychiatric and drug abuse disorders in both men and women.
In this study, we apply multivariate genetic analyses to the following 10 psychiatric syndromes as assessed in more than 5600 members of male-male (MM) and female-female (FF) twin pairs ascertained from a population-based registry: major depression, generalized anxiety disorder, phobia, panic disorder, animal phobia, situational phobia, alcohol dependence, drug abuse/dependence, adult antisocial behavior, and conduct disorder.
Because of computational limitations, our analyses focus on 7 disorders, chosen to balance internalizing and externalizing syndromes. We then follow up these results by examining 5 internalizing disorders. We sought answers to the following questions:
- Can we uncover, from the pattern of comorbidity observed among common psychiatric and drug abuse disorders, evidence of the effects of a small number of genetic and environmental risk factors? Is there a pattern that reflects the broad groupings of the internalizing and externalizing disorders, and, if so, is this due to the effects of genetic or environmental factors?
- Given differences in prevalence, how similar is the underlying pattern of genetic and environmental risk factors for common psychiatric and drug abuse disorders in men and women?
METHODS
SAMPLE AND ASSESSMENT PROCEDURES
The twins in this study derive from the population-based Virginia Twin Registry.20 Female-female twin pairs, from the birth years 1934 through 1974, became eligible if both members previously responded to a mailed questionnaire in 1987 through 1988, the response rate to which was approximately 64%. They have been approached for 4 subsequent waves of personal interviews from 1988 to 1997, with cooperation rates ranging from 85% to 92%. The MM and male-female (MF) twin pairs, from the birth years 1940 through 1974, were ascertained in a separate study, with an initial cooperation rate of 72.4%, and have been approached for 2 waves of interviews from 1993 until 1998. Zygosity was determined by a combination of standard questions,21 photographs, and DNA analysis.20, 22-23 The mean (SD) ages of the FF and MM/MF samples at their final interview were 36.6 (8.1) and 36.8 (9.1) years, respectively. Interviewers had a master's degree in a mental health–related field or a bachelor's degree in this area plus 2 years of clinical experience. At each wave, members of a twin pair were interviewed by different interviewers who were blind to clinical information about the cotwin. In this report, we examined only same-sex twin pairs.
The following diagnostic criteria were used: for major depression, DSM-III-R24; alcohol dependence, DSM-IV25; drug abuse/dependence, DSM-IV; and conduct disorder, DSM-III-R. We defined adult antisocial behavior as meeting at least 3 of the DSM-III-R C criteria for antisocial personality disorder. Phobia was diagnosed using an adaptation of DSM-III criteria,26 which required the presence of 1 or more of 22 fears that the respondent recognized as unreasonable and that, in the judgment of the interviewer, objectively interfered with the respondent's life.13 Situational phobia involved irrational fears of closed-in places and high places, including fear of flying. To reduce the effects of a social desirability bias as suggested by previous research,27-28 conduct disorder and adult antisocial behavior were assessed by means of self-report questionnaires distributed during waves 2 and 4 of the interviews in the MM and FF samples, respectively. Because the low prevalence of generalized anxiety and panic disorders had been problematic in previous analyses,29-30 we adopted a broad diagnostic approach to these 2 disorders by reducing the minimum duration from 6 to 1 month for generalized anxiety disorder and requiring a history of panic attacks meeting at least 2 criteria within 30 minutes. We have shown that these approaches reflect the same continuum of liability as the fully syndromal disorders.29-30 We chose situational phobia and animal phobia for these analyses because they had relatively high prevalences and their patterns of comorbidity were typical for the phobic subtypes.13
The diagnostic data used in these analyses came from various waves of the 2 samples. In the FF sample, all diagnoses came from wave 4 except for generalized anxiety disorder (wave 1) and panic disorder (wave 2). For the MM sample, all diagnoses came from wave 2, with the exception of major depression and alcohol dependence. For the MM sample, these disorders were assessed in the total sample size (the numbers of complete monozygotic and dizygotic twin pairs, and the number of unpaired twins [which will not sum precisely because of a small number of higher multiple births in the sample]) as follows: 3529 (866, 651, and 510, respectively) at the wave 1 interview; 2926 (707, 491, and 542, respectively) at the wave 2 interview; and 2768 (641, 435, and 628, respectively) at the wave 2 questionnaire. Parallel figures for the FF sample assessed at the wave 4 interview were 1929 (505, 326, and 270, respectively); at the wave 4 questionnaire, 1486 (345, 210, and 376, respectively). For generalized anxiety disorder in the FF sample, the parallel figures were 2154 (697, 432, and 96, respectively); for panic disorder in the FF sample, 1996 (555, 381, and 124, respectively).
STATISTICAL METHODS
Our approach to multivariate genetic analysis has been outlined elsewhere.12, 31 The models described herein are based on a liability threshold model, the strengths and limitations of which have been previously discussed.31-32 Like traditional factor analysis, multivariate genetic analysis seeks to explain covariation among multiple variables with a few factors. However, traditional exploratory factor analysis is purely descriptive, whereas multivariate genetic analysis provides insight into the sources of resemblance.
Using the software package Mx,33 we fit models by the method of maximum likelihood to data from all individual twins, including those without an interviewed co-twin. This method reduces the impact of cooperation bias and is a binary data maximum likelihood application of the "missing-at-random" principle expounded by Little and Rubin.34
For these analyses, we used independent pathway models that contained 2 genetic common, 2 shared environmental common, and 2 unique environmental common factors in addition to the disorder-specific factors. Two factors were used because of computational limitations and because we sought to detect 2 factor structures (internalizing vs externalizing and anxious-misery vs fear6-8).
We fit this model to the MM and FF data sets, first allowing all the parameters, including thresholds, to vary by sex. We then constrained all the path estimates (but not the thresholds) to be equal in the 2 sexes. Twice the difference in log-likelihood (2LL) between the 2 models yields a statistic that is asymptotically distributed as  2 with degrees of freedom equal to the difference in their number of parameters. We used Akaike's information criterion (AIC)35-36 for model selection. The lower its value, the better the balance is between explanatory power and parsimony. To help ensure detection of the best model, we ran each model 4 times (with the estimated parameter values for one model serving as the starting values for the next model) and picked the result with the best fit.
We present herein only the results of the best full model for combining data across the sexes. Although we have performed extensive further model fitting, the best-fit models add little to the results of the full model.37
For computational reasons, our analyses were limited to 7 disorders. In our first analyses, we selected the following relatively common disorders, approximately balanced across internalizing and externalizing conditions: major depression, generalized anxiety disorder, (any) phobia, alcohol dependence, drug abuse/dependence, adult antisocial behavior, and conduct disorder. Despite these restrictions, the run times for these models on our 667-MHz 21264 dual-processor computer (Alpha; Microway, Inc, Plymouth, Mass) still often exceeded 1 week.
In our second series of analyses, we examined the following 5 internalizing disorders: major depression, generalized anxiety disorder, panic disorder, animal phobia, and situational phobia. After model fitting, using the SAS routine PROC FACTOR,38 factor loadings were rotated using Varimax criterion for the 7 disorders and Promax criterion for the 5 internalizing disorders. We used an oblique rotation for the 5 internalizing disorders because these were conceptualized as subfactors of a higher-order internalizing factor. We define a substantial factor loading in these analyses that accounts for more than 10% of the variance in the dependent variable (  0.10 or 0.32). We define a moderate factor loading as one that accounts for 5% to 10% of the variance in the dependent variable (ie, values of 0.22-0.31).
RESULTS
7 PSYCHIATRIC AND SUBSTANCE USE DISORDERS
Phenotypic Patterns of Comorbidity
Table 1 depicts the lifetime prevalence rates for the 7 major psychiatric and substance use disorders in the male and female twins. The level of comorbidity between these disorders, as assessed by means of odds ratios and tetrachoric correlations, is also seen for twins from MM and FF pairs (above and below the diagonal, respectively). The pattern of phenotypic comorbidity was broadly similar in men and women.
|
|
|
|
Table 1. Prevalence Rates and Comorbidity Between 7 Major Psychiatric and Substance Use Disorders*
|
|
|
Full Model in Men and Women
Fitting our full model to the MM and FF pairs and allowing all parameters to differ across sexes yielded the following: -2LL = 30 242.1; df = 34,150; AIC = -38 057.9. Constraining all parameters (except thresholds) to be equal in the 2 sexes produced a considerably better balance of parsimony and explanatory power:  LL = 38.8; df = 60; AIC = -81.2.
The parameter estimates for this model are shown in Figure 1 as path estimates and Table 2 as proportions of variance in liability. The first genetic common factor (seen on the right side of Figure 1) had substantial loadings on all 4 externalizing disorders, whereas the second genetic common factor had high loadings on all 3 of the internalizing disorders. In addition, the 2 substance use disorders—alcohol dependence and drug abuse/dependence—had substantial disorder-specific genetic loadings.
|
|
|
|
Figure 1. The full model for 7 common psychiatric and drug abuse disorders. Latent variables (all of which have variance of 1.0) are depicted in circles, whereas observed variables are depicted in rectangles. A indicates additive genetic effects; S, shared environmental effects (previously often termed "common" environment); E, unique environmental effects; subscript C, common factors; subscript Sp, disorder-specific factors; and subscripts 1 and 2, for the first and second common factor. Thus, AC1 refers to the first common genetic factor, whereas ESp refers to a disorder-specific unique environmental factor. The path coefficients represent standardized partial regression coefficients, so they must be squared to equal the amount of variance in the dependent (downstream) variable that is accounted for by the independent (upstream) variable. Paths that account for more than 10% of the variance in the dependent variable (0.10 or 0.32) are depicted in red. For the sake of clarity, the first common factor is depicted on the right and the second common factor on the left.
|
|
|
|
|
|
|
Table 2. Proportion of Variance in Liability to 7 Major Psychiatric and Substance Use Disorders From Common and Disorder-Specific Genetic and Environmental Risk Factors in MM and FF Twin Pairs*
|
|
|
The first shared environmental common factor had substantial loadings on only conduct disorder, although this factor also had a moderate loading on adult antisocial behavior. The second shared environmental common factor had moderate loadings on phobia and conduct disorder. All the shared environmental-specific loadings were quite small.
The first unique environmental common factor had substantial loadings on adult antisocial behavior and conduct disorder only, whereas the second factor had substantial loadings on major depression, generalized anxiety disorder, and alcohol dependence. All of the disorder-specific unique environmental loadings, which include measurement error, were substantial.
5 INTERNALIZING DISORDERS
Phenotypic Patterns of Comorbidity
Because our initial 7-disorder model included only 3 internalizing syndromes, we ran a second series of analyses to examine the fine structure of risk factors for internalizing disorders. Table 3 depicts the lifetime prevalence rates for these disorders in the MM and FF twins and the level of comorbidity. The pattern of phenotypic comorbidity was again broadly similar in men and women.
|
|
|
|
Table 3. Prevalence Rates and Comorbidity Between 5 Internalizing Psychiatric Disorders*
|
|
|
Full Model in Males and Females
Fitting our full model to the MM and FF pairs and allowing all parameters to differ across sexes yielded the following fit: -2LL = 19 165.5; df = 25,158; AIC = -31 150.5. Constraining all the parameters (except thresholds) to be equal in the two sexes again produced a superior balance of parsimony and explanatory power: LL = 32.3; df = 42; AIC = -51.7.
The parameter estimates for this full model are seen in Figure 2 and Table 4 (which contains an extra source of variance due to the covariance of the common factors). The 2 common genetic factors were positively correlated, the first of which had substantial loadings on major depression and generalized anxiety disorder and a more moderate loading on panic disorder. The second common genetic factor had substantial loadings on animal phobia and situational phobia. Panic disorder was the only condition with a significant disorder-specific genetic loading.
|
|
|
|
Table 4. Proportion of Variance in Liability to 5 Internalizing Psychiatric Disorders From Common and Disorder-Specific Genetic and Environmental Risk Factors in MM and FF Twin Pairs*
|
|
|
No substantial loadings were seen for the 2 common shared environmental factors (which were negatively correlated) or for the disorder-specific shared environmental factors. The first and second unique environmental common factors, which were positively correlated, had substantial loadings only on generalized anxiety disorder and situational phobia, respectively. All the disorder-specific unique environmental factors had substantial loadings.
COMMENT
We sought in this report to determine whether the pattern of genetic and environmental risk factors for common psychiatric and substance abuse disorders were similar in men and women and then to clarify the underlying structure of those risk factors. We review these questions in turn.
SEX DIFFERENCES IN THE PATTERN OF GENETIC AND ENVIRONMENTAL RISK FACTORS
The genetic and environmental parameters in both of our analyses could easily be constrained to be the same in the MM and FF twin pairs. Despite large differences in prevalence rates for nearly all of the disorders, the same configuration of underlying risk factors accounted for the patterns of comorbidity in men and women.
We are aware of only 1 comparable finding. In a multivariate analysis of 10 disorders from the National Comorbidity Survey, Krueger7 found the same 3-factor model produced similar parameter estimates in men and women. From a genetic-epidemiological perspective, these results suggest that the most pronounced sex differences are in the level of liability required to manifest clinical illness, rather than in the underlying pattern of the risk factors themselves.
Our separate analyses in the MM and FF twins can be seen as replicate samples. In that sense, these results reflect the robustness of our findings, as the results were so similar in 2 large independent samples.
THE STRUCTURE OF GENETIC AND ENVIRONMENTAL RISK FACTORS FOR COMMON PSYCHIATRIC AND SUBSTANCE USE DISORDERS
The second goal of this report was to clarify the structure of the genetic and environmental risk factors for common psychiatric and substance use disorders. We examined this question in 2 stages, the first of which involved fitting multivariate genetic models jointly to 3 internalizing and 4 externalizing disorders.
The full model identified 2 genetic common factors. The first factor had substantial loadings on all 4 of the externalizing disorders (alcohol dependence, drug abuse/dependence, adult antisocial behavior, and conduct disorder), whereas the second factor had substantial loadings on all 3 of the internalizing disorders (major depression, generalized anxiety disorder, and phobia). Substantial disorder-specific genetic factors were seen only for the 2 substance use disorders, alcohol dependence and drug abuse/dependence. These analyses identified the following 4 major sets of genetic risk factors for these 7 common disorders: (1) a broad liability to externalizing disorders, (2) a broad liability to internalizing disorders, (3) a factor specific for alcohol dependence, and (4) a factor specific for drug abuse/dependence. Some of the disorder-specific factors may reflect genetic differences in the metabolism, end-organ responsiveness, and hedonic effects of psychoactive substances.39-40
The results showed a large shared-environment effect only on conduct disorder and a more modest effect on adult antisocial behavior. The first unique environmental common factor apparently reflected experiences that had an impact mainly on risk for adult antisocial behavior and conduct disorder. The second factor indexes exposures that influenced risk for major depression, generalized anxiety disorder, and alcohol dependence.
Of the 3 sources of variance in risk examined, the distinction between internalizing-externalizing disorders was seen clearly only for genetic factors. Nothing resembling these 2 dimensions of psychopathology was seen with the 2 shared environmental common factors. A variant of the internalizing-externalizing distinction was seen in the 2 unique environmental common factors, but with 2 critical differences from the structure seen with the genetic factors. The first or externalizing unique environmental factor did not load substantially on the 2 substance use disorders. The second or internalizing unique environmental factor loaded substantially on alcohol dependence but not phobia. These results suggest strongly that genetic factors are largely responsible for the pattern of comorbidity that results in the 2 frequently co-occurring clusters of internalizing and externalizing disorders. By contrast, at least some of the subgrouping within these 2 clusters may be driven by environmental experiences (eg, a set of individual-specific environmental events [EC1 in Figure 1] that influences the risk for conduct disorder and adult antisocial behavior but not for alcohol dependence and drug abuse/dependence).
In our second analyses, we examined the structure of risk factors for internalizing disorders. The full model identified the following 2 major sources of genetic risk: (1) a common factor with substantial loadings on major depression and generalized anxiety disorder, and (2) a common factor with strong loadings on animal phobia and situational phobia. As would be expected if these 2 genetic common factors were components of a higher-order internalizing factor, they were positively correlated. Unexpectedly, panic disorder did not load strongly with the 2 phobic disorders, with its genetic risk coming largely from the first common genetic factor, and only modestly from the second common genetic factor, and disorder-specific effects. In the shared and the unique environmental common factors, there was no trace of 2 etiologic dimensions reflecting anxious-misery and fear. This pattern of results suggests that genetic factors are also largely responsible for the pattern of comorbidity that results in the division of internalizing disorders into 2 frequently co-occurring subclusters reflecting anxious-misery and fear.
Synthesizing the results of our 2 model-fitting efforts, a tentative model for the structure of the genetic risk factors for common psychiatric disorders in men and women is shown in Figure 3. The picture is oversimplified because it ignores evidence of crossloadings (eg, the internalizing general genetic factor consistently loads modestly on the externalizing disorders and vice versa). The structure of these genetic risk factors bears a conspicuous resemblance to the phenotypic structure of adult psychiatric disorders proposed by Krueger et al6-7 and Vollebergh et al.8
|
|
|
|
Figure 3. A proposed structure for the genetic risk factors for common psychiatric and substance use disorders in men and women. Strong relationships are depicted by solid lines and, in the case of panic disorder only, weaker relationships by dotted lines. This model exaggerates the clarity of the factor structure obtained in our analyses, as the evidence suggests that internalizing disorders load weakly on the externalizing common factor and vice versa.
|
|
|
Our results are broadly consistent with those of a prior multivariate analysis of a more restricted set of disorders in women from our group.15 That study found the following 3 major sources of genetic variance: (1) a common factor loading largely on major depression and generalized anxiety disorder; (2) a common factor loading largely on panic disorder, phobia, and bulimia; and (3) disorder-specific loadings for alcohol dependence. In the present larger sample, the structure of the second factor appears to be restricted to phobia subtypes. If more externalizing disorders were included in the earlier analysis with women,15 our current results would suggest that the genetic loadings for alcohol dependence would divide into those that are disorder specific and those that are shared with other externalizing syndromes. Our findings are also in general agreement with a previous analysis of family history data from the National Comorbidity Study, which identified 2 familial factors (for internalizing and externalizing disorders) that were transmitted across generations with reasonable fidelity16 and a recent study of adolescent twins from the general population that identified a highly heritable externalizing factor that included substance dependence, antisocial behavior, and a disinhibited personality style.41
What intermediate phenotypes might best reflect the 3 common genetic factors identified in these analyses? It is tempting to speculate that these genetic effects on risk might be mediated through personality.42-45 Further work in genetically informative samples will be needed to test this hypothesis.
This study also produced estimates for the etiologic role of genetic and environmental factors for the 10 individual disorders examined (Table 2 and Table 4). As might be expected, for most of the disorders, these results agree relatively well with previous estimates from this12, 20, 23, 29, 46-48 and other studies,11, 49-52 although the heritability estimates for panic disorder and animal phobia are somewhat lower than previously reported.13, 30
For gene-finding studies for these common disorders, these results raise the question of whether it would be more efficient to focus on groups of disorders with shared genetic risk factors rather than on individual disorders.
LIMITATIONS
These results should be interpreted in the context of 6 potential methodological limitations. First, the sample consisted of white twins born in Virginia. How well these findings extrapolate to other ethnic groups is uncertain. Second, all of the diagnostic assessments were based on a single interview that includes substantial error variance.53-55 In multivariate models, most measurement error is confounded with true disorder-specific unique environmental effects and produces downward biases on other parameter estimates. Third, parameter estimates from such modeling ideally should be presented with confidence intervals. However, the additional computational burden required to estimate these would have made the analyses infeasible. Fourth, our twin model assumes that comorbidity results from the impact of latent genetic and environmental risk factors. Other models of comorbidity are possible,56 but were not examined here. Fifth, for computational reasons, we included in these analyses only same-sex twin pairs and therefore could examine only quantitative sex effects, ie, whether the magnitude of genetic and environmental effects differ in men and women. Our present analyses do not address the question of whether the same genetic and shared environmental factors have an impact on risk in men and women.57-58 Sixth, as noted previously,57 our lifetime prevalence rates for major depression are higher than those reported from most previous studies. We used clinical rather than lay interviewers and a semistructured rather than a highly structured interview, assessed the history for depression twice in the interview, and used multiple methods to encourage effortful responding. Our identified cases reported substantial levels of impairment, distress, and treatment seeking.59 Our sex-averaged 1-year prevalence estimates of major depression (9.7%) are nearly identical to those reported in the National Comorbidity Survey18 (10.3%), suggesting that we achieved a considerably lower ratio of last-year to lifetime cases. We may have identified milder cases than some other studies. However, previous studies54, 57 have shown that heritability of depressive illness in this sample is not related to the narrowness of the definition.
CONCLUSIONS
The underlying structure of genetic and environmental risk factors for common psychiatric and substance use disorders is very similar in men and women. The patterns of comorbidity of these disorders (internalizing vs externalizing, and within internalizing, anxious-misery vs fear) is driven largely by genetic factors. Shared environmental risk factors (eg, family disruption, poor parental monitoring, or low social class of rearing60) may contribute to comorbidity within at least a subgroup of externalizing disorders. Within syndromal groups, exposure to unique environmental experiences may explain why one disorder vs another develops in vulnerable individuals. Substantial disorder-specific genetic factors were found only for the substance use disorders.
Widiger and Clark61 recently wrote that the future of psychiatric nosology "rests on investigating the factors—genetic structures and environmental processes—that underlie the domain of psychopathology and determining how these factors combine to produce the range of clinically observed disorders."61(p956) We concur and hope these analyses contribute toward that goal.
AUTHOR INFORMATION
| |
Corresponding author and reprints: Kenneth S. Kendler, MD, Department of Psychiatry, PO Box 980126, Richmond, VA 23298-0126.
Submitted for publication July 24, 2002; final revision received December 18, 2002; accepted January 9, 2003.
This study was supported by grants MH/AA49492, MH-01458, AA-00236, and DA11287 from the National Institutes of Health, Bethesda, Md. The Mid-Atlantic Twin Registry, directed by L. Corey, PhD, and L. Eaves, PhD, has received support from the National Institutes of Health, Bethesda; the Carman Trust, Richmond, Va; the W. M. Keck Foundation, Los Angeles, Calif; the John Templeton Foundation, Radnor, Pa; and the Robert Wood Johnson Foundation, Princeton, NJ.
We acknowledge the contribution of the Virginia Twin Registry, now part of the Mid-Atlantic Twin Registry, to ascertainment of subjects for this study.
From the Virginia Institute for Psychiatry and Behavioral Genetics (Drs Kendler, Prescott, and Neale and Mr Myers) and the Departments of Psychiatry (Drs Kendler, Prescott, and Neale and Mr Myers) and Human Genetics (Drs Kendler and Neale), Medical College of Virginia, Virginia Commonwealth University, Richmond.
REFERENCES
1. Boyd JH, Burke JD Jr, Gruenberg E, Holzer CE III, Rae DS, George LK, Karno M, Stoltzman R, McEvoy L, Nestadt G. Exclusion criteria of DSM-III: a study of co-occurrence of hierarchy-free syndromes. Arch Gen Psychiatry. 1984;41:983-989.
FREE FULL TEXT
2. Kessler RC. The prevalence of psychiatric comorbidity. In: Wetzler S, Sanderson WC, eds. Treatment Strategies for Patients With Psychiatric Comorbidity. New York, NY: John Wiley & Sons Inc; 1997:23-48.
3. Fergusson DM, Mullen PE. Childhood Sexual Abuse: An Evidence Based Perspective. Thousand Oaks, Calif: Sage Publications; 1999.
4. Kendler KS, Myers J, Prescott CA. Parenting and adult mood, anxiety and substance use disorders in female twins. Psychol Med. 2000;30:281-294.
FULL TEXT
|
ISI
| PUBMED
5. Kessler RC, Davis CG, Kendler KS. Childhood adversity and adult psychiatric disorder in the US National Comorbodity Survey. Psychol Med. 1997;27:1101-1119.
FULL TEXT
|
ISI
| PUBMED
6. Krueger RF, Caspi A, Moffitt TE, Silva P. The structure and stability of common mental disorders (DSM-III-R). J Abnorm Psychol. 1998;107:216-227.
FULL TEXT
|
ISI
| PUBMED
7. Krueger RF. The structure of common mental disorders. Arch Gen Psychiatry. 1999;56:921-926.
FREE FULL TEXT
8. Vollebergh WAM, Iedema J, Bijl RV, de Graaf R, Smit F, Ormel J. The structure and stability of common mental disorders: the NEMESIS Study. Arch Gen Psychiatry. 2001;58:597-603.
FREE FULL TEXT
9. Kendler KS, Heath AC, Neale MC, Kessler RC, Eaves LJ. Alcoholism and major depression in women: a twin study of the causes of comorbidity. Arch Gen Psychiatry. 1993;50:690-698.
FREE FULL TEXT
10. Merikangas KR, Risch NJ, Weissman MM. Comorbidity and co-transmission of alcoholism, anxiety and depression. Psychol Med. 1994;24:69-80.
ISI
| PUBMED
11. Lyons MJ, True WR, Eisen SA, Goldberg J, Meyer JM, Faraone SF, Eaves LJ, Tsuang MT. Differential heritability of adult and juvenile antisocial traits. Arch Gen Psychiatry. 1995;52:906-915.
FREE FULL TEXT
12. Kendler KS, Neale MC, Kessler RC, Heath AC, Eaves LJ. The genetic epidemiology of phobias in women: the inter-relationship of agoraphobia, social phobia, situational phobia, and simple phobia. Arch Gen Psychiatry. 1992;49:273-281.
FREE FULL TEXT
13. Kendler KS, Myers J, Prescott CA, Neale JM. The genetic and epidemiology of irrational fears and phobias in men. Arch Gen Psychiatry. 2001;58:257-265.
FREE FULL TEXT
14. Tsuang MT, Lyons MJ, Meyer JM, Doyle T, Eisen SA, Goldberg J, True W, Lin N, Toomey R, Eaves L. Co-occurence of abuse of different drugs in men. Arch Gen Psychiatry. 1998;55:967-972.
FREE FULL TEXT
15. Kendler KS, Walters EE, Neale MC, Kessler RC, Heath AC, Eaves LJ. 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. Arch Gen Psychiatry. 1995;52:374-383.
FREE FULL TEXT
16. Kendler KS, Davis CG, Kessler RC. The familial aggregation of common psychiatric and substance use disorders in the National Comorbidity Survey: a family history study. Br J Psychiatry. 1997;170:541-548.
FREE FULL TEXT
17. Robins LN, ed, Regier DA, ed. Psychiatric Disorders in America. New York, NY: Free Press; 1991.
18. Kessler RC, McGonagle KA, Zhao S, Nelson CB, Hughes M, Eshleman S, Wittchen H-U, Kendler KS. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States: results from the National Comorbidity Survey. Arch Gen Psychiatry. 1994;51:8-19.
FREE FULL TEXT
19. Maes HH, Neale JM, Kendler KS, Hewit JK, Silberg JL, Foley DL, Meyer JM, Rutter M, Simonoff E, Pickles A, Eaves LJ. Assortive mating for major psychiatric diagnosis in two population-based samples. Psychol Med. 1998;28:1389-1401.
FULL TEXT
|
ISI
| PUBMED
20. Kendler KS, Prescott CA. A population-based twin study of lifetime major depression in men and women. Arch Gen Psychiatry. 1999;56:39-44.
FREE FULL TEXT
21. Eaves LJ, Eysenck HJ, Martin NG, Jardine R, Heath AC, Feingold L, Young PA, Kendler KS. Genes, Culture and Personality: An Empirical Approach. Orlando, Fla: Academic Press Inc; 1989.
22. Spence JE, Corey LA, Nance WE, Marazita ML, Kendler KS, Schieken RM. Molecular analysis of twin zygosity using VNTR DNA probes [abstract]. Am J Hum Genet. 1988;43:A159.
23. Kendler KS, Karkowski L, Neale MC, Prescott CA. Illicit psychoactive substance use, heavy use, abuse, and dependence in a US population-based sample of male twins. Arch Gen Psychiatry. 2000;57:261-269.
FREE FULL TEXT
24. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition. Washington, DC: American Psychiatric Association; 1987.
25. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Washington, DC: American Psychiatric Association; 1994.
26. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Third Edition. Washington, DC: American Psychiatric Association; 1980.
27. Siemiatycki J. A comparison of mail, telephone, and home interview stategies for household health surveys. Am J Public Health. 1979;69:238-245.
FREE FULL TEXT
28. Nederhof AJ. Methods of coping with social desirability bias: a review. Eur J Soc Psychol. 1985;15:263-280.
FULL TEXT
|
ISI
29. Hettema JM, Prescott CA, Kendler KS. A population-based twin study of generalized anxiety disorder in men and women. J Nerv Ment Dis. 2001;189:413-420.
FULL TEXT
|
ISI
| PUBMED
30. Kendler KS, Gardner CO, Prescott CA. Panic syndromes in a population-based sample of male and female twins. Psychol Med. 2001;31:989-1000.
FULL TEXT
|
ISI
| PUBMED
31. Neale MC, Cardon LR. Methodology for Genetic Studies of Twins and Families. Norwell, Mass: Kluwer Academic Publishers; 1992.
32. Kendler KS, Neale MC, Kessler RC, Heath AC, Eaves LJ. A population-based twin study of major depression in women: the impact of varying definitions of illness. Arch Gen Psychiatry. 1992;49:257-266.
FREE FULL TEXT
33. Neale MC, Boker SM, Xie G, Maes HH. Mx: Statistical Modeling. 5th ed. Richmond: Dept of Psychiatry, Medical College of Virginia, Virginia Commonwealth University; 1999.
34. Little RJA, Rubin DB. Statistical Analysis With Missing Data. New York, NY: John Wiley & Sons Inc; 1987.
35. Akaike H. Factor analysis and AIC. Psychometrika. 1987;52:317-332.
FULL TEXT
|
ISI
36. Williams LJ, Holahan PJ. Parsimony-based fit indices for multiple-indicator models: do they work? Struct Equation Model. 1994;1:161-189.
37. Sullivan PF, Eaves LJ. Evaluation of analyses of univariate discrete twin data. Behav Genet. 2002;32:221-227.
FULL TEXT
|
ISI
| PUBMED
38. SAS Institute I. SAS/STAT User's Guide, V8. Cary, NC: SAS Institute Inc; 2000.
39. Thomasson HR, Edenberg HJ, Crabb DW, Mai X-L, Jerome RE, Li T-K, Wang S-P, Lin Y-T, Lu R-B, Yin S-J. Alcohol and aldehyde dehydrogenase genotypes and alcoholism in Chinese men. Am J Hum Genet. 1991;48:677-681.
ISI
| PUBMED
40. Lyons MJ, Toomey R, Meyer JM, Green AI, Eisen SA, Goldberg J, True WR, Tsuang MT. How do genes influence marijuana use? the role of subjective effects. Addiction. 1997;92:409-417.
FULL TEXT
|
ISI
| PUBMED
41. Krueger RF, Hicks BM, Patrick CJ, Carlson SR, Iacono WG, McGue M. Etiologic connections among substance dependence, antisocial behavior, and personality: modeling the externalizing spectrum. J Abnorm Psychol. 2002;111:411-424.
FULL TEXT
|
ISI
| PUBMED
42. Cloninger CR. A systematic method for clinical description and classification of personality variants: a proposal. Arch Gen Psychiatry. 1987;44:573-588.
FREE FULL TEXT
43. Kendler KS, Neale MC, Kessler RC, Heath AC, Eaves LJ. A longitudinal twin study of personality and major depression in women. Arch Gen Psychiatry. 1993;50:853-862.
FREE FULL TEXT
44. Bienvenu OJ, Brown C, Samuels JF, Liang KY, Costa PT, Eaton WW, Nestadt G. Normal personality traits and comorbidity among phobic, panic and major depressive disorders. Psychiatry Res. 2001;102:73-85.
FULL TEXT
|
ISI
| PUBMED
45. Slutske WS, Heath AC, Madden PAF, Bucholz KK, Statham DJ, Martin NG. Personality and the genetic risk for alcohol dependence. J Abnorm Psychol. 2002;111:124-133.
FULL TEXT
|
ISI
| PUBMED
46. Kendler KS, Gardner CO, Prescott CA. Corrections to 2 prior published articles [letter]. Arch Gen Psychiatry. 2000;57:94-95.
FREE FULL TEXT
47. Prescott CA, Kendler KS. Genetic and environmental contributions to alcohol abuse and dependence in a population-based sample of male twins. Am J Psychiatry. 1999;156:34-40.
FREE FULL TEXT
48. Jacobson KC, Prescott CA, Kendler KS. Sex differences in genetic and environmental influences on antisocial behavior from childhood to adulthood. Dev Psychopathol. 2002;14:395-416.
FULL TEXT
|
ISI
| PUBMED
49. Sullivan PF, Neale MC, Kendler KS. The genetic epidemiology of major depression: review and meta-analysis. Am J Psychiatry. 2000;157:1552-1562.
FREE FULL TEXT
50. Kendler KS, Prescott CA, Neale MC, Pedersen NL. Temperance board registration for alcohol abuse in a national sample of Swedish male twins born 1902-1949. Arch Gen Psychiatry. 1997;54:178-184.
FREE FULL TEXT
51. Heath AC, Bucholz KK, Madden PAF, Dinwiddie SH, Slutske WS, Bierut LJ, Statham DJ, Dunne MP, Whitfield JB, Martin NG. Genetic and environmental contributions to alcohol dependence risk in a national twin sample: consistency of findings in women and men. Psychol Med. 1997;27:1381-1396.
FULL TEXT
|
ISI
| PUBMED
52. van den Bree MBM, Johnson EO, Neale MC, Pickens RW. Genetic and environmental influences on drug use and abuse/dependence in male and female twins. Drug Alcohol Depend. 1998;52:231-241.
FULL TEXT
|
ISI
| PUBMED
53. Prusoff BA, Merikangas KR, Weissman MM. Lifetime prevalence and age of onset of psychiatric disorders: recall 4 years later. J Psychiatr Res. 1988;22:107-117.
FULL TEXT
|
ISI
| PUBMED
54. Kendler KS, Neale MC, Kessler RC, Heath AC, Eaves LJ. The lifetime history of major depression in women: reliability of diagnosis and heritability. Arch Gen Psychiatry. 1993;50:863-870.
FREE FULL TEXT
55. Williams JBW, Gibbon M, First MB, Spitzer RL, Davies M, Borus J, Howes MJ, Kane J, Pope HG Jr, Rounsaville B, Wittchen H-U. The Structured Clinical Interview for DSM-III-R (SCID), II: multisite test-retest reliability. Arch Gen Psychiatry. 1992;49:630-636.
FREE FULL TEXT
56. Neale MC, Kendler KS. Models of comorbidity for multifactorial disorders. Am J Hum Genet. 1995;57:935-953.
ISI
| PUBMED
57. Kendler KS, Gardner CO, Neale MC, Prescott CA. Genetic risk factors for major depression in men and women: similar or different heritabilities and same or partly distinct genes? Psychol Med. 2001;31:605-616.
FULL TEXT
|
ISI
| PUBMED
58. Prescott CA, Aggen S, Kendler KS. Sex differences in the sources of genetic liability to alcohol abuse and dependence in a population-based sample of US twins. Alcohol Clin Exp Res. 1999;23:1136-1144.
FULL TEXT
|
ISI
| PUBMED
59. Kendler KS, Gardner CO, Prescott CA. Clinical characteristics of major depression that predict risk of depression in relatives. Arch Gen Psychiatry. 1999;56:322-327.
FREE FULL TEXT
60. Moffitt TE, Caspi A, Rutter M, Silva PA. Sex Differences in Antisocial Behavior: Conduct Disorder, Delinquency, and Violence in the Dunedin Longitudinal Study. New York, NY: Cambridge University Press; 2001.
61. Widiger TA, Clark LA. Toward DSM-V and the classification of psychopathology. Psychol Bull. 2000;126:946-963.
FULL TEXT
|
ISI
| PUBMED
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati
What's this?
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
|
Role of GABRA2 in Trajectories of Externalizing Behavior Across Development and Evidence of Moderation by Parental Monitoring
Dick et al.
Arch Gen Psychiatry 2009;66:649-657.
ABSTRACT
| FULL TEXT
Tests of Causal Links Between Alcohol Abuse or Dependence and Major Depression
Fergusson et al.
Arch Gen Psychiatry 2009;66:260-266.
ABSTRACT
| FULL TEXT
The Structure of Genetic and Environmental Risk Factors for DSM-IV Personality Disorders: A Multivariate Twin Study
Kendler et al.
Arch Gen Psychiatry 2008;65:1438-1446.
ABSTRACT
| FULL TEXT
Comorbid Forms of Psychopathology: Key Patterns and Future Research Directions
Cerda et al.
Epidemiol Rev 2008;30:155-177.
ABSTRACT
| FULL TEXT
A Developmental and Evolutionary Perspective on Obsessive-Compulsive Disorder: Whence and Whither Compulsive Hoarding?
Leckman and Bloch
Am. J. Psychiatry 2008;165:1229-1233.
FULL TEXT
Parental Smoking and Adolescent Problem Behavior: An Adoption Study of General and Specific Effects
Keyes et al.
Am. J. Psychiatry 2008;165:1338-1344.
ABSTRACT
| FULL TEXT
Cannabinoid Receptor 1 Gene Association With Nicotine Dependence
Chen et al.
Arch Gen Psychiatry 2008;65:816-823.
ABSTRACT
| FULL TEXT
Explanatory Models for Psychiatric Illness
Kendler
Am. J. Psychiatry 2008;165:695-702.
ABSTRACT
| FULL TEXT
Underage Drinking: A Developmental Framework
Masten et al.
Pediatrics 2008;121:S235-S251.
ABSTRACT
| FULL TEXT
The neuronal nicotinic receptor subunit genes (CHRNA6 and CHRNB3) are associated with subjective responses to tobacco
Zeiger et al.
Hum Mol Genet 2008;17:724-734.
ABSTRACT
| FULL TEXT
Using Dimensional Models of Externalizing Psychopathology to Aid in Gene Identification
Dick et al.
Arch Gen Psychiatry 2008;65:310-318.
ABSTRACT
| FULL TEXT
The Relationship Between Depressive Personality Disorder and Major Depressive Disorder: A Population-Based Twin Study
Orstavik et al.
Am. J. Psychiatry 2007;164:1866-1872.
ABSTRACT
| FULL TEXT
Alcohol Consumption and Posttraumatic Stress After Exposure to Terrorism: Effects of Proximity, Loss, and Psychiatric History
Hasin et al.
Am. J. Public Health 2007;97:2268-2275.
ABSTRACT
| FULL TEXT
Prevalence, Correlates, Disability, and Comorbidity of DSM-IV Alcohol Abuse and Dependence in the United States: Results From the National Epidemiologic Survey on Alcohol and Related Conditions
Hasin et al.
Arch Gen Psychiatry 2007;64:830-842.
ABSTRACT
| FULL TEXT
Prevalence, Correlates, Disability, and Comorbidity of DSM-IV Drug Abuse and Dependence in the United States: Results From the National Epidemiologic Survey on Alcohol and Related Conditions
Compton et al.
Arch Gen Psychiatry 2007;64:566-576.
ABSTRACT
| FULL TEXT
Juvenile Mental Health Histories of Adults With Anxiety Disorders
Gregory et al.
Am. J. Psychiatry 2007;164:301-308.
ABSTRACT
| FULL TEXT
Addiction: A Disease of Learning and Memory
Hyman
Focus 2007;5:220-228.
ABSTRACT
| FULL TEXT
The Nature of Genetic Influences on Behavior: Lessons From "Simpler" Organisms
Kendler and Greenspan
Am. J. Psychiatry 2006;163:1683-1694.
ABSTRACT
| FULL TEXT
"A Gene for. . .":The Nature of Gene Action in Psychiatric Disorders
Kendler
Focus 2006;4:391.
ABSTRACT
| FULL TEXT
The Genetics of Addictions: Uncovering the Genes
Goldman et al.
Focus 2006;4:401.
ABSTRACT
| FULL TEXT
The Caregiving Environments Provided to Children by Depressed Mothers With or Without an Antisocial History
Kim-Cohen et al.
Am. J. Psychiatry 2006;163:1009-1018.
ABSTRACT
| FULL TEXT
A Population-Based Twin Study of the Relationship Between Neuroticism and Internalizing Disorders
Hettema et al.
Am. J. Psychiatry 2006;163:857-864.
ABSTRACT
| FULL TEXT
Treating Patients for Comorbid Depression, Anxiety Disorders, and Somatic Illnesses
Dolnak
JAOA: Journal of the American Osteopathic Association 2006;106:S1-S8.
ABSTRACT
| FULL TEXT
Caffeine Dependence in Combination With a Family History of Alcoholism as a Predictor of Continued Use of Caffeine During Pregnancy
Svikis et al.
Am. J. Psychiatry 2005;162:2344-2351.
ABSTRACT
| FULL TEXT
Categorical and Continuous Models of Liability to Externalizing Disorders: A Direct Comparison in NESARC
Markon and Krueger
Arch Gen Psychiatry 2005;62:1352-1359.
ABSTRACT
| FULL TEXT
Mental Health Disparities Across Education and Sex: A Prospective Analysis Examining How They Persist Over the Life Course
Miech et al.
Journals of Gerontology Series B: Psychological Sciences and Social Science 2005;60:S93-S98.
ABSTRACT
| FULL TEXT
Shared Genetic Contributions to Pathological Gambling and Major Depression in Men
Potenza et al.
Arch Gen Psychiatry 2005;62:1015-1021.
ABSTRACT
| FULL TEXT
Addiction: A Disease of Learning and Memory
Hyman
Am. J. Psychiatry 2005;162:1414-1422.
ABSTRACT
| FULL TEXT
Developments in the Epidemiology of Drug Use and Drug Use Disorders
Compton et al.
Am. J. Psychiatry 2005;162:1494-1502.
ABSTRACT
| FULL TEXT
"A Gene for...": The Nature of Gene Action in Psychiatric Disorders
Kendler
Am. J. Psychiatry 2005;162:1243-1252.
ABSTRACT
| FULL TEXT
Nature and Nurture: Genetic and Environmental Influences on Behavior
Plomin and Asbury
The ANNALS of the American Academy of Political and Social Science 2005;600:86-98.
ABSTRACT
The Association of Early Adolescent Problem Behavior With Adult Psychopathology
McGue and Iacono
Am. J. Psychiatry 2005;162:1118-1124.
ABSTRACT
| FULL TEXT
Classification of Psychopathology: Goals and Methods in an Empirical Approach
Acton and Zodda
Theory Psychology 2005;15:373-399.
ABSTRACT
Two-Year Prevalence and Stability of Individual DSM-IV Criteria for Schizotypal, Borderline, Avoidant, and Obsessive-Compulsive Personality Disorders: Toward a Hybrid Model of Axis II Disorders
McGlashan et al.
Am. J. Psychiatry 2005;162:883-889.
ABSTRACT
| FULL TEXT
Physician Substance Abuse and Recovery: What Does It Mean for Physicians--and Everyone Else?
Gastfriend
JAMA 2005;293:1513-1515.
FULL TEXT
Toward a Philosophical Structure for Psychiatry
Kendler
Am. J. Psychiatry 2005;162:433-440.
ABSTRACT
| FULL TEXT
Maternal Depression and Children's Antisocial Behavior: Nature and Nurture Effects
Kim-Cohen et al.
Arch Gen Psychiatry 2005;62:173-181.
ABSTRACT
| FULL TEXT
The Structure of Genetic and Environmental Risk Factors for Anxiety Disorders in Men and Women
Hettema et al.
Arch Gen Psychiatry 2005;62:182-189.
ABSTRACT
| FULL TEXT
Nicotinic receptor mechanisms and cognition in normal states and neuropsychiatric disorders
Sacco et al.
J Psychopharmacol 2004;18:457-474.
ABSTRACT
Using Survey Results to Improve the Validity of the Standard Psychiatric Nomenclature
Robins
Arch Gen Psychiatry 2004;61:1188-1194.
ABSTRACT
| FULL TEXT
Family Transmission and Heritability of Externalizing Disorders: A Twin-Family Study
Hicks et al.
Arch Gen Psychiatry 2004;61:922-928.
ABSTRACT
| FULL TEXT
Reduced Serotonin Type 1A Receptor Binding in Panic Disorder
Neumeister et al.
J. Neurosci. 2004;24:589-591.
ABSTRACT
| FULL TEXT
Other articles noted: 25 Jul 03 to 7 Nov 03
Evid. Based Nurs. 2004;7:e1-1.
FULL TEXT
|
