Sample

Twins were ascertained for this study from the Norwegian Institute of Public Health Twin Panel (NIPHTP), established in 1992. The twins were identified through the Medical Birth Registry, established 1 January 1967, which receives mandatory notification of all births in Norway. The first NIPHTP questionnaire study was conducted in 1992. A follow-up study of all Norwegian twins born 1967–79 was conducted in 1998. Altogether, 12 700 twins received the second questionnaire, and 8045 (63%) responded after one reminder. The sample included 3334 complete pairs (53%). The NIPHTP is described in detail elsewhere. ^{Reference Harris, Magnus and Tambs16}

As an extension of the 1998 questionnaire study an interview study of Axis I and Axis II mental health disorders – Mental Health in Twins (MHT) – was started in 1999. All complete pairs from the questionnaire study in which both twins had agreed to further contact (3153 pairs) were invited. An additional 68 pairs were drawn directly from the NIPHTP sample. Altogether, 1391 pairs (43%) and 19 single twins were interviewed. There were valid anxiety data for 1385 pairs – 219 male monozygotic (MZ), 117 male dizygotic (DZ), 446 female MZ, 264 female DZ and 339 opposite-gender DZ – and for 21 single twins. Age when interviewed was 19–36 years, mean 28.1 years. Among non-participants was a small percentage of twin pairs in which one or both twins could not be traced, and an unknown proportion for whom migration, illness or other circumstances made participation impossible. Informed consent was obtained from all participants after complete description of the study. Zygosity was determined by molecular methods based on the genotyping of 24 microsatellite markers in all but 385 pairs, for whom zygosity was determined from questionnaire information. The estimated misclassification rate in the entire sample, based on comparison between questionnaire information and the results of DNA analysis, was 0.7%.

Measures

Axis I disorders according to DSM–IV were assessed using a computerised version of the Composite International Diagnostic Interview (CIDI). ^{17,Reference Wittchen and Pfister18} The interviews took place between June 1999 and May 2004 and were conducted face to face except for 231 telephone interviews (8.3%). The majority of the 28 interviewers were psychology students in their final training or experienced psychiatric nurses. All received a standardised training programme by teachers certified by the World Health Organization and passed a user licence test for the CIDI. They were supervised during the data collection period. Each twin in a pair was interviewed by different interviewers masked to the results of the co-twin.

For the five lifetime anxiety disorders (including subthreshold scores) here examined (panic disorder, GAD, phobias, OCD and PTSD), DSM–IV diagnoses were assigned without hierarchical rules. Preliminary analyses indicated that the prevalence rates for the full diagnostic categories for four of the diagnoses (panic disorder, GAD, OCD and PTSD) were not high enough to produce stable estimates for twin modelling with our sample size. Moreover, the limited prevalence rates required the collapsing of agoraphobia, social phobia and the other forms of phobias. Using empirically validated methods, detailed below, we therefore defined subthreshold diagnostic groups. Full anxiety disorders were scored ‘2’, subthreshold anxiety disorders were scored ‘1’ and the remainder of the sample was scored ‘0’.

Criteria for defining subthreshold cases

The process of generating subthreshold data took place in two steps. Initially we used only data from the CIDI interview as criteria. However, preliminary standard error of the mean (s.e.m.) testing showed that not even a careful relaxation based on the single CIDI items gave sufficiently high subthreshold prevalences for three of the variables to arrive at stable analytic solutions. As a second step it was therefore decided to extend the subthreshold groups using available questionnaire data as criteria as well.

Statistical analysis

The phenotypic correlation structure was examined using confirmatory factor analysis. First, we tested whether the structure could be explained by a single factor. Then possible gender differences were explored by constraining the anxiety disorder factor loadings to be equal in men and women. Finally, we explored whether adding subthreshold cases might have changed the multivariate structure of the disorders by comparing results using trichotomous (including subthreshold scores) and dichotomous (full or no diagnosis) data. Model fit is assessed by the root mean squared error of approximation (RMSEA) where good-fitting models have a value under 0.05. ^{Reference Bollen and Curran20}

Our twin modelling assumed that liability to illness is continuous and normally distributed in the population, with individuals who exceed a first theoretical threshold expressing a subsyndromal form, and those who exceed a higher threshold expressing the full disorder. Resemblance in twin pairs is assessed using a polychoric correlation. ^{Reference Olsson21} Using the multiple threshold model in the PRELIS program, ^{Reference Jöreskog and Sörbom22} we tested for deviations from an underlying bivariate normal distribution of the ordinal three-category data. This test was used for examining whether the subthreshold and fully syndromal cases reflect quantitatively different levels of liability on the same underlying dimension.

Individual differences in liability are assumed to arise from three sources: additive genetic ‘A’, from genes whose allelic effects combine additively; common environment ‘C’, which includes all sources similarly influencing both twins; and specific environment ‘E’, which includes environmental experiences not shared by co-twins and measurement error. Monozygotic co-twin similarity is due to identical genes, A, and, by definition, common environment, C. Dizygotic pairs share (on average) half of their A and all of their C.

Univariate twin studies use data on co-twin similarity for a single trait or illness. Multivariate studies use observed similarity between the same trait in co-twins, between one trait in one twin and another trait in the co-twin, and between the various traits observed within individuals. Besides yielding estimates of A, C and E for individual disorders, multivariate analyses estimate the extent to which variation in comorbid disorders results from the same genetic or environmental factors v. genetic and environmental factors specific to each disorder.

We used single-factor multivariate models because these served our purpose of dividing genetic and environmental variance into that shared between anxiety disorders and that specific to each disorder. We tested two forms of this model: an independent pathway and a common pathway model. ^{Reference Neale and Cardon23} The latter is nested under the former and differs in that all common variance, genetic and environmental, is assumed to be mediated through one single latent phenotype. The best-fitting of these two models was chosen using Akaike's information criterion (AIC). ^{Reference Akaike24}

Ideally, quantitative and qualitative gender-specific effects would be tested as part of our multivariate modelling. This was not feasible with these data because multivariate analyses are especially vulnerable to the combination of low prevalences and modest sample size (especially in our male DZ pairs). For some of the sets of disorders we could not find any pair with two affected twins (e.g. PTSD in one twin and OCD in the other). Such empty cells destabilised solutions. We therefore evaluated gender-specific effects for one disorder at a time, assuming that we could ignore such effects in multivariate models unless they were robustly detected across single disorders. Briefly, no evidence for any qualitative gender effect (which allows for gender-specific sources of genetic or environmental effects) or quantitative gender effect (which permits differing estimates of genetic and environmental effects by gender) was found for panic disorder, GAD or OCD. Modelling indicated some support for qualitative gender effects for phobia and quantitative gender effects for PTSD. In the light of these modest and inconsistent findings, we excluded gender effects from our multivariate modelling.

Twin models are often simplified by dropping insignificant paths. However, Sullivan & Eaves have shown that in the presence of low power – as is the case in these analyses – full models may better approximate reality than do simpler best-fit models. ^{Reference Sullivan and Eaves25} This is because, with low power, the effects originally distributed among several parameters may be aggregated into a few inflated parameters with unrealistically small confidence intervals. With the limited power of our data, we present results from the full best-fitting multivariate model with no attempt at further simplification. The Mx computer program was used for the analyses. ^{Reference Neale, Boker, Xie and Maes26} Raw data analysis was applied and the thresholds (prevalences) were permitted to vary between men and women.

Prevalence and phenotypic correlational structure

The prevalence estimates for the full and subthreshold definitions of panic disorder, GAD, phobia, OCD and PTSD are shown in Table 1. The phenotypic polychoric correlations between these disorders are presented in Table 2. Most vary between 0.35 and 0.55. In both men and women, panic disorder and GAD were the most strongly and OCD and PTSD the least strongly inter-correlated disorders. By confirmatory factor analysis, a single-factor solution allowing estimates to differ across genders fitted the data very well (χ² ₁₀ = 6.86, P = 0.739, RMSEA = 0.000). Factor loadings were similar across genders except for a lower loading for OCD in women (Table 2). Constraining the factor loadings to equality in men and women hardly worsened the fit (χ² ₁₅ = 11.66, P = 0.705, RMSEA = 0.000). We performed the same analysis on our dichotomous data eliminating subthreshold cases. The results were similar to those seen including the subthreshold cases (Table 2).

Testing the assumption of a single dimension of liability

To examine further whether full-criteria and subthreshold diagnoses reflected the same underlying liability, we applied the multiple threshold model to all bivariate combinations – within individuals, between twins within disorder, and cross-twin cross-disorder – testing 45 relationships in each of five zygosity groups. The mean probability value for these 225 tests was 0.43, close to 0.50 expected; 7.6% of the values exceeded 0.05, close to chance expectations.

Multivariate model fitting and results

The common pathway model provided a better fit to the data than the independent pathway model (Δχ² ₇ = 11.60, P = 0.11, ΔAIC = −2.40). The results for the full common pathway model are shown in Fig. 1, where squaring the path coefficients gives the proportions of variance explained. The latent phenotypic factor – a general liability to all anxiety disorders – is substantially influenced by genetic factors, with an estimated heritability of 54%. In contrast, the contribution of shared environment was small (6%) and not statistically significant. Individual-specific environment equalled 40%.

The paths from the common factor to the individual disorders closely mirror those found in the confirmatory factor analysis (Table 2), with highest loadings seen for panic disorder and GAD scores and lowest loadings for OCD and PTSD scores. The genetic and environmental effects specific to each anxiety disorder score are seen in the lower part of Fig. 1. Disorder-specific genetic effects are negligible for panic disorder and GAD, intermediate but non-significant for OCD and PTSD and strongest for phobia. A more informative way to interpret these results is seen in Table 3, which presents estimated total heritability and the percentage of genetic effects for each disorder score resulting from the common factor and unique to each disorder score. Total heritabilities were generally modest, ranging from 23% for PTSD to 40% for phobias. The proportions of genetic effects unique to each disorder score were more variable, ranging from 4% for GAD to 40% for phobia and 45% for OCD.

Fig. 1 Parameter estimates for five anxiety disorders from a full multivariate common pathway model. A, additive genetic factors; C, environmental factors shared by co-twins; E, environmental non-shared factors; GAD, generalised anxiety disorder; OCD, obsessive–compulsive disorder; PTSD, post-traumatic stress disorder. Subscripts Pa, G, Ph, O and Pt denote panic, GAD, phobias, OCD and PTSD respectively; subscript C denotes ‘common’ (i.e. common to all disorders). Note: some of the confidence intervals are approximate.

The estimated shared environmental effects specific to each disorder score were modest and none reached significance. They vary, being estimated at zero for panic disorder and phobia scores, and to account for 8% of total variance in liability for GAD scores and 10% for OCD scores. As seen in Table 3, for three of the anxiety disorder scores – GAD, OCD and PTSD – most of the shared environmental effects appeared to be disorder-specific. For the remaining two disorder scores – panic disorder and phobia – the very modest shared environmental effects were entirely common to all disorders. Non-shared environment contributed to the comorbidity with about two-thirds of the genetic contribution.

Interpretation and comparison with prior results

Epidemiological studies from New Zealand, ^{Reference Krueger, Caspi, Moffitt and Silva9} the USA, ^{Reference Krueger10} Australia ^{Reference Slade and Watson11} and Holland ^{Reference Vollebergh, Iedema, Bijl, de Graaf, Smit and Ormel12} have all shown correlations and factor loadings for the anxiety disorders that correspond well with our results. Our heritability estimates for panic disorder, GAD, phobia and OCD are similar to or slightly lower than those previously reported. ^{Reference Middeldorp, Birley, Cath, Gillespie, Willemsen and Statham1–Reference Van Grootheest, Cath, Beekman and Boomsma8} A meta-analysis of previous twin studies estimated heritabilities of 0.43 for panic disorder, 0.32 for generalised anxiety disorder and 0.20–0.37 for various types of phobias. ^{Reference Hettema, Neale and Kendler2} A review of twin studies on obsessive–compulsive disorders reported heritabilities of 0.27 to 0.47. ^{Reference Van Grootheest, Cath, Beekman and Boomsma8} Analyses of the only large twin sample with PTSD data, the Vietnam Era Twin Registry, have shown a heritability of 0.35, ^{Reference Chantarujikapong, Scherrer, Xian, Eisen, Lyons and Goldberg3} compared with our estimate of 0.23. Our results may be lower because the rates of severe trauma – a prerequisite for a PTSD diagnosis – were probably much lower in our community sample than in a cohort of male war veterans. This would be likely to reduce heritability, since our sample would contain individuals at high genetic risk of PTSD that would not be manifested owing to the absence of trauma exposure.

Our multivariate findings can be usefully compared with those from the two most comparable prior studies. Chantarujikapong et al found that a single-factor independent pathway model best fitted lifetime PTSD and symptoms of GAD and panic disorder in 3371 male pairs from the Vietnam Era Twin Registry. ^{Reference Chantarujikapong, Scherrer, Xian, Eisen, Lyons and Goldberg3} Their results agreed with ours in finding nearly all genetic effects on GAD to be shared with the other anxiety disorders and approximately a third of the genetic risk of PTSD to be disorder-specific. Their results differed, however, in finding a much higher proportion of genetic effects on panic disorder to be disorder-specific (49% in their study v. 9% in ours). Hettema et al analysed data on panic disorder, GAD, agoraphobia and social, animal and situational phobias in approximately 5000 twins in the USA. ^{Reference Hettema, Prescott, Myers, Neale and Kendler4} Their results differed from ours in suggesting that two genetic factors were required to explain the observed patterns of comorbidity. Their results concurred with ours in finding that GAD and panic disorder shared nearly all genetic risk factors whereas at least some subtypes of phobias were strongly influenced by genetic factors only weakly related to panic disorder and GAD.

A notable result from our model fitting is the higher heritability for the common anxiety disorder factor than for any of the individual disorders. This is, however, not unexpected from a psychometric perspective. Unreliability of measurement, which is a concern for some anxiety disorders, especially when assessed in non-clinical populations, ^{Reference Kendler, Karkowski and Prescott27–Reference Wittchen, Kessler, Zhao and Abelson29} will more substantially attenuate the heritability of the individual disorders than the latent common factor.

Implications for DSM–V

These results have four implications for those pondering the structure of anxiety disorders in the fifth edition of the DSM. First, despite strong evidence that GAD and major depressive disorder are genetically closely related, ^{Reference Kendler, Neale, Kessler, Heath and Eaves13–Reference Roy, Neale, Pedersen, Mathe and Kendler15} our results suggest that GAD is also strongly related genetically to the other anxiety disorders. Thus, genetic findings alone cannot justify its removal from the anxiety disorders and placement within the mood disorders. The genetic relationship between major depression and GAD may be non-specific and indicative of a broad shared genetic liability across a wide range of internalising disorders. ^{Reference Hettema, Goldberg, Kendler, Sirovatka and Regier30} Second, our results provide some support for the aetiological coherence of the anxiety disorders. All five dimensionally scored disorders do have appreciable loadings on the common factor. However, third, OCD and PTSD do differ from the other three anxiety disorders in that they have the lowest loadings on the common factor, and appear to have appreciable disorder-specific genetic and shared environmental influences. Thus, these two disorders in our data are the least closely related to the common factor. Fourth, the results for phobias are somewhat anomalous: on the one hand this disorder has a relatively high loading on the common factor, but on the other it has the greatest disorder-specific genetic risk factors. This might be the result of combining the different phobias, which may have partially distinct genetic and environmental risk factors as suggested by prior findings. ^{Reference Hettema, Prescott, Myers, Neale and Kendler4,Reference Kendler, Myers, Prescott and Neale31,Reference Sundet, Skre, Okkenhaug and Tambs32} However, we also cannot exclude the possibility that our deviating findings for phobia to some extent reflect our choice of a common pathway model, which in terms of AIC value was only marginally favourable to the independent pathway model. The latter, on which previous estimates were based, produced somewhat different results.

Limitations

These results should be interpreted in the context of eight potential methodological limitations. Our sample consisted of young-adult Norwegian twins, and these results may not generalise to other populations. Despite our substantial sample size, limited prevalence for all the anxiety disorders except phobias required that we use subthreshold cases to permit meaningful model fitting. These cases were empirically defined, and for three variables where questionnaire data were used to extend the subthreshold groups, the questionnaire data correlated moderately to highly with the diagnostic data. Their addition did not appreciably alter the results of confirmatory factor analysis. Multiple threshold analyses showed that they reflected the same liability dimensions as the syndromal DSM–IV cases. However, our results might still have differed somewhat if based on DSM-defined disorders only.

As detailed elsewhere, ^{Reference Kendler, Aggen, Tambs and Reichborn-Kjennerud33} only pairs who had participated in a previous questionnaire study were invited to the MHT study. Thus, considerable attrition, taking place in two steps, might imply recruitment bias of the results. However, unpublished results have shown only a moderate selection towards superior mental health in previously completed questionnaires. Biometric genetic analyses of mental health variables from the questionnaires did not differ between MHT participants and non-participants. Accordingly, substantial recruitment bias of the biometric genetic analyses in this study is unlikely. Univariate analyses suggested that there could be quantitative and qualitative gender differences for phobias and PTSD that we were unable to incorporate into our multivariate model. Therefore, results for these variables should be interpreted as an approximate average across genders rather than fully valid for men and women specifically. Qualitative gender-specific effects if ignored will bias the estimates of heritability upwards. However, most of the heritability estimates for our modelling were somewhat lower than expected from previous results. It is unlikely that our results were substantially biased by our inability to model gender effects.

Phobia subtypes may be partly influenced by different genes. ^{Reference Hettema, Prescott, Myers, Neale and Kendler4,Reference Kendler, Myers, Prescott and Neale31,Reference Sundet, Skre, Okkenhaug and Tambs32} Results from a twin study suggest a particularly strong familial covariance between agoraphobia and panic anxiety. ^{Reference Tsuang, Domschke, Jerskey and Lyons34} Given low rates of certain subtypes, especially in our male participants, we could not include phobia subtypes in our multivariate models. Therefore, our results for phobias are inevitably averaged across the subtypes.

Because our analyses included only anxiety disorders, they cannot address the important question of whether the genetic and environmental risk factors common to all anxiety disorders are specific only to anxiety disorders or shared with other internalising disorders. The specification of genetic or environmental effects common to two or more phenotypes does not exclude the possibility of causal relationships between these phenotypes. If phenotype X causes phenotype Y, genetic or environmental factors primarily affecting X will be mediated through X and indirectly affect Y. Our twin modelling and data are not informative on possible causal relationships between the anxiety disorders. Such causal relationship will only be expressed as genetic or environmental variance common to the disorders.

Finally, the observed genetic covariance structure as well as the diagnosis-specific genetic variance might perhaps be further decomposed into effects of genes coding for possible endophenotypes. The latter are by definition more fundamental and genetically more homogeneous than complex phenotypes such as anxiety disorders. Possible endophenotypes might include behavioural characteristics such as ‘behavioural inhibition’, ^{Reference Stein and Vythilingum35} biological factors such as gamma-aminobutyric acid type A receptor diversity, ^{Reference Mohler36} or perhaps a combination of the two such as sensitivity to hypercapnia. ^{Reference Battaglia, Pesenti-Gritti, Spatola, Ogliari and Tambs37} Although our study, not informative on such factors, first and foremost needs replication based on diagnostic data, future twin studies of diagnostic anxiety data together with endophenotypic data may further extend our understanding of the comorbidity among anxiety disorders.

Subthreshold criteria

Panic disorder

Meeting criteria for panic attack.

OR

Confirming ‘ever had an attack when all of a sudden you felt frightened, anxious or very uneasy? Some people call it a panic attack’ without being in danger, AND endorsing four or more of the 17 types of symptoms listed in the interview.

Generalised anxiety disorder

Two of the six DSM criteria were relaxed in various ways.

(i) (A) Felt worried, tense or anxious over longer than 3 months (originally 6 months); worried 2–3 days a week (originally ≥4 days); worried about everyday events, but did not perceive the worrying to be ‘excessive, that is, stronger than in other people in similar situation’ (originally required to be ‘excessive’).

(E) Anxiety interfered at least ‘somewhat’ (originally at least ‘a lot’) with life/daily activities; reported at least three of seven types of symptoms (originally in DSM–IV, three of six types of listed symptoms are required. An extra type of symptom, ‘feels like having a lump in one's throat’ is added in the CIDI).

OR

(ii) As (i), except (A): the period lasted 6 months, and (E): only two types of symptoms were required.

OR

(iii) As (i), except (A): worrying was also perceived by the individual to be excessive and (E): only two types of symptoms were required.

Obsessive–compulsive disorder

Endorsing any of the CIDI OCD screening questions about clearly obsessive or compulsive symptoms.

Post-traumatic stress disorder

Three of the six DSM criteria were relaxed:

(C) Reported at least one type (originally ≥3) of avoidance reaction.

(D) Reported at least one symptom (originally ≥2) of increased arousal. (E) Duration criterion (>1 month) dropped.

From fully diagnosed and subthreshold PTSD cases, 13% and 12% respectively reported only a type of traumatic event not listed in the interview.