B. de Brettes and J.P. Le´pine
Hoˆpital Fernand Widal, Paris, France
INTRODUCTION
Due to the extremely fast development of molecular genetic methods in the past 10 years, more and more studies have been and are being currently carried out on the genetic factors of schizophrenia, bipolar disorder and Alzheimer’s disease. However, in connection with environmental factors, genetic vulnerabilities are suspected in many other psychiatric disorders such as alcoholism and other addictive disorders, autism, eating disorders, and also anxiety disorders. Indeed, familial aggregation of anxiety disorders has been repeatedly reported, but this phenomenon may be explained by various aetiologic factors, namely familial environment and genes.
Early theories, as developed by Darwin, suggested that through natural selection humans have evolved an inherited tendency to anxiety and phobic reaction to certain stimuli (Kendler et al., 1992c). More recently, family and twin studies, as well as linkage and association studies have been conducted on the various nosological categories of anxiety disorders, with conflicting but in some cases positive results.
Since the majority of genetic studies in anxiety disorders have been carried out with a categorical approach, we will present the main results obtained syndrome by syn-drome. However, it is worth noting, in order to understand discrepancies between studies, that complex disorders like anxiety disorder pose numerous challenges for genetic research. Indeed, most cases are the result of the interaction of environmental effects with a set of genes and each accounts only for a small part in the liability of the disorder, with the possibility, as not fully studied, of gene–gene interactions (epistasis).
Furthermore, genetic complexity is compounded by the complexity of the psychiatric phenotype. Where available, after a review of the results for generalised anxiety disorder and phobias in terms of family, twins, linkage and genetic association studies, the methods and results for refining phenotypes to improve future research will be discussed.
Anxiety Disorders: An Introduction to Clinical Management and Research. Edited by E. J. L. Griez, C. Faravelli, D. Nutt and J. Zohar. © 2001 John Wiley & Sons, Ltd.
GENERALISED ANXIETY DISORDER (GAD)
Genetics studies of generalised anxiety disorder (GAD) were especially influenced by the progressive modifications of the diagnostic systems. Indeed, GAD as defined in DSM-III bears at least only partial resemblance to the GAD described by the DSM-III-R criteria, in which the core symptom for GAD is chronic worry, with excessive or unrealistic worries involving two or more life circumstances. The increas-ingly restrictive criteria for GAD, from RDC, DSM-III, DSM-III-R to current DSM-IV, obviously sought more reliability and to reduce clinic heterogeneity, although it remains unclear and controversial whether the more stringent criteria have improved this syndromal validity. This results, however, in a more independent familial transmission of GAD from other anxiety disorders or depressive disorders (Wolk et al., 1996), but on the other hand, few studies exploring GAD, genetics or pharmacologicals are able to respect those stringent criteria (Swinson et al., 1993).
Familial Aggregation Studies
Three studies focused clearly on GAD familial transmission (Cloninger et al., 1981;
Noyes et al., 1987; Reich, 1995). First, among thefirst degree relatives of anxious subjects with a GAD-like syndrome in fact classified as ‘‘other anxiety neurosis’’, there was no significant excess of anxiety disorders compared with control probands (Cloninger et al., 1981).
Second, with DSM-III criteria (Noyes et al., 1987), rates of GAD appeared significantly higher among 123 relatives of ‘‘pure GAD’’ (without panic disorder or panic attack) probands compared to relatives of non-psychiatry ill subjects (19.5% vs.
3.5%, P 0.001). Relatives of probands with GAD who shared the same disorder were at the onset of illness significantly older than the probands. More had remissions and seemed stress-related and fewer reported secondary depression and abnormal personality traits. Therefore, the familial risk for GAD appears specific for the disorder: the frequency of GAD appeared no higher among relatives of GAD probands versus relatives of panic (5.4%, N = 40) or agoraphobic probands (3.9%, N = 40) and rates of major depressive disorder among relatives of GAD probands were similar compared to controls (7.3% vs. 7.1%).
A third study (Reich, 1995) confirmed the family predisposition, in a male popula-tion only, using family history methods. The prevalence of GAD among relatives of GAD probands (12.7%) was significantly higher compared with relatives of subjects with major depressive disorder (6.8%), GAD with major depressive disorder (4.2%), or control subject (1.9%).
Twin Studies
Three studies used the conservative, purely descriptive, statistical measure of twin concordance to analyse the familial heredity of GAD (Table 3.1). All studies found no
TABLE3.1 Twin studies of concordance for GAD
Diagnostic Concordance Concordance Relative criteria for MZ twins for DZ twins risk
Torgersen, 1983 DSM-III 0% (0/12) 5% (1/12) 0
Andrews et al., 1990 DSM-III 20.6% 13.6% 1.5
Skre et al., 1993 DSM-III-R 60% (3/5) 14% (1/7) 4.3
significant difference between monozygotic (MZ) and dizygotic (DZ) twins: these studies were Torgersen (1983) in a sample of 159 pair of psychiatric ill twins (32 MZ and 53 DZ with anxiety disorder; GAD probands with major depressive disorder were excluded); Andrews et al. (1990) among 446 pairs of twins in the general population, with no diagnostic hierarchy for GAD (186 MZ and 260 DZ); and Skre et al. (1993) in a total sample of 81 same-sex twin-pairs mainly hospitalised, where all cases of GAD had, however, a lifetime history of mood disorder.
Kendler et al. (1992a), using another approach and statistical measure of the twin concordance, the tetrachoric correlation coefficient (TCC), tried to determine the relative support for a genetic or environmental influences, or both influences, in the explanation of the familial resemblance for GAD. However, this method is currently under discussion (Kraemer, 1997; Lyons et al., 1997). In fact, tetrachoric correlation coefficient analysis is based on the hypothesis that there is a latent trait, often unknown in psychiatric diseases, that is unidimensional with a standard normal distribution on which the diagnosis are based.
In afirst study on 2163 female twins (Kendler et al., 1992a), the twin correlation was investigated for different definitions of GAD: GAD with and without panic disorder and major depressive disorder (MDD), and with one-month or six-month duration of GAD. The prevalence of GAD with a six-month duration was 5.9%, and 5.7% if subjects presenting a PD co-occurring with GAD are excluded, and 3.6% if subjects presenting MDD co-occurring with GAD are excluded. Tetrachoric correla-tion coefficient for one-month GAD diagnosed without hierarchy were +0.35 ± 0.07 among MZ and +0.12 ± 0.08 among DZ twins, arguing for a genetic susceptibility of GAD. Hierarchical conditions do not modify these results significantly. For GAD six-month without hierarchy, the correlation presented quite the same value among MZ and DZ (0.28 ± 0.15 and 0.28 ± 0.14). In this study, GAD correlation within twins seems to be only due to genetics factors (bestfitting model from nine tested);
however, the estimated liability of heredity of GAD appeared moderate, ranging from 19% to 30% for different definitions (one- or six-month duration, diagnostic hierarchy, models with threshold). In addition, the remainder of the variance in liability seems to result from individual–specific environmental experiences, probably critical for the emergence of GAD, and not from familial environmental factors.
Duration of the episode does not seem to affect this heritability, quite the same with one-month or six-month definitions of GAD. For the authors, there was a modest decline in the estimated heritability of GAD when exclusion of the probands who concurrently had GAD and MDD was applied. However, it should be outlined that
comorbidity in this report was in fact restricted to the co-occurrence of two disorders, so uncertainty remains about the impact of the comorbidity between GAD and MDD in the familial/genetic transmission of GAD.
In the same sample of female twins (Kendler et al., 1992b), the correlation in one twin between MDD and GAD one-month was systematically higher than any of the cross-twin cross-disorder correlation, suggesting that subject-specific experiences contribute to the GAD/MDD correlation. Furthermore, they indicated that cross-twin MDD/GAD one-month correlation was found more than twice as often in MZ vs. DZ (+0.37 and +0.13, respective means), suggesting that genetic factors contrib-ute to the correlation. However, a possible causality between these disorders cannot be evaluated: MDD may cause GAD, or the inverse. They suggested at least that genetic factors influencing the two disorders are highly correlated in women, and that GAD and MDD could be the different manifestations of the same underlying transmissible factors.
Roy et al. (1995), in a study of male and female twins combining clinically ascertained and general population samples, tried to replicate these findings concerning the aetiologic determinants of comorbidity. For GAD (with modifications of criteria:
one-month duration and a single area of worry were sufficient, no hierarchy with MDD), the familial aggregation of GAD could be fully accounted for by genetic factors, but as in the Virginian sample of Kendler, heritability remains moderate (49.0% in the bestfitting modelusing broad definitionsof GAD, to 14.3% with narrower definitions).
In contrast, estimations for the heritability of MDD were systematically higher (62.1%
and 50.9% with respectively broad or narrow definitions of MDD).
Finally, it seems that genetic factors could play a role in the aetiology of GAD.
However, last reports suggest that heredity, if it exists, is moderate. In addition, despite the family predisposition indicated for GAD by familial aggregation studies, classical twins studies (Torgersen 1983; Andrews et al., 1990; Skre et al., 1993) report no significant differences between MZ and DZ twins, although with small sample size. What is noteworthy, in the various studies exploring genetic factors in GAD, is that inclusion or exclusion of cases of GAD with a mood disorder co-occurring or comorbid seems to have a major influence on the results and on the interpretation.
Thus, there currently remain doubts about the heredity of ‘‘pure’’ GAD, and some authors suggest that GAD is hereditary only when there is a comorbid history of MDD (Skre et al., 1993). Comorbidity and co-segregation for GAD and MDD could also be understood as alternative expressions of the same aetiologic factors. Other-wise, the hypothesis that genes may act mainly by a predisposition to a general distress, rather than specific symptom or disorder was also suggested by some family studies that suggested that GAD and MDD co-segregate within families (Weissman et al., 1984; Angst et al., 1990).
PHOBIAS
All phobias show an irrational and fearful avoidance of objects or situations that are not explained as a function of the threat, truly posed therewith. However, they
seriously differ in terms of age at onset (Ost, 1987), patterns of comorbidity (Boyd et al., 1984), and type of phobic stimulus, which is well circumscribed for specific phobia or relatively diffuse for agoraphobia and social phobia. Consequently, an important question for phobias investigates whether each of them is familial and has a specific familial aggregation: are the subtypes of phobias distinct, unrelated syndromes, or do subtypes of phobias represent minor variations of a single disorder?
Social Phobia
The familial transmission of social phobia (SP) was mainly investigated by the Study Group of Columbia. Restricting the probands to individuals who have only one of the three phobic disorders (simple, social or agoraphobia), and with their largest social phobia sample (Fyer et al., 1995), they found that DSM-III-R Social Phobia is associated with a significant but moderate familial risk (relative risk: 2.5 (CI: 1.2–5)).
Rates of DSM-III-R anxiety disorders other than SP did not differ significantly among the relatives of SP probands as compared with those of controls who were not ill (15% vs. 8%, PO 0.01). Otherwise, the two other phobic disorders are not associated with increased familial risk for social phobia. Thus, the specificity of this pattern of intergenerational transmission supports the existence of an SP category that is separate from other phobic disorders, consistent with the current DSM-IV.
Homogeneity, both clinical and aetiologic, within the SP category remains, how-ever, a subject of investigation, in terms of social phobic stimuli or in terms of generalised/not generalised criterion. For instance, rate of SP was significantly greater among relatives of 67 patients with generalised vs. relatives of 62 non-generalised SP (16% vs. 6%, P 0.05), and significantly greater among relatives of patients with generalised vs. relatives of non-psychiatry ill subjects (16% vs. 6%, P 0.05) (Mannuzza et al., 1995). However, there was no evidence that patients with generalised SP were more likely to transmit this form of the syndrome. Another study had replicated these results in an independent group, with a relative risk for generalis-ed SP (and avoidant personality disorder) approximately 10 times higher amongfirst degree relatives (N = 106) of generalised SP probands compared with first degree relatives (N = 74) of comparison subjects (Stein et al., 1998). In contrast, when the subtypes are defined as a class of speaking fears only, versus a class of a broader range of social fears, there is no difference in terms of family history of SP (and in age at onset), from the data of the National Comorbidity Survey (Kessler et al., 1998).
However, maternal generalised anxiety was lower among those with pure speaking fears than among those with other social phobias (P 0.001).
Furthermore, there is no evidence suggesting an exact specificity of intergenera-tional symptom transmission. Although within a small sample size, this issue was assessed by Fyer et al. (1993) with the 13 relatives of SP probands who also received a DSM-III-R SP diagnosis: none had exactly the same types and number of social phobias than the probands to whom they were related, but in 10 cases, there was a partial intergenerational overlap of social phobias types. Otherwise, it seems that
irrational social fears that occur in individuals who do not also have SP are neither familial nor associated with an increased familial risk for SP (Fyer et al., 1993). The rate of threshold social fears, that do not meet the DSM-III-R impairment/distress criterion, among relatives of probands with social fears only, was not significantly different from that among relatives of probands with no fears and no phobias (46% vs.
52%). Rates of DSM-III-R SP in the relatives of these two groups also did not differ (7% vs. 4%). These result differ from twin and family studies of social fears and shyness, which have uniformly showed heritable components (Plomin and Daniels, 1986; Stevenson et al., 1992; Thapar and McGuffin, 1995). However, many subjects in those studies might have social phobia criteria, although they were not recruited from clinical settings. In another study with four probands groups (PD, SP, PD + SP, not ill controls), Fyer et al. (1996) examined the effect of comorbidity between PD and SP on familial transmission, since an unexpectedly high comorbidity has been noted in both epidemiological and clinical samples (Barlow, 1988; Stein et al., 1989;
Klerman et al., 1991). Relatives of SP probands had a higher rate of SP (15%), but not of PD (2%), relatives of probands with PD only had a higher rate of PD (10%) but not of SP (9%), when compared with relatives of controls (SP: 6%, PD: 3%). Among the relatives of probands with SP + PD, familial aggregation of PD was not affected by proband social comorbidity (rate of PD: 9%). In contrast, SP among these relatives was not different when compared with relatives of controls. From a genetic point of view, this suggests that SP in individuals who have, or subsequently develop, PD differs from SP which occurs without lifetime anxiety comorbidity, and that at least some cases of SP + PD may be non-familial and/or causally related to PD.
Three twin studies have examined clinically defined phobias. First, Carey and Gottesman (1981), examining 21 twin probands hospitalised with phobia, found low and similar concordance rates in monozygotic (MZ) and dizygotic (DZ) twins.
However, using a broad definition of phobic ‘‘symptoms or features’’, they found a much higher concordance rate in MZ (88%) than in DZ (38%) twins. In a second study among 12 twin probands with a primary diagnosis of phobia, Torgersen (1983) found that none of the co-twins were phobic. Third, with 2163 female twins from a population-based registry, Kendler et al. (1992c) showed a less than two times higher probandwise concordance for SP in MZ when compared with DZ. Nevertheless, the familial aggregation of SP appeared to result solely from genetic, and not from familial-environmental factors, with estimation of genetic heritability of liability of 30% (Kendler et al., 1992c).
Agoraphobia
Although family studies could challenge categorical distinctions between agorapho-bia and panic disorder, and between agoraphoagorapho-bia and other phoagorapho-bias, few data are currently available on this topic. The risk for agoraphobia was initially noted to be significantly higher among parents and siblings of 60 agoraphobic patients than estimates of the population incidence (Moran and Andrews, 1985). A second family
study, including non-anxious controls and their relatives, confirmed this familial aggregation of agoraphobia, showing that the morbidity risk for agoraphobia was significantly increased among relatives of agoraphobics but not the relatives of PD patients nor non-anxious subjects (Noyes et al., 1986). Furthermore, with 144 patients with PD and/or agoraphobia according to DSM-III, agoraphobia was strictly clus-tered in families of agoraphobic patients (Gruppo Italiano Disturbi d’Ansia, 1989).
This familial aggregation of agoraphobia seems moderate, with a threefold increased risk for DSM-III-R PD with agoraphobia versus not ill controls (10% vs. 3%, P 0.001), but with a specific familial loading for other phobias (Fyer et al., 1995). In contrast to this, Kendler et al. (1992c) found evidence of both partial distinctness and overlap with respect to the genetic contribution to the aetiology of agoraphobia, social and situational phobias. Similarly, in a second epidemiologically based twin study including panic agoraphobia and social phobia probands, no genetic contribu-tions were specific to either phobia (Andrews et al., 1990). It is noteworthy that those two twin studies did not report separately single and comorbid cases of phobias, otherwise the two sets offindings should be consistent.
For agoraphobia, heredity of liability was 39% in a female twin population, whereas the rest of the variance in liability was due to individual–specific environ-mental effects. Probandwise concordance for agoraphobia was 23.2 among MZ and 15.3 among DZ twins, and tetrachoric correlation ranged from 0.41 ± 0.11 among MZ to 0.15 ± 0.13 among DZ twins (Kendler et al., 1992c).
Specific Phobias
As for other phobias, a moderate but statistically significant and specific familial aggregation was found for situational phobias, with a relative risk, as compared with not ill controls, of 3.9 (95% CI: 1.8–8.1) (Fyer et al., 1995). However, twin studies are less conclusive. Kendler et al. (1992c) failed to show a clear genetic effect for situational phobias, in contrast, they found that disease liability was solely the result of individual specific environmental effects (73% of the variance ) in conjunction with familial environmental influences, although a model with additive genetic and speci-fic environmental effects could not be rejected. Correlation in MZ twins was similar or much lower than the corresponding DZ correlation (respectively, for probandwise concordance 22.2 vs. 23.7, and for tetrachoric correlation 0.27 ± 0.10 vs.
0.27 ± 0.11). With an expanded definition of situational phobias including other simple, non-animal phobias (fear of water, of thunderstorms), tetrachoric correlations remained similar. A new sample supports this conclusion, with no significant differen-ces between MZ and DZ co-twins (Skre et al., 1993). For isolated animal phobia (Kendler et al., 1992c), it seems that disease liability may result from additive genetic effects (32% of the variance) and individual specific, but not familial, environmental effects (68% of the variance).
Finally, family studies support the existence of a specific familial contribution to each particular phobia, with a relative risk ranging from 2.5 for social phobia to 3.9
for specific phobia, with an intermediate risk for agoraphobia. Despite its specificity, the magnitude of this increased familial risk appears only moderate, suggesting that although familial factors contribute to the aetiology of those disorders, other non-familial factors require investigation. Supporting this conclusion, twin studies indicate
for specific phobia, with an intermediate risk for agoraphobia. Despite its specificity, the magnitude of this increased familial risk appears only moderate, suggesting that although familial factors contribute to the aetiology of those disorders, other non-familial factors require investigation. Supporting this conclusion, twin studies indicate