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Anticipation of age at onset of obsessive-compulsive spectrum disorders in patients with obsessive-compulsive disorder
Psychiatry Research 111 (2002) 1–9
Anticipation of age at onset of obsessive-compulsive spectrum disorders in patients with obsessive-compulsive disorder Maria Cristina Cavallini*, Monia Albertazzi, Laura Bianchi, Laura Bellodi Department of Neuropsychiatric Sciences, Universita` Vita-Salute Ospedale San Raffaele, Via Stamira D’Ancona, 20127 Milan, Italy Received 16 May 2001; received in revised form 23 April 2002; accepted 28 May 2002
Abstract Anticipation of age at onset has been observed in several neuropsychiatric disorders. Recent studies have associated anticipation with the presence of unstable DNA and have suggested that trinucleotide repeats may be the main cause in some of these diseases. However, several selection biases may mimic the presence of such an effect. In this study we evaluated the presence of this effect in 40 families of probands with obsessive-compulsive disorder (OCD) compared with affected subjects in the parental generation. We controlled for ascertainment biases by taking into account the age at interview of probands. Using a different recruitment strategy, we controlled for anticipation in a sub-sample of offspring of 13 OCD patients, affected with OC spectrum disorders. While the younger generation showed a significantly earlier age at onset than the parental generation, no effect of age at interview was observed. Drawing on the results, we hypothesised that the presence of anticipation in OCD and OC spectrum disorders could be due to a specific genetic effect (unstable DNA), as it has been hypothesised for other disorders showing this effect. 䊚 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Anticipation; Tic disorders; Imprinting; Unstable DNA; Genetics
1. Introduction The phenomenon of anticipation, i.e. reduced age at onset for a specific disease in offspring generations, has been described for several neurologic and psychiatric diseases wfragile X syndrome (Sherman et al., 1985), Huntington’s disease (Ridley et al., 1988), schizophrenia (Bassett and Honer, *Corresponding author. Tel.: q39-2-2643-3315; fax: q392-2643-3265. E-mail address: [email protected] (M.C. Cavallini).
1994; Gorwood et al., 1996; Ohara et al., 1997). Recently, Ohara et al. (1999) observed the presence of anticipation of age at onset for anxiety disorders in 17 probands affected with anxiety disorders (panic disorder, obsessive-compulsive disorder and other anxiety disorders) when compared with cases in the parental generation. Similarly, Battaglia and colleagues (Battaglia et al., 1998) described a significant decrease of the age at onset of the first panic attack and panic disorder
0165-1781/02/$ - see front matter 䊚 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 1 6 5 - 1 7 8 1 Ž 0 2 . 0 0 1 4 0 - 3
2
M.C. Cavallini et al. / Psychiatry Research 111 (2002) 1–9
from the older to the younger generation in 38 unilineal pedigrees. In some disorders, the presence of anticipation has been associated with the molecular phenomenon of trinucleotide repeats in DNA sequence (Petronis and Kennedy, 1995; Ohara, 2001). The degree of expansion of CAGyCTG and CCGy CGG triplets in the genes has been found to vary across generations of affected families in correlation with clinical symptoms. The increase in the number of trinucleotide repeats correlated with an increase in the severity of the disorder and a decrease of the age at onset in the younger generation, as observed in some monogenic diseases (i.e. Huntington’s disease). Although there is no accepted biological mechanism for genetic anticipation in complex disorders or polygenic diseases, it has been suggested that it can play a role in such illnesses as bipolar disorder, schizophrenia, Crohn’s disease, and rheumatoid arthritis (Picco et al., 2001). Nevertheless, as Penrose pointed out, the determination of a true phenomenon of anticipation represents a burdensome task (Penrose, 1945, 1948). In fact, early onset cases in the offspring generation may be more frequently ascertained, while preferential selection of late-onset parents may often occur because the parents become ill after having children. Furthermore, differential age at interview between parent and child may produce severely biased samples exhibiting apparent anticipation (Heiman et al., 1996). Various techniques have been applied to more accurately control for these biases. Petronis et al. (1995) formulated different strategies to test for the presence of true anticipation, i.e. to compare the age at onset of affected unclesyaunts with the age at onset of probands in the offspring generation. Gorwood et al. (1996) proposed an additional strategy to overcome selection biases in the definition of anticipation of age at onset of schizophrenia. For each patient in the younger generation, they calculated the expected age at onset corresponding to the age at which the patient would become ill if the patient had belonged to the older generation. They then compared the observed vs. the expected age at onset in probands
to determine the presence of true anticipation. This method takes into account the difference between generations in age at interview, and thus controls for the fact that subjects are not interviewed at the same period of their lives across generations. We decided to apply this strategy to our research on obsessive–compulsive disorder (OCD). OCD belongs to a psychopathological spectrum (Hollander and Wong, 1995) of psychiatric disorders with a probable genetic component in its aetiology (Cavallini et al., 1999; Alsobrook et al., 1999; Nestadt et al., 2000a). Several studies have shown that OCD and related disorders have an early onset with a younger age at onset for males compared with females (Rasmussen and Eisen, 1992; Bogetto et al., 1999). Following these results, the purpose of the present study was to control for the presence of anticipation in OCD in families of OCD probands, taking into account potential biases due to sample ascertainment. 2. Materials and methods Forty in- and out-patients affected with OCD (19 male and 21 female) were recruited at the Anxiety Clinical and Research Unit of San Raffaele Hospital in Milan for the treatment of adult patients. All OCD diagnoses were made according to DSM-IV diagnostic criteria (American Psychiatric Association, 1994). Second-degree relatives of the patients (aunts and uncles) were ascertained using the family history method. Only certain diagnoses and clinical information were retained, based on accurate description of symptoms, notice of hospitalisation or medical treatment. To collect the actual sample, 309 families out of 349 initially screened families of patients were discarded because the proband was a sporadic case in the family (175 families) or because information on age at onset for affected relatives was unavailable or transmission of the disease was not unilineal (134 families). Only unilineal families were retained for the present study. Mean age at onset and mean actual age in offspring and parental generations are reported in Table 1 by sex. Regarding the probands excluded from the analysis, in the case of 134 families with
M.C. Cavallini et al. / Psychiatry Research 111 (2002) 1–9
3
Table 1 Characteristics of the selected sample 40 OCD probands
Total
M
F
Mean Mean Mean Mean Mean Mean
30.52"10.33 15.25"7.96 55.79"13.34 27.10"14.61 56.27"12.17 28.20"15.57
28.15"9.75 15.35"8.94 60.10"11.15 21.4"15.65 48.5"9.67 31.5"15.96
32.9"10.58 15.15"7.09 60.71"14.11 30.10"13.49 60.71"11.7 27.42"16.43
actual age age at onset actual age of parents (29) age at onset of parents (29) actual age of unclesyaunts (11) age at onset of unclesyaunts (11)
Table 2 Distribution of diagnosis in the proband generation Diagnosis
Co-diagnoses of probands
tics, Tourette’s syndrome Eating disorder (anorexia) Mood disorders Hypochondriasis Panic disorder
9 1 4 – 8
a positive family history for OCD, the mean age at onset (14.98"6.48) was not significantly different when compared with the mean age at onset of the 40 selected probands (Student’s t-tests 0.653, with 174 d.f. and Ps0.515). In the case of the 175 probands with a negative family history, the mean age at onset (19.43"9.34) was significantly different from that of the selected samples. This observation is in accord with the literature indicating that an early age at onset in probands is associated with a significant increase in familial risk for OCD (Pauls et al., 1995; Nestadt et al., 2000b). Affected parents were directly interviewed and asked for their age at onset by senior psychiatrists who were unaware of the age at onset of probands. The age at onset for OCD was defined as the age at which the obsessive symptoms impaired the patient’s activities ( job, study, etc.), according to
criterion C of DSM-IV and was recognisable by the subject or their relatives. Co-morbid diagnoses of probands and diagnoses in relatives are reported in Table 2. In addition, we recruited and evaluated an additional group of 13 OCD patients who had children affected with OC spectrum disorders. The patients were analysed separately from the previous sample for two reasons: (1) a different ascertainment procedure was used (the proband is one of the two parents) and OCD spectrum disorders were included in the analysis; and (2) the young age of affected children increased the probability that their age at onset would be lower than that of their parents. The characteristics of this sample are summarised in Table 3. The offspring of OCD patients were affected with OCD (one male and three females), or with tics or Tourette’s syndrome (nine males and one female). 2.1. Statistical analysis Differences of age at onset and actual age distributions between males and females in the offspring and in the parental generations were compared by the Mann–Whitney U-test. To evaluate the anticipation phenomenon, the non-parametric Wilcoxon signed rank test was
Table 3 Characteristics of sample of 13 OCD patients with affected children Actual age (years)
Age at onset (years)
Parental diagnosis Obsessive–compulsive disorder
4 Males 48.5"6.24
9 Females 43.22"8.34
4 Males 14.5"4.20
9 Females 20.00"9.06
Offspring diagnosis 13 OCDyticyTourette syndrome
10 Males 14.6"2.11
3 Females 15.66"3.05
10 Males 8.6"1.71
3 Females 13"2
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applied to compare each parental age at onset with the corresponding age at onset in the offspring generation. Furthermore, comparison of onset distributions between all the members of older and younger generations was made by life table analysis (Mantel-Cox test of significance). Regression analysis was used to test if parental age could predict the degree of anticipation. If observed differences were due to regression effects, the hypothesis of anticipation might not be supported. In this case, late onset parents would have earlier onset children, closer to average onset, while early onset parents would have later onset children closer to the average onset. Regression to the mean indicates the presence of a simple linear dependence in which the degree of anticipation gradually decreases with the decreasing parental age at onset. It is possible to control the presence of regression to the mean as applied to anticipation by plotting the difference between age at onset for parents and offspring (DAO) against the age at onset of parents (PAO) and evaluating the relationship. Nevertheless, McInnis et al. (1994) showed that the correlation between x and xyy is significantly high, for any randomly generated set of measurement x and y; moreover, the x intercept corresponding to xyys0 coincides with the mean value of x in the case of the regression to the mean. Therefore, if there is true anticipation, when the intercept on the line of PAO (x values) corresponding to a point 0 of anticipation (xyy) is less than the mean parental age of onset, then the finding is inconsistent with regression to the mean. It is well known that the age at interview may condition age at onset report; therefore we applied the method of proposed by Gorwood et al. (1996), as explained in the introduction, for correcting for this bias. We evaluated for each proband the expected age at onset under the hypothesis that the proband would belong to the parental generation (mean age at onset evaluated in the parental generation at the time when the proband was interviewed). These values were then compared with those observed in the probands. All the analyses were
performed using the Statistica package (Statsoft, 1993). 3. Results 3.1. Sample of 40 OCD probands No significant differences between male and female probands, or between affected male and female parents, were observed for actual age or age at onset (Fig. 1). We observed that the males had an earlier age at onset of obsessive–compulsive spectrum disorders than the females (23.41"15.74 vs. 28.25"14.18 years). In five families (12.5% of the sample) the age at onset for OCD in the parental generation was lower than in the offspring generation, in four families (the 10% of the sample) the age at onset for OCD in the parental generation was equal to that in the offspring generation, while in 31 families the age at onset for OCD in the parental generation was higher than that in the offspring generation. The median age at onset in the offspring generation was also significantly lower than that in the parental generation (Wilcoxon matched pair test zs5.01 and Ps0.000001 after rank correction). Analysis of the life table distributions in parental and offspring generations showed that the offspring developed OCD significantly earlier than the parents (Fig. 2, Mantel-Cox: tests2.384, Ps 0.017). When we considered the phenomenon of the regression to the mean, we found a significant association between PAO and DAO. The regression coefficient for DAO as to PAO was 0.844 (ns40, R 2s0.704, Fs94.08, Ps0.000) (see Fig. 3), with the x intercept for an anticipation value of 0 at 10.86, well below the mean parental age at onset of 25.71"14.67 (no regression to the mean). No difference was observed in DAO between parents and unclesyaunts (mean for 29 parentss 11.72"12.26 vs. 11 unclesyauntss13.09"16.8, ANOVA: Fs0.08, d.f.s1, 38, Ps0.778). There were 26 maternal and 14 paternal transmissions, but no difference in age at onset was
M.C. Cavallini et al. / Psychiatry Research 111 (2002) 1–9
Fig. 1. Age of onset distributions in probands and parental generation.
Fig. 2. Comparison of age at onset between parental and offspring generation.
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Fig. 3. Parental age at onset and differential age at onset.
observed between probands who inherited liability to OCD from their mothers and those who inherited liability to OCD from their fathers (Mann– Whitney test: Us129, zsy1.49, Ps0.133). The age at onset in the older generation was normally distributed with a mean of 27.6"14.70 years. When the expected (21.374"7.006) age at onset in probands was compared with the observed (15.80"8.82) age at onset, following the method proposed by Gorwood et al. (1996), the Wilcoxon matched pairs test yields Zs3.97 and P0.000069. The significant difference between the two indicates that the anticipation effect may be present. 3.2. Sample of 13 OCD probands and their affected offspring The comparison between the age at onset of each offspring with the corresponding parental age at onset produced a significant difference: Wilcoxon matched pairs test: Zs3.18, Ps0.0014. Analysis of the life table distributions in parental and offspring generations showed that the off-
spring developed OCD significantly earlier than the parents (Mantel–Cox tests3.93, Ps0.000) (Fig. 4). There was a significant association between PAO and DAO. The regression coefficient for DAO as to PAO was 0.931 (ns13, R 2s0.89, Fs (1,11)s99.56, d.f.s1,11, P-0.000) with the x intercept 8.69 well below the parental mean age at onset 18.30"8.13 (no regression to the mean). 4. Discussion Our results suggest the presence of anticipation of age at onset in the younger generation with OCD and OC spectrum diseases. Information available to date did not allow us to evaluate whether OCD in the offspring was also more severe than in the parents or the unclesyaunts. Records of hospitalisation of a directly related family member (20% of affected parents) as a criterion for degree of severity revealed that only a few of parents have been hospitalised or showed marked interference in functioning when compared with their offspring. All the probands in fact have
M.C. Cavallini et al. / Psychiatry Research 111 (2002) 1–9
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Fig. 4. Surviving percentage of age at onset in sample of 13 OCD patients and their offspring.
been hospitalised. A potential explanation could be that in older generations fewer cases seek help for psychiatric disorders (75%, frequently treated without specific drug therapy) probably due to the social stigma related to a psychiatric condition. Taking into account the age at interview of probands, which is described as potential bias in these studies, we can confirm the presence of an anticipation effect (Gorwood et al., 1996). Ohara et al. (1999) in their study on the anticipation phenomenon in a sample of families with anxiety disorders (four probands affected with OCD) found that the age at onset decreased in the younger generations. Consistent with their observations, we did not find differences in father-tooffspring and mother-to-offspring transmission, not supporting the presence of imprinting. Frequently, the true age at onset for psychiatric disorders is not easily determined. Patients may not recognise their early symptoms or become aware of them only when they start to cause a marked level of distress. Sometimes the onset of OCD is slow; in cases of chronic illness, patients
(parents, but also probands) may underestimate its true duration. Furthermore, the degree of specificity of clinical information may suggest a spurious anticipation of age at onset. The quality and quantity of clinical information concerning the subjects’ illness vary with the generations as well as with the severity of illness, influencing the definition of true age at onset (Merette et al., 2000). The affected children (OCD or tic disorders) of OCD patients show a decrease in age at onset, although affected offspring of affected parents may have a preferential ascertainment rate (see Penrose biases). For this reason we analysed this sub-group of patients separately. The offspring of OCD patients are frequently affected with tic disorders, that belong to the OC spectrum (Hollander and Wong, 1995). Generally, tics have an earlier onset than OCD. Our clinical experience demonstrates that 53.84% of Tourette syndrome (TS) patients develop OCD (Cavallini et al., 2000), whereas 28–63% of TS patients described in the literature have obsessive-compulsive symptoms. Frequently,
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patients with childhood OCD also have a tic disorder that disappears in adulthood and is not completely recognised by the proband or heryhis parents at the time of the interview. This fact could be related to the problem of the lifetime stability of OCD diagnosis. It would be interesting to follow over time those offspring that affected with a tic at the time of the interview to assess the course of illness. Finally, in our study we found a significant association between DAO (the difference between the parental age at onset and the child’s age at onset) and PAO (parental age at onset) in the analysed samples. It has been described that the presence of ‘regression to the mean’ could be a potential bias (McInnis et al., 1994). Regression to the mean represents the decrease in the degree of anticipation when the age at onset in the parental generation decreases. We controlled for this effect, as suggested by McInnis et al. (1994). The intercept for DAO as to PAO on the ‘x’ axis was less than the mean parental age at onset for the two OCD samples. This finding is inconsistent with regression to the mean in the Galtonian sense of the age at onset of probands. Furthermore, Hodge and Wickramaratne (1995) have proposed that correlation (regression) and anticipation are two distinct phenomena and that regression analysis is not a useful means of detecting ascertainment bias of false anticipation. The genetic meaning of anticipation phenomenon has been widely debated. It has been proposed that anticipation could potentially explain the observed non-Mendelian inheritance patterns in diseases, as it might cause variability in penetrance and gene expression (Hall, 1990). In fact, anticipation has been related to the presence of unstable DNA (Petronis and Kennedy, 1995). To our knowledge, a genetic component may well play some role in the aetiology of OCD and spectrum disorders, but hypotheses derived from molecular genetics are still too weak to identify a gene with a major effect on the development of these disorders. Nevertheless, anticipation in OCD and the hypothetical relationship between this effect and trinucleotide repeats could provide fertile terrain for the exploration of trinucleotide expansion in this group of disorders as well.
Acknowledgments The authors gratefully acknowledge P.L. Cavallini for his statistical contribution to the analysis. References American Psychiatric Association, 1994. DSM-IV: Diagnostic and Statistical Manual of Mental Disorders, 4th ed. American Psychiatric Press, Washington, DC. Alsobrook, J.P., Leckman, J.F., Goodman, W.K., Rasmussen, S.A., Pauls, D.L., 1999. Segregation analysis of obsessivecompulsive disorder using symptom-based factor scores. American Journal of Medical Genetics 88, 669–675. Bassett, A.S., Honer, W.G., 1994. Evidence for anticipation in schizophrenia. American Journal of Human Genetics 54, 864–870. Battaglia, M., Bertella, S., Bajo, S., Binaghi, F., Bellodi, L., 1998. Anticipation of age at onset in panic disorder. American Journal of Psychiatry 155, 590–595. Bogetto, F., Venturello, S., Albert, U., Maina, G., Ravizza, L., 1999. Gender-related clinical differences in obsessive-compulsive disorder. European Psychiatry 14, 434–441. Cavallini, M.C., Pasquale, L., Bellodi, L., Smeraldi, E., 1999. Complex segregation analysis for obsessive compulsive disorder and related disorders. American Journal of Medical Genetics 88, 38–43. Cavallini, M.C., Di Bella, D., Catalano, M., Bellodi, L., 2000. An association study between 5-HTTLPR polymorphism, COMT polymorphism, and Tourette’s syndrome. Psychiatry Research 97, 93–100. Gorwood, P., Leboyer, M., Falissard, B., Jay, M., Rouillon, F., Feingold, J., 1996. Anticipation in schizophrenia: new light on a controversial problem. American Journal of Psychiatry 153, 1173–1177. Hall, J.G., 1990. Genomic imprinting: review and relevance to human diseases. American Journal of Human Genetics 46, 853–857. Heiman, G.A., Hodge, S.E., Wickramaratne, P., Hsu, H., 1996. Age-at-interview bias in anticipation studies: computer simulations and an example with panic disorder. Psychiatric Genetics 6, 61–66. Hodge, S.E., Wickramaratne, P., 1995. Statistical pitfalls in detecting age-of-onset anticipation: the role of correlation in studying anticipation and detecting ascertainment bias. Psychiatric Genetics 5, 43–47. Hollander, E., Wong, C.M., 1995. Obsessive-compulsive spectrum disorders. Journal of Clinical Psychiatry 56, 3–6 discussion 53–55. McInnis, M.G., McMahon, F.J., Stine, O.C., Ross, C.A., 1994. Reply to A. Petronis, R. Sherrington, J.L. Kennedy: regression to the mean does not exclude anticipation and unstable DNA disease (Letter). American Journal of Human Genetics 55, 590–592. Merette, C., Roy-Gagnon, M.H., Ghazzali, N., Savard, F., Boutin, P., Roy, M.A., Maziade, M., 2000. Anticipation in schizophrenia and bipolar disorder: controlling for an information bias. American Journal of Medical Genetics 96,
M.C. Cavallini et al. / Psychiatry Research 111 (2002) 1–9 61–68. Nestadt, G., Samuels, J., Riddle, M., Bienvenu, III O.J., Liang, K.Y., LaBuda, M., Walkup, J., Grados, M., Hoehn-Saric, R., 2000. A family study of obsessive-compulsive disorder. Archives of General Psychiatry 57, 358–363. Nestadt, G., Lan, T., Samuels, J., Riddle, M., Bienvenu, O.J. III, Liang, K.Y., Hoehn-Saric, R., Cullen, B., Grados, M., Beaty, T.H., Shugart, Y.Y., 2000. Complex segregation analysis provides compelling evidence for a major gene underlying obsessive–compulsive disorder and for heterogeneity by sex. American Journal of Human Genetics 67, 1611–1616. Ohara, K., 2001. Anticipation, imprinting, trinucleotide repeat expansions and psychoses. Progress in Neuro-Psychopharmacology & Biological Psychiatry 25, 167–192. Ohara, K., Suzuki, Y., Ochiai, M., Yoshida, K., Ohara, K., 1999. Age of onset anticipation in anxiety disorders. Psychiatry Research 89, 215–221. Ohara, K., Xu, H.D., Mori, N., Suzuki, Y., Xu, D.S., Ohara, K., Wang, Z.C., 1997. Anticipation and imprinting in schizophrenia. Biological Psychiatry 42, 460–466. Pauls, D.L., Alsobrook, J.P., Goodman, W., Rasmussen, S., Leckman, J.F., 1995. A family study of obsessive-compulsive disorder. American Journal of Psychiatry 152, 76–84. Penrose, L.S., 1945. Survey of cases of familial mental illness. European Archives of Psychiatry and Clinical Neuroscience 240, 315–324 discussion 314–315.
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Penrose, L.S., 1948. The problem of anticipation in pedigrees of dystrophia myotonica. Annals of Eugenics 14, 125–132. Petronis, A., Kennedy, J.L., 1995. Unstable genes—unstable mind? American Journal of Psychiatry 152, 164–172. Petronis, A., Sherrington, R.P., Paterson, A.D., Kennedy, J.L., 1995. Genetic anticipation in schizophrenia: pro and con. Clinical Neuroscience 32, 76–80. Picco, M.F., Goodman, S., Reed, J., Bayless, T.M., 2001. Methodological pitfalls in the determination of genetic anticipation: the case of Crohn disease. Annals of Internal Medicine 134, 1124–1129. Rasmussen, S.A., Eisen, J.L., 1992. The epidemiology and clinical features of obsessive compulsive disorder. Psychiatric Clinics of North America 15, 743–758. Ridley, R.M., Frith, C.D., Crow, T.J., Conneally, P.M., 1988. Anticipation in Huntington’s disease is inherited through the male line but may originate in the female. Journal of Medical Genetics 25, 589–595. Sherman, S.L., Jacobs, P.A., Morton, N.E., Froster-Iskenius, U., Howard-Peebles, P.N., Nielsen, K.B., Partington, N.W., Sutherland, G.R., Turner, G., Watson, M., 1985. Further segregation analysis of the fragile X syndrome with special reference to transmitting males. Human Genetics 68, 289–299. Statsoft, 1993. Statistica for Windows. Author, Tulsa, OK.
Anticipation of age at onset of obsessive-compulsive spectrum disorders in patients with obsessive-compulsive disorder Maria Cristina Cavallini*, Monia Albertazzi, Laura Bianchi, Laura Bellodi Department of Neuropsychiatric Sciences, Universita` Vita-Salute Ospedale San Raffaele, Via Stamira D’Ancona, 20127 Milan, Italy Received 16 May 2001; received in revised form 23 April 2002; accepted 28 May 2002
Abstract Anticipation of age at onset has been observed in several neuropsychiatric disorders. Recent studies have associated anticipation with the presence of unstable DNA and have suggested that trinucleotide repeats may be the main cause in some of these diseases. However, several selection biases may mimic the presence of such an effect. In this study we evaluated the presence of this effect in 40 families of probands with obsessive-compulsive disorder (OCD) compared with affected subjects in the parental generation. We controlled for ascertainment biases by taking into account the age at interview of probands. Using a different recruitment strategy, we controlled for anticipation in a sub-sample of offspring of 13 OCD patients, affected with OC spectrum disorders. While the younger generation showed a significantly earlier age at onset than the parental generation, no effect of age at interview was observed. Drawing on the results, we hypothesised that the presence of anticipation in OCD and OC spectrum disorders could be due to a specific genetic effect (unstable DNA), as it has been hypothesised for other disorders showing this effect. 䊚 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Anticipation; Tic disorders; Imprinting; Unstable DNA; Genetics
1. Introduction The phenomenon of anticipation, i.e. reduced age at onset for a specific disease in offspring generations, has been described for several neurologic and psychiatric diseases wfragile X syndrome (Sherman et al., 1985), Huntington’s disease (Ridley et al., 1988), schizophrenia (Bassett and Honer, *Corresponding author. Tel.: q39-2-2643-3315; fax: q392-2643-3265. E-mail address: [email protected] (M.C. Cavallini).
1994; Gorwood et al., 1996; Ohara et al., 1997). Recently, Ohara et al. (1999) observed the presence of anticipation of age at onset for anxiety disorders in 17 probands affected with anxiety disorders (panic disorder, obsessive-compulsive disorder and other anxiety disorders) when compared with cases in the parental generation. Similarly, Battaglia and colleagues (Battaglia et al., 1998) described a significant decrease of the age at onset of the first panic attack and panic disorder
0165-1781/02/$ - see front matter 䊚 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 1 6 5 - 1 7 8 1 Ž 0 2 . 0 0 1 4 0 - 3
2
M.C. Cavallini et al. / Psychiatry Research 111 (2002) 1–9
from the older to the younger generation in 38 unilineal pedigrees. In some disorders, the presence of anticipation has been associated with the molecular phenomenon of trinucleotide repeats in DNA sequence (Petronis and Kennedy, 1995; Ohara, 2001). The degree of expansion of CAGyCTG and CCGy CGG triplets in the genes has been found to vary across generations of affected families in correlation with clinical symptoms. The increase in the number of trinucleotide repeats correlated with an increase in the severity of the disorder and a decrease of the age at onset in the younger generation, as observed in some monogenic diseases (i.e. Huntington’s disease). Although there is no accepted biological mechanism for genetic anticipation in complex disorders or polygenic diseases, it has been suggested that it can play a role in such illnesses as bipolar disorder, schizophrenia, Crohn’s disease, and rheumatoid arthritis (Picco et al., 2001). Nevertheless, as Penrose pointed out, the determination of a true phenomenon of anticipation represents a burdensome task (Penrose, 1945, 1948). In fact, early onset cases in the offspring generation may be more frequently ascertained, while preferential selection of late-onset parents may often occur because the parents become ill after having children. Furthermore, differential age at interview between parent and child may produce severely biased samples exhibiting apparent anticipation (Heiman et al., 1996). Various techniques have been applied to more accurately control for these biases. Petronis et al. (1995) formulated different strategies to test for the presence of true anticipation, i.e. to compare the age at onset of affected unclesyaunts with the age at onset of probands in the offspring generation. Gorwood et al. (1996) proposed an additional strategy to overcome selection biases in the definition of anticipation of age at onset of schizophrenia. For each patient in the younger generation, they calculated the expected age at onset corresponding to the age at which the patient would become ill if the patient had belonged to the older generation. They then compared the observed vs. the expected age at onset in probands
to determine the presence of true anticipation. This method takes into account the difference between generations in age at interview, and thus controls for the fact that subjects are not interviewed at the same period of their lives across generations. We decided to apply this strategy to our research on obsessive–compulsive disorder (OCD). OCD belongs to a psychopathological spectrum (Hollander and Wong, 1995) of psychiatric disorders with a probable genetic component in its aetiology (Cavallini et al., 1999; Alsobrook et al., 1999; Nestadt et al., 2000a). Several studies have shown that OCD and related disorders have an early onset with a younger age at onset for males compared with females (Rasmussen and Eisen, 1992; Bogetto et al., 1999). Following these results, the purpose of the present study was to control for the presence of anticipation in OCD in families of OCD probands, taking into account potential biases due to sample ascertainment. 2. Materials and methods Forty in- and out-patients affected with OCD (19 male and 21 female) were recruited at the Anxiety Clinical and Research Unit of San Raffaele Hospital in Milan for the treatment of adult patients. All OCD diagnoses were made according to DSM-IV diagnostic criteria (American Psychiatric Association, 1994). Second-degree relatives of the patients (aunts and uncles) were ascertained using the family history method. Only certain diagnoses and clinical information were retained, based on accurate description of symptoms, notice of hospitalisation or medical treatment. To collect the actual sample, 309 families out of 349 initially screened families of patients were discarded because the proband was a sporadic case in the family (175 families) or because information on age at onset for affected relatives was unavailable or transmission of the disease was not unilineal (134 families). Only unilineal families were retained for the present study. Mean age at onset and mean actual age in offspring and parental generations are reported in Table 1 by sex. Regarding the probands excluded from the analysis, in the case of 134 families with
M.C. Cavallini et al. / Psychiatry Research 111 (2002) 1–9
3
Table 1 Characteristics of the selected sample 40 OCD probands
Total
M
F
Mean Mean Mean Mean Mean Mean
30.52"10.33 15.25"7.96 55.79"13.34 27.10"14.61 56.27"12.17 28.20"15.57
28.15"9.75 15.35"8.94 60.10"11.15 21.4"15.65 48.5"9.67 31.5"15.96
32.9"10.58 15.15"7.09 60.71"14.11 30.10"13.49 60.71"11.7 27.42"16.43
actual age age at onset actual age of parents (29) age at onset of parents (29) actual age of unclesyaunts (11) age at onset of unclesyaunts (11)
Table 2 Distribution of diagnosis in the proband generation Diagnosis
Co-diagnoses of probands
tics, Tourette’s syndrome Eating disorder (anorexia) Mood disorders Hypochondriasis Panic disorder
9 1 4 – 8
a positive family history for OCD, the mean age at onset (14.98"6.48) was not significantly different when compared with the mean age at onset of the 40 selected probands (Student’s t-tests 0.653, with 174 d.f. and Ps0.515). In the case of the 175 probands with a negative family history, the mean age at onset (19.43"9.34) was significantly different from that of the selected samples. This observation is in accord with the literature indicating that an early age at onset in probands is associated with a significant increase in familial risk for OCD (Pauls et al., 1995; Nestadt et al., 2000b). Affected parents were directly interviewed and asked for their age at onset by senior psychiatrists who were unaware of the age at onset of probands. The age at onset for OCD was defined as the age at which the obsessive symptoms impaired the patient’s activities ( job, study, etc.), according to
criterion C of DSM-IV and was recognisable by the subject or their relatives. Co-morbid diagnoses of probands and diagnoses in relatives are reported in Table 2. In addition, we recruited and evaluated an additional group of 13 OCD patients who had children affected with OC spectrum disorders. The patients were analysed separately from the previous sample for two reasons: (1) a different ascertainment procedure was used (the proband is one of the two parents) and OCD spectrum disorders were included in the analysis; and (2) the young age of affected children increased the probability that their age at onset would be lower than that of their parents. The characteristics of this sample are summarised in Table 3. The offspring of OCD patients were affected with OCD (one male and three females), or with tics or Tourette’s syndrome (nine males and one female). 2.1. Statistical analysis Differences of age at onset and actual age distributions between males and females in the offspring and in the parental generations were compared by the Mann–Whitney U-test. To evaluate the anticipation phenomenon, the non-parametric Wilcoxon signed rank test was
Table 3 Characteristics of sample of 13 OCD patients with affected children Actual age (years)
Age at onset (years)
Parental diagnosis Obsessive–compulsive disorder
4 Males 48.5"6.24
9 Females 43.22"8.34
4 Males 14.5"4.20
9 Females 20.00"9.06
Offspring diagnosis 13 OCDyticyTourette syndrome
10 Males 14.6"2.11
3 Females 15.66"3.05
10 Males 8.6"1.71
3 Females 13"2
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applied to compare each parental age at onset with the corresponding age at onset in the offspring generation. Furthermore, comparison of onset distributions between all the members of older and younger generations was made by life table analysis (Mantel-Cox test of significance). Regression analysis was used to test if parental age could predict the degree of anticipation. If observed differences were due to regression effects, the hypothesis of anticipation might not be supported. In this case, late onset parents would have earlier onset children, closer to average onset, while early onset parents would have later onset children closer to the average onset. Regression to the mean indicates the presence of a simple linear dependence in which the degree of anticipation gradually decreases with the decreasing parental age at onset. It is possible to control the presence of regression to the mean as applied to anticipation by plotting the difference between age at onset for parents and offspring (DAO) against the age at onset of parents (PAO) and evaluating the relationship. Nevertheless, McInnis et al. (1994) showed that the correlation between x and xyy is significantly high, for any randomly generated set of measurement x and y; moreover, the x intercept corresponding to xyys0 coincides with the mean value of x in the case of the regression to the mean. Therefore, if there is true anticipation, when the intercept on the line of PAO (x values) corresponding to a point 0 of anticipation (xyy) is less than the mean parental age of onset, then the finding is inconsistent with regression to the mean. It is well known that the age at interview may condition age at onset report; therefore we applied the method of proposed by Gorwood et al. (1996), as explained in the introduction, for correcting for this bias. We evaluated for each proband the expected age at onset under the hypothesis that the proband would belong to the parental generation (mean age at onset evaluated in the parental generation at the time when the proband was interviewed). These values were then compared with those observed in the probands. All the analyses were
performed using the Statistica package (Statsoft, 1993). 3. Results 3.1. Sample of 40 OCD probands No significant differences between male and female probands, or between affected male and female parents, were observed for actual age or age at onset (Fig. 1). We observed that the males had an earlier age at onset of obsessive–compulsive spectrum disorders than the females (23.41"15.74 vs. 28.25"14.18 years). In five families (12.5% of the sample) the age at onset for OCD in the parental generation was lower than in the offspring generation, in four families (the 10% of the sample) the age at onset for OCD in the parental generation was equal to that in the offspring generation, while in 31 families the age at onset for OCD in the parental generation was higher than that in the offspring generation. The median age at onset in the offspring generation was also significantly lower than that in the parental generation (Wilcoxon matched pair test zs5.01 and Ps0.000001 after rank correction). Analysis of the life table distributions in parental and offspring generations showed that the offspring developed OCD significantly earlier than the parents (Fig. 2, Mantel-Cox: tests2.384, Ps 0.017). When we considered the phenomenon of the regression to the mean, we found a significant association between PAO and DAO. The regression coefficient for DAO as to PAO was 0.844 (ns40, R 2s0.704, Fs94.08, Ps0.000) (see Fig. 3), with the x intercept for an anticipation value of 0 at 10.86, well below the mean parental age at onset of 25.71"14.67 (no regression to the mean). No difference was observed in DAO between parents and unclesyaunts (mean for 29 parentss 11.72"12.26 vs. 11 unclesyauntss13.09"16.8, ANOVA: Fs0.08, d.f.s1, 38, Ps0.778). There were 26 maternal and 14 paternal transmissions, but no difference in age at onset was
M.C. Cavallini et al. / Psychiatry Research 111 (2002) 1–9
Fig. 1. Age of onset distributions in probands and parental generation.
Fig. 2. Comparison of age at onset between parental and offspring generation.
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Fig. 3. Parental age at onset and differential age at onset.
observed between probands who inherited liability to OCD from their mothers and those who inherited liability to OCD from their fathers (Mann– Whitney test: Us129, zsy1.49, Ps0.133). The age at onset in the older generation was normally distributed with a mean of 27.6"14.70 years. When the expected (21.374"7.006) age at onset in probands was compared with the observed (15.80"8.82) age at onset, following the method proposed by Gorwood et al. (1996), the Wilcoxon matched pairs test yields Zs3.97 and P0.000069. The significant difference between the two indicates that the anticipation effect may be present. 3.2. Sample of 13 OCD probands and their affected offspring The comparison between the age at onset of each offspring with the corresponding parental age at onset produced a significant difference: Wilcoxon matched pairs test: Zs3.18, Ps0.0014. Analysis of the life table distributions in parental and offspring generations showed that the off-
spring developed OCD significantly earlier than the parents (Mantel–Cox tests3.93, Ps0.000) (Fig. 4). There was a significant association between PAO and DAO. The regression coefficient for DAO as to PAO was 0.931 (ns13, R 2s0.89, Fs (1,11)s99.56, d.f.s1,11, P-0.000) with the x intercept 8.69 well below the parental mean age at onset 18.30"8.13 (no regression to the mean). 4. Discussion Our results suggest the presence of anticipation of age at onset in the younger generation with OCD and OC spectrum diseases. Information available to date did not allow us to evaluate whether OCD in the offspring was also more severe than in the parents or the unclesyaunts. Records of hospitalisation of a directly related family member (20% of affected parents) as a criterion for degree of severity revealed that only a few of parents have been hospitalised or showed marked interference in functioning when compared with their offspring. All the probands in fact have
M.C. Cavallini et al. / Psychiatry Research 111 (2002) 1–9
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Fig. 4. Surviving percentage of age at onset in sample of 13 OCD patients and their offspring.
been hospitalised. A potential explanation could be that in older generations fewer cases seek help for psychiatric disorders (75%, frequently treated without specific drug therapy) probably due to the social stigma related to a psychiatric condition. Taking into account the age at interview of probands, which is described as potential bias in these studies, we can confirm the presence of an anticipation effect (Gorwood et al., 1996). Ohara et al. (1999) in their study on the anticipation phenomenon in a sample of families with anxiety disorders (four probands affected with OCD) found that the age at onset decreased in the younger generations. Consistent with their observations, we did not find differences in father-tooffspring and mother-to-offspring transmission, not supporting the presence of imprinting. Frequently, the true age at onset for psychiatric disorders is not easily determined. Patients may not recognise their early symptoms or become aware of them only when they start to cause a marked level of distress. Sometimes the onset of OCD is slow; in cases of chronic illness, patients
(parents, but also probands) may underestimate its true duration. Furthermore, the degree of specificity of clinical information may suggest a spurious anticipation of age at onset. The quality and quantity of clinical information concerning the subjects’ illness vary with the generations as well as with the severity of illness, influencing the definition of true age at onset (Merette et al., 2000). The affected children (OCD or tic disorders) of OCD patients show a decrease in age at onset, although affected offspring of affected parents may have a preferential ascertainment rate (see Penrose biases). For this reason we analysed this sub-group of patients separately. The offspring of OCD patients are frequently affected with tic disorders, that belong to the OC spectrum (Hollander and Wong, 1995). Generally, tics have an earlier onset than OCD. Our clinical experience demonstrates that 53.84% of Tourette syndrome (TS) patients develop OCD (Cavallini et al., 2000), whereas 28–63% of TS patients described in the literature have obsessive-compulsive symptoms. Frequently,
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patients with childhood OCD also have a tic disorder that disappears in adulthood and is not completely recognised by the proband or heryhis parents at the time of the interview. This fact could be related to the problem of the lifetime stability of OCD diagnosis. It would be interesting to follow over time those offspring that affected with a tic at the time of the interview to assess the course of illness. Finally, in our study we found a significant association between DAO (the difference between the parental age at onset and the child’s age at onset) and PAO (parental age at onset) in the analysed samples. It has been described that the presence of ‘regression to the mean’ could be a potential bias (McInnis et al., 1994). Regression to the mean represents the decrease in the degree of anticipation when the age at onset in the parental generation decreases. We controlled for this effect, as suggested by McInnis et al. (1994). The intercept for DAO as to PAO on the ‘x’ axis was less than the mean parental age at onset for the two OCD samples. This finding is inconsistent with regression to the mean in the Galtonian sense of the age at onset of probands. Furthermore, Hodge and Wickramaratne (1995) have proposed that correlation (regression) and anticipation are two distinct phenomena and that regression analysis is not a useful means of detecting ascertainment bias of false anticipation. The genetic meaning of anticipation phenomenon has been widely debated. It has been proposed that anticipation could potentially explain the observed non-Mendelian inheritance patterns in diseases, as it might cause variability in penetrance and gene expression (Hall, 1990). In fact, anticipation has been related to the presence of unstable DNA (Petronis and Kennedy, 1995). To our knowledge, a genetic component may well play some role in the aetiology of OCD and spectrum disorders, but hypotheses derived from molecular genetics are still too weak to identify a gene with a major effect on the development of these disorders. Nevertheless, anticipation in OCD and the hypothetical relationship between this effect and trinucleotide repeats could provide fertile terrain for the exploration of trinucleotide expansion in this group of disorders as well.
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