0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Original Article |

Genetic and Environmental Contributions to the Child Behavior ChecklistObsessive-Compulsive Scale:  A Cross-cultural Twin Study FREE

James J. Hudziak, MD; C. E. M. van Beijsterveldt, PhD; Robert R. Althoff, MD, PhD; Catherine Stanger, PhD; David C. Rettew, MD; Elliot C. Nelson, MD; Richard D. Todd, MD, PhD; Meike Bartels, PhD; Dorret I. Boomsma, PhD
[+] Author Affiliations

From the Department of Psychiatry, University of Vermont, Burlington(Drs Hudziak, Althoff, Stanger, and Rettew); Vrije University, Amsterdam,the Netherlands (Drs van Beijsterveldt, Bartels, and Boomsma); and the Departmentsof Psychiatry and Genetics, Washington University School of Medicine, St Louis,Mo (Drs Nelson and Todd).


Arch Gen Psychiatry. 2004;61(6):608-616. doi:10.1001/archpsyc.61.6.608.
Text Size: A A A
Published online

Context  We have reported elsewhere on the development of an 8-item Obsessive-Compulsive Scale (OCS) contained in the Child Behavior Checklist (CBCL) to identify children who meet criteria for DSM-IV obsessive-compulsive disorder. Twin studies of obsessive-compulsive disorder have indicated a significant genetic component to its expression.

Objective  To determine the relative contributions of genetic and environmental influences on childhood obsessive-compulsive behavior using the CBCL OCS in twin samples.

Design  The CBCL data were received by survey of twins in the Netherlands Twin Registry (NTR) and the Missouri Twin Study (USA/MOTWIN).

Setting  General community twin samples.

Participants  Participants were 4246 twin pairs aged 7 years, 2841 aged 10 years, and 1562 aged 12 years (who also participated in the study at 7 and 10 years of age) from the NTR and 1461 mixed-age twin pairs (average age, approximately 9 years) from the USA/MOTWIN.

Main Outcome Measures  Model fitting to test for genetic and environmental influences, sex differences, and sibling interaction/rater contrast effects on the CBCL OCS.

Results  In each case, the best-fitting model was one that indicated significant additive genetic influences (range, 45%-58%; 95% confidence interval [CI], 45%-61%), and unique environmental influences (range, 42%-55%; 95% CI, 39%-55%), with shared environmental influences in the NTR sample aged 12 years (16%). Sex differences were seen in the mixed-age USA/MOTWIN model, but not in the NTR samples. No evidence of dominance, sibling interaction, or rater-contrast effects was seen. These data were relatively consistent across age and cultures.

Conclusions  The CBCL OCS is influenced by genetic factors (approximately 55%) and unique environmental factors (approximately 45%) in the younger sample, with common environmental influences only at 12 years of age. These effects do not vary with differences in sex or sibling interaction/rater contrast effects. Our data reveal higher genetic influences for obsessive-compulsive behavior and do not demonstrate genetic differences across sex.

Figures in this Article

Obsessive-compulsive disorder (OCD) is common in children and adults.It is associated with serious impairment and, in many cases, has a lifelongcourse. Studies on prevalence indicate that the lifetime rates of OCD in adolescentsrange from 1.9% to 4.1%,16 witha higher prevalence in girls than in boys.7 Thewide variability in prevalence rates may be due to differences in the populationssampled and the methods used for assessment. Nonetheless, the prevalence ofOCD in children and adolescents may be higher than originally thought. Otherreports8 (including unpublished data March2003: J.J.H., R.R.A., C.S., C.E.M.v B., E.C.N., G. L. Hanna, MD, D.I.B., andR.D.T.) have described our development of an 8- item Obsessive-CompulsiveScale (OCS) contained in the Child Behavior Checklist (CBCL) that is usefulin identifying children aged 7 to 12 years who meet criteria for DSM-IV OCD (Table 1). Usinga summed score of 5 (the borderline clinical range, >95th percentile basedon the CBCL normative sample), the CBCL OCS demonstrated high sensitivity(92%), moderate specificity (67%), high negative predictive value (90%), andmoderate positive predictive value (73%) in subjects who had been diagnosedas having DSM-IV OCD by board-certified psychiatrists.Using a higher 98% clinical range, which corresponds to a score of 6, thesensitivity of the test was 79%; specificity was 78.1%; positive predictivevalue was 77.8%; and negative predictive value was 79.4%. In 4 large twinsamples (1 in the United States and 3 in the Netherlands), the percentageof participants with CBCL OCS scores in the borderline clinical range was2.4% to 4.3%, with 1.4% to 3.8% in the clinical range (Table 2).

Table Graphic Jump LocationTable 2. Percentage of Whole Sample Meeting CBCL OCS Cut Points

The purpose of the present study was to extend our previous work anddetermine the contributions of environment, genes, sex, and age to the expressionof CBCL OCS and, by extension, childhood OCD.

The estimation of genetic and environmental influences on a disordertypically includes twin, family, adoption, and molecular genetic approaches.Tsuang et al9 argued that although our moleculargenetic techniques have advanced to the point that identifying genetic variantsthat contribute to the development of a phenotype is now a trivial laboratoryexercise, the development of phenotypic identification strategies that refinediagnoses for molecular genetic investigations remain problematic. This isespecially true in childhood OCD, where relatively few genetic studies havebeen performed. Family and twin studies of OCD are rare relative to the studiesof other psychiatric disorders. Of the OCD studies, many have used small samplesthat were generally derived from highly comorbid clinical populations, witha resultant reduction in the generalizability of the results.10 Despitethese limitations, the belief that OCD is influenced by genetic factors iswidely held; in fact, initial reports on the genetic contributions to OCDare more than 60 years old.11

Family studies to date have revealed conflicting results. The percentageof affected first-degree relatives of patients with OCD has ranged from beingindistinguishable from control subjects12 to30%,13 with several estimates between.1418 ManyOCD studies include patients with other disorders such as Tourette syndromeand other tic disorders. These studies have reported rates of OCD as highas 26% among first-degree relatives of patients with Tourette syndrome, afamilial condition known to have significant genetic influences.19,20 Arecent meta-analysis21 demonstrated an unadjustedaggregate risk of 8.2% in first-degree relatives of patients with OCD vs 2%in relatives of controls. In summary, published family studies support thecontention that OCD, alone or comorbid, is a condition that is influencedby genetic factors.

Twin studies have also demonstrated genetic influences on OCD. Monozygotic(MZ) twins have been shown to have a concordance rate for OCD as high as 70%to 80%, compared with 22% to 47% among dizygotic (DZ) twins.22,23 Heritabilityestimates have been calculated in the range of 26% to 33%.10,24 However,Hettema et al21 were unable to find any twinstudies of adequate size without ascertainment bias to meet their criterionfor inclusion, although they noted that published twin studies had found consistentevidence of genetic contributions to obsessions and compulsions.

Most molecular genetic studies of OCD have focused on the monoaminepathway genes. Numerous molecular genetic studies have aimed to determinethe relative contributions of different candidate genes to the pathophysiologyof OCD. The catechol O-methyltransferase (COMT) gene,2528 theserotonin 2β receptor (5HT2B) gene,29,30 the serotonin transporter gene,31,32 the serotonin 2α receptor (5HT2A) gene,33,34 andthe 7 repeat of the dopamine D4 receptor (DRD4) gene,35 among others, have all beenimplicated in OCD or OCD-like phenotypes, some perhaps in a sex-specific36 or a population-specific27,37 fashion.Other reports have shown the contrary.3840 Ineach of these studies, the authors considered the results preliminary andcalled for studies on much larger populations and more refined samples toclearly understand the contribution of individual gene variations to the etiologyof OCD.

In aggregate, family, twin, and molecular genetics studies support thepremise that OCD or features of OCD are influenced by genetic factors. Mostof these studies did not control for sex, age, referral bias, or comorbidity.Thus, confusion remains about the best way to conceptualize and refine theOCD phenotype for genetic analysis.

There were multiple aims of this study. The first was to determine thegenetic and environmental contributions to CBCL OCS scores. The second wasto determine whether evidence of sex-genetic interactions existed. The thirdwas to determine whether the age of the child contributed to the genetic/environmentalinfluences on CBCL OCS scores by analyzing these data in samples of twinsaged 7, 10, and 12 years and a mixed sample of twins aged 8 to 12 years. Finally,the study assessed cultural differences by determining whether the genetic/environmentalcontributions differed by country (the Netherlands vs the United States).

SUBJECTS AND PROCEDURE
The Netherlands Twin Registry

The study was part of an ongoing twin-family study of health-relatedcharacteristics, personality, and behavior in the Netherlands. The subjectswere all part of the Netherlands Twin Registry (NTR).41 Atpresent, the NTR has data on more than 25 000 twin pairs from ages 3to 30 years. For this study, we assessed a sample of Dutch twin pairs whoseparents reported on their behavior when they were 7, 10, and 12 years of age(NTR-7, NTR-10, and NTR-12 samples, respectively). The total sample with CBCLdata available in the NTR at these age groups at the time of the study included4484, 2905, and 1664 twin pairs aged 7, 10, and 12 years, respectively. Ofthese, 238, 64, and 102 twin pairs, respectively, were excluded owing to missingdata, leaving a total of 4246, 2841, and 1562 twin pairs available for analysisat ages 7, 10, and 12 years, respectively. The socioeconomic status of theparents of the twins was somewhat higher than the level in the general Dutchpopulation.42

The assessment procedures at ages 7, 10, and 12 years have been describedelsewhere.41 Parents received a CBCL by mail.Parents who did not return the forms within 2 months received a reminder.Those who did not respond after 4 months were called by the NTR research assistant.This procedure resulted in an average continued participation rate of 80%from 7 to 10 and 10 to 12 years of age.

Zygosity were determined by means of DNA analyses of blood group polymorphismsfor 634 same-sex twin pairs. For the remaining twins, zygosity was determinedby questionnaire items about physical similarity and frequency of confusionof the twins by family and strangers. The classification of zygosity was basedon a discriminant analysis, relating the questionnaire items to zygosity basedon blood/DNA typing. According to this analysis, the zygosity was correctlyclassified by questionnaire in nearly 95% of the cases.43

Missouri Twin Study Sample

To apply this screening tool to a large sample of twins with differentages and mixed ethnicity, we selected twins from an ongoing project, the MissouriTwin Study (USA/MOTWIN). This sample has been described previously.44 Briefly, an attempt was made to contact parents ofall twins born in Missouri from 1975 to 1991 to invite them to participate.They were paid $5 for completing survey materials. At the time that the geneticanalyses were performed, data on 1461 of 1565 twin pairs who were sent CBCLswere used. One hundred four pairs were excluded because 1 or more of the 8items of the CBCL OCS were missing. The CBCL OCS scores from each of theseremaining twin pairs were computed.

Zygosity was determined by means of questionnaire items as for the NTRsamples, with assignment based on a latent class approach. In a comparisonof genotypic determination of 121 twin pairs, only 1 pair was misassignedusing this method.45

Table 3 provides a descriptionof the numbers of twin pairs by sex and zygosity for the 4 samples. Therewas a small but statistically significant difference in age, with girls slightlyyounger; however, there was no statistical age difference by zygosity group.Although the USA/MOTWIN sample was ethnically mixed (85% European American,13.4% African American, and <1% Hispanic, Asian, or Native American), theNTR samples consisted primarily of children of European descent. The NTR-10sample was a subset of the NTR-7 sample studied 3 years later, and the NTR-12sample was a subset of the NTR-10 sample.

Table Graphic Jump LocationTable 3. Numbers and Ages of Twin Pairs
MEASURES

The CBCL is a widely used questionnaire for parents to respond to 118problem behaviors exhibited by their child during the previous 6 months. Theparent responds along a 3-point scale with the code of 0 if the item is nottrue of the child, 1 for sometimes true, and 2 for often true. The characteristicsand psychometric stability of the CBCL have been well established.46 The analyses performed herein used the 1991 versionof the CBCL, but the same items can be scored on the more recent 2001 version.47

The CBCL OCS was developed using factor analysis on 11 CBCL items thatwere thought to likely predict OCD.8 Usinga 1-factor model, 8 items were retained and were shown to have good internalconsistency (Cronbach α = .84). Those items retained are shown in Table 1, along with their CBCL item number.A numerical value for the CBCL OCS is created by adding the scores on these8 items (0, 1, or 2 for each), thus limiting the scale to a range of 0 to16. The CBCL OCS was tested to determine prevalence, specificity, and sensitivity.9

DATA ANALYSES
Differences in Means

Means, variances, and twin correlations were calculated using Mx.48 Differences in mean scores and variances betweensex and zygosity were tested by means of likelihood ratio c2 tests.These tests were performed taking into account the dependency that existsbetween scores of the twins. Because the CBCL OCS score was not normally distributed,the data were square root transformed to approximate a normal distribution.

Models

Genetic and environmental influences on CBCL OCS scores were computedusing structural equation modeling. The relative contributions of geneticand environmental factors to individual differences in CBCL OCS scores canbe inferred from the different level of genetic relatedness of MZ and DZ twins.49Figure 1 summarizesthe fundamental univariate genetic model that underlies our analyses. Thevariance may be due to additive genetic factors (A), common or shared environmentfactors (C), or nonshared environment effects (E). We also tested for dominancegenetic effects (D), which correlate at 1.0 in MZ twins and 0.25 in DZ twins.Estimating D and C at the same time is not possible in a design using onlyMZ and DZ twins reared together. Using D instead of C in the models did notcontribute to a better fit; thus, D was not examined further. The geneticfactors are correlated at 1.0 in MZ twins, as they are genetically identical.For DZ twins, the additive genetic factors are correlated at 0.5, becauseDZ twins share on average half of their genes. The environment shared by atwin pair is assumed not to depend on zygosity, and thus shared environmentalfactors correlate at 1.0 in both MZ and DZ twins. The E term is by definitionuncorrelated. All uncorrelated error is also absorbed in the E term. The parameters a, c, and e are loadings of the observed phenotype on the latent factors A, C,and E and indicate the degree of relations between the latent factors andthe observed phenotype. The proportion of the variance accounted for by geneticand environmental influences is calculated by squaring the parameters a, c, and e and dividing them by the total variance (a2+c2+e2). In addition, in the univariate model, the effects of sibling interaction(path s) are also considered. Sibling interactionreflects the effect of the behavior of one twin on the behavior of the othertwin. The interaction effect may also be due to bias in parental reports whenparents rate their children's behavior in comparison with each other. Whetherthe sibling interaction effects are a function of rater contrast or of realsibling interaction cannot be tested with the current data, but would needinformation from more than 1 informant. The AE model with sibling interactionwas tested and did not lead to a better fit than the AE model without siblinginteraction, and it was not examined further.

Place holder to copy figure label and caption
figure

Sex-genetic model. Additive genetic factors are correlated at 0.5in dizygotic (DZ) twins, because DZ twins share on average half of their genes,and at 1.0 in monozygotic (MZ) twins. The parameters a, c, and e are loadings of the observed phenotype (P) onthe latent additive genetic factors (A), common or shared environment factors(C), and nonshared environment effects (E) and indicate the degree of relationsbetween the latent factors and the observed P. The proportion of the varianceaccounted for by genetic and environmental influences is calculated by squaringthe parameters a, c, and e and dividingthem by the total variance (a2+c2+e2). In addition, in the univariate model,the effects of sibling interaction (path s) are also considered.Genotype×sex interaction effects (illustrated for the case of unlike-sexsibling pairs) may take the form of sex differences in the magnitude of geneticor environmental influences (paths am, cm, and em vs af, cf, and ef) or the form of an additionalgenetic or common environmental influence on only 1 of the unlike-sex siblingpairs (paths a′ and c′). OCS indicatesObsessive-Compulsive Scale.

Graphic Jump Location

Figure 1 extends the latentvariable component of the model by allowing for genotype×sex interactioneffects (illustrated for the case of unlike-sex sibling pairs). This may takethe form of sex differences in the magnitude of genetic or environmental influences(paths am, cm, and em vs af, cf, and ef) or the form of an additional genetic or common environmentalinfluence on only 1 of the unlike-sex sibling pairs (paths a′ and c′). These analyses allowedus to test for sex differences on CBCL OCS scores.

Model Fitting

To estimate the genetic and environmental contributions, the data fortwins 1 and 2 were summarized into 2 × 2 covariance matrices, computedby PRELIS scientific software.50 All modelfitting was performed with Mx,48 a statisticalsoftware package designed for conducting genetic analyses with an approachthat is standard in structural equation modeling.51 Thebasic model tested was an ACE model. The significance of the A and C factorswas tested by dropping each of these variance components one at a time andusing the c2 difference test. The c2 statistic was computedby subtracting the c2 statistic for the full model from that fora reduced model. The degrees of freedom for this test are equal to the differencesbetween the degrees of freedom for the full and the reduced model. If thec2 statistic is significant, this means that the variance componentmakes a significant contribution to the fit of the full model, because removingit significantly worsens the fit of the model. In addition, the Akaike informationcriterion, a goodness-of-fit index that considers the rule of parsimony, wascalculated. A smaller Akaike information criterion indicates a better fit.We also computed likelihood-based 95% confidence intervals (CIs) for eachparameter.48,52 More technicaldetails of genetic model-fitting analyses are reviewed elsewhere.49

The square root–transformed mean CBCL OCS scores and variancesacross sex and zygosity are presented in Table 4. Raw CBCL OCS scores were quite similar across age and country.The homogeneity of the variance across sex was tested with Mx48 andrevealed significant sex differences for CBCL OCS scores in all 3 samples.In the USA/MOTWIN sample, boys had higher scores; in both Dutch samples, girlshad higher scores. The variance and covariance matrices for all zygosity groupsare given in Table 5. There wereno differences in the means, variances, and covariances across the 5 zygositygroups for the USA/MOTWIN sample and the NTR-10 or NTR-12 samples. In theNTR-7 sample, the means and the variances of the DZ twins were larger thanfor MZ twins (Δc28 = 21.18). As shown in Table 5, although significant, these differenceswere very small.

Table Graphic Jump LocationTable 4. Estimated Square Root–Transformed CBCL OCS Scores
Table Graphic Jump LocationTable 5. Observed Variance-Covariance Matrix for the Square Root–TransformedCBCL OCS Scores*

The twin correlations for the CBCL OCS score are shown in Table 6. Analysis of twin correlations yielded evidence of the influenceof genetic and environmental factors. In all 3 samples, MZ correlations werelarger than DZ correlations, indicating the influences of genes. The MZ andDZ correlations were not different across sex, with 1 exception. The femaleDZ correlation was lower than the male DZ correlation in all samples, butonly significantly so in the USA/MOTWIN sample. In the remaining samples,the magnitude of genetic and environmental effects was equal across sex. Inaddition, the DZ opposite-sex correlations equaled the same-sex male correlationsin all 3 samples, suggesting that the same genes and environmental influencesplay a role for boys and girls.

Table Graphic Jump LocationTable 6. Twin Correlations for Transformed CBCL OCS Syndrome

A summary of the model-fitting results is given in Table 7. The c2 statistic indicates the goodness of fit,and smaller c2 statistics indicate better agreement of the observeddata with the model. First, we computed a model for each sample that allowedthe variance components to differ between boys and girls. In the second setof models, A, C, and E parameters were constrained to be equal across sex.These constrained models were compared with the unconstrained models, andthe best-fitting models were selected. These results showed no deteriorationin fit in the 2 Dutch samples when the parameters were constrained to be thesame across sex. In the USA/MOTWIN sample, this resulted in a worsening ofthe fit (Δc23 = 16.85). This sex difference wasprobably due to differences in total variance between boys and girls seenin this sample only. Next, the significance of the C factor was tested bydropping it from the models and calculating change in the goodness of fit.Dropping C from the model did not lead to a deterioration of the fit in anyof the samples except for the NTR-12, meaning that the AE was the best modelfor all 3 of the other samples, with an ACE model being the best fit for theNTR-12 sample only.

Table Graphic Jump LocationTable 7. Model-Fitting Results for Square Root–Transformed CBCLOCS Scores*
SUMMARY OF MODEL FITTING

The best-fitting model for 3 samples included A and E contributions(Table 7), with C contributionsevident in the NTR-12 sample. There were no sex effects in the Dutch samples,although there were minor sex effects in the USA/MOTWIN sample, likely dueto underlying differences in the means and variances of the CBCL OCS scorein this mixed-aged sample. Across age groups and cultures, the additive geneticinfluence of the CBCL OCS varied from 45% to 58% (95% CI, 45%-61%). The Efactors (which conspire to make members of a twin pair different) ranged from42% to 55% (95% CI, 39%-55%). In the NTR-12 only, the magnitude of the sharedenvironmental influences was about 16%.

With these results, we extend our previous work on the CBCL OCS by revealingthat scores on this proposed scale for assessing childhood OCD are highlyheritable and influenced by additive genetic and unique environmental factorsin younger children, with common environmental influences appearing to playa role beginning at 12 years of age. The magnitude and type of the geneticand environmental influences were surprisingly stable across age, sex, andculture within the younger group, but may differ as the children enter puberty,given the differences reported herein at 12 years of age.

The magnitude of the genetic contribution for each sample is largerthan previous estimates,10,24 whichfell in the range of 26% to 33%. There are several reasons for this difference.First, restriction of range introduced by examining genetic effects on OCDin clinical samples may have attenuated previous estimated genetic contributions.Clinical cases are often more severe, with higher rates of comorbid illnessthat may be influenced by environmental factors that, in concert with geneticrisks, may lead to the expression of OCD (eg, pediatric autoimmune neuropsychiatricdisorders associated with streptococcal infections53).We also used a continuous CBCL OCS score rather than the dichotomous DSM-IV diagnoses used by others. Previous studies haveobserved high rates of subclinical OCD symptoms in family members of OCD probands.By using CBCL OCS scores, we may have better characterized the underlyingtrait.

Second, the environmental contributions for each of the younger samplesare of the unique or unshared type. There are a variety of propositions aboutwhich unique environmental contributions may lead to the expression of OCD,including the presence of autoimmune processes. The unique environmental contributionfound in all 3 samples may explain earlier reports of genetic-environmentalinteraction leading to the expression of OCD. We did not directly test forpediatric autoimmune neuropsychiatric disorders associated with streptococcalinfections in our samples. Other possibilities include differences in parenting,school, activities, etc, as well as error that is part of the E term in structuralequation modeling.

Third, although we did not test for developmental factors (these datawill be reported later once our samples are large enough to follow up childrenacross key developmental periods), it is important to note the similarityof the genetic/environmental contributions to CBCL OCS scores within and acrossthe young age groups. Collapsing twin pairs aged 8 to 12 years into the sameanalyses (ie, the USA/MOTWIN sample), and therefore introducing a possibledevelopmental bias into the analyses, had no effect on the magnitude of thegenetic or environmental contributions, with the possible exception of inflatingthe contribution of sex. However, looking only at the cross-sectional analysisat 12 years of age, shared environmental influences first appear. This maymean that investigation of these same twins in adolescence (a topic for furtherstudy) may help reveal why sex differences change after puberty and why othergenetic studies have shown lower estimates of OCD.

Fourth, no sex-genetic differences were apparent in most of these models,except in the USA/MOTWIN group. This may be due to the inclusion of childrenwho are mostly younger than 12 years. Previous work on the epidemiology ofOCD in children has shown that the prevalence of OCD in children increasesmarkedly after 13 years of age54 and that ashift in prevalence from affecting boys more frequently at a young age toaffecting women more frequently in adulthood likely occurs after 18 yearsof age.55 In our study, we see little, if any,sex difference affecting the heritability of the CBCL OCS scores up to 12years of age. Future research will be directed at the adolescent period todetermine whether sex effects increase during this time of life.

Finally, in studies of psychopathology, there have been notable differencesbetween the European and US psychiatric communities. These include, but arenot limited to, differences in how schizophrenia vs bipolar affective disorderswere conceptualized in the 1950s and 1960s, leading to markedly differentrates of both disorders across continents.56 Morerecently, there have been differences in how children with symptoms of inattention,hyperactivity, and impulsivity were characterized across the two continents.In England, the International Classification of Diseases,Eighth Revision, described hyperkinetic conduct disorder, whereas inthe United States during the same time period, the era of attention-deficit/hyperactivitydisorder was born.57 These across-continentdifferences led to different diagnostic paradigms, different prevalences,and different treatment approaches. Our data on the CBCL OCS provide a nicecontrast. In our previous work, using normative data with the same instrumentin the Netherlands and the United States, we were able to compute rates ofthe prevalence of CBCL OCS in both cultures independent of bias that may emergeby imposing standards of one culture on another (unpublished data March 2003:J.J.H., R.R.A., C.S.,C.E.M.v B., E.C.N., G. L. Hanna, MD, D.I.B., and R.D.T.)We then tested for genetic contributions to a continuous distribution of CBCLOCS scores across both cultures, and essentially found the same results. Whetherthese results apply to clinically diagnosed OCD can only be determined byfuture studies; however, the similarity across age, sex, and culture supportsthe premise that deviance on the CBCL OCS represents a prevalent syndromeand that scores on the CBCL OCS are stable across ages and cultures with asignificant genetic component.

These similar genetic and prevalence data raise another dilemma. Estimatesof the prevalence of attention-deficit/hyperactivity disorder in the UnitedStates range from 3% to 5% in general population studies and are somewhathigher in twin studies.58 Attention-deficit/hyperactivitydisorder is the second most common disorder seen in US child psychiatry clinicsand the most common psychiatric disorder treated by pediatricians.59 If OCD is nearly as common as attention-deficit/hyperactivitydisorder, with prevalence rates in the range of 2% to 4% according to ourstudies, and is highly stable across age and culture, why are so few childrenidentified and treated for this diagnosis? Although our data cannot directlyanswer this question, one possible explanation has to do with the difficultyin screening for and thus diagnosing OCD when using existing OCD diagnosticinstruments. Furthermore, the psychopathology measured by deviance on theOCS may not be impairing enough to parents or teachers to lead to early identificationand referral. As March and colleagues60 havedemonstrated, the obsessional and compulsive characteristics of children withOCD are often not viewed as pathologic by parents or teachers. In fact, manyparents become so familiar with their childrens' symptom complex that theylose the ability to discriminate what is normal vs pathologic. Finally, withthe high and stable heritability estimates that have emerged in this study,together with the family study data that indicate OCD is highly familial,1218 itis also possible that children with OCD are not being identified as havingan illness, because their parents have a similar or the same malady. Thesequestions can be answered only by extending this research to a twin/familydesign. In such a study, twins with deviant scores on the OCS could be enrolledin a twin/family design to test for endophenotypic, genetic, and environmentalcontributions to this disorder. The prevalence and genetic data that haveemerged from our studies suggest that such research should be performed soon,as it is likely that most children with this illness are not being identified,are not receiving treatment, and are suffering in private.

The genetic and environmental contributions presented in this reportreflect CBCL OCS scores, not clinical measures of DSM-IV OCD. Although we have performed prior studies to demonstrate the validity,specificity, sensitivity, and predictive power of the CBCL OCS in relationto DSM-IV OCD, it remains possible that the CBCLOCS may overidentify or underidentify cases in general population samples.One specific set of cases that may be underrepresented is the population ofchildren who may have an alternative manifestation of OCD associated withtics. No item in the CBCL OCS assesses tics. Prospective studies of the CBCLOCS or similar measures with more traditional end-point clinical assessmentsare needed to address this issue. The cutoffs used for the CBCL OCS were 92%sensitive but only 67% specific, resulting in many false-positive findings.The CBCL OCS cut points could be changed, (eg, a score of 7 instead of 6 for10-year-old children), and the scale will become less sensitive and more specific.Higher cut points may be needed for gene-finding expeditions where false-positivefindings are less acceptable.

A further limitation is the fact that parent ratings of the same twinswere included at 7, 10, and 12 years of age. Although this provides us a windowon the genetic and environmental contributions to CBCL OCS at specific ages,it could also introduce an ascertainment bias (ie, why do specific parentsparticipate at each wave and others do not?). A long-term aim of this workis to test developmental stability and change when our sample sizes are largeenough to allow for such analyses. An additional limitation is the relianceon parental report, given the secrecy that is inherent to children's OCD symptoms.61 Although youth self-report may be of questionablevalue, as these children move into adolescence a reassessment of the CBCLOCS using youth-self report will be important.

These data support the contention that childhood obsessive compulsivebehavior is prevalent, influenced by both genetic and environmental factors,and affects children of both genders across the 7- to 12-year age range. Thefindings provide a strategy for using quantitative, gender, and developmentallysensitive screening approaches to identify children at risk for this commonand impairing disorder. Future studies using self-reports from children andadolescents may reveal more sensitive and specific ways to screen for OCDacross the lifespan of an individual.

Corresponding author and reprints: James J. Hudziak, MD, Departmentof Psychiatry, University of Vermont, Given Bldg, Room B229, Burlington, VT05405 (e-mail: james.hudziak@uvm.edu).

Submitted for publication May 1, 2003; final revision received August20, 2003; accepted December 18, 2003.

This study was supported by grants MH58799 and MH52813 from the NationalInstitute of Mental Health, Rockville, Md.

We thank Jeri Ogle for her assistance.

Flament  MFWhitaker  ARapoport  JLDavies  MBerg  CZKalikow  KSceery  WShaffer  D Obsessive compulsive disorder in adolescence: an epidemiological study. J Am Acad Child Adolesc Psychiatry. 1988;27764- 771
PubMed Link to Article
Costello  EJAngold  ABurns  BJStangl  DKTweed  DLErkanli  AWorthman  CM The Great Smoky Mountains Study of Youth: goals, design, methods, andthe prevalence of DSM-III-R disorders. Arch Gen Psychiatry. 1996;531129- 1136
PubMed Link to Article
Zohar  AH The epidemiology of obsessive-compulsive disorder in children and adolescents. Child Adolesc Psychiatr Clin N Am. 1999;8445- 460
PubMed
Karno  MGolding  JMSorenson  SBBurnam  MA The epidemiology of obsessive-compulsive disorder in five US communities. Arch Gen Psychiatry. 1988;451094- 1099
PubMed Link to Article
Kolada  JLBland  RCNewman  SC Epidemiology of psychiatric disorders in Edmonton: obsessive-compulsivedisorder. Acta Psychiatr Scand Suppl. 1994;37624- 35
PubMed Link to Article
Weissman  MMBland  RCCanino  GJGreenwald  SHwu  HGLee  CKNewman  SCOakley-Browne  MARubio-Stipec  MWickramaratne  PJWittchen  HUYeh  EKCross National Collaborative Group, The cross national epidemiology of obsessive compulsive disorder. J Clin Psychiatry. 1994;55suppl5- 10
PubMed
Barkley  RABiederman  J Toward a broader definition of the age-of-onset criterion for attention-deficithyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 1997;361204- 1210
PubMed Link to Article
Edelbrock  CCostello  AJDulcan  MKConover  NCKala  R Parent-child agreement on child psychiatric symptoms assessed via structuredinterview. J Child Psychol Psychiatry. 1986;27181- 190
PubMed Link to Article
Tsuang  MTFaraone  SVLyons  MJ Identification of the phenotype in psychiatric genetics. Eur Arch Psychiatry Clin Neurosci. 1993;243(special issue)131- 142
PubMed Link to Article
Jonnal  AHGardner  COPrescott  CAKendler  KS Obsessive and compulsive symptoms in a general population sample offemale twins. Am J Med Genet. 2000;96791- 796
PubMed Link to Article
Brown  FW Heredity in the psychoneuroses. Proc R Soc Med. 1942;35785- 790
McKeon  PMurray  R Familial aspects of obsessive-compulsive neurosis. Br J Psychiatry. 1987;151528- 534
PubMed Link to Article
Lenane  MCSwedo  SELeonard  HPauls  DLSceery  WRapoport  JL Psychiatric disorders in first degree relatives of children and adolescentswith obsessive compulsive disorder. J Am Acad Child Adolesc Psychiatry. 1990;29407- 412
PubMed Link to Article
Pauls  DLAlsobrook  JP  IIGoodman  WRasmussen  SLeckman  JF A family study of obsessive-compulsive disorder. Am J Psychiatry. 1995;15276- 84
PubMed
Swedo  SERapoport  JLLeonard  HLenane  MCheslow  D Obsessive-compulsive disorder in children and adolescents: clinicalphenomenology of 70 consecutive cases. Arch Gen Psychiatry. 1989;46335- 341
PubMed Link to Article
Black  DWNoyes  R  JrGoldstein  RBBlum  N A family study of obsessive-compulsive disorder. Arch Gen Psychiatry. 1992;49362- 368
PubMed Link to Article
Bellodi  LSciuto  GDiaferia  GRonchi  PSmeraldi  E Psychiatric disorders in the families of patients with obsessive-compulsivedisorder. Psychiatry Res. 1992;42111- 120
PubMed Link to Article
Nestadt  GSamuels  JRiddle  MBienvenu  OJ  IIILiang  KYLaBuda  MWalkup  JGrados  MHoehn-Saric  R A family study of obsessive-compulsive disorder. Arch Gen Psychiatry. 2000;57358- 363
PubMed Link to Article
Pauls  DLRaymond  CLStevenson  JMLeckman  JF A family study of Gilles de la Tourette syndrome. Am J Hum Genet. 1991;48154- 163
PubMed
Pauls  DLTowbin  KELeckman  JFZahner  GECohen  DJ Gilles de la Tourette's syndrome and obsessive-compulsive disorder:evidence supporting a genetic relationship. Arch Gen Psychiatry. 1986;431180- 1182
PubMed Link to Article
Hettema  JMNeale  MCKendler  KS A review and meta-analysis of the genetic epidemiology of anxiety disorders. Am J Psychiatry. 2001;1581568- 1578
PubMed Link to Article
Inouye  E Similar and dissimilar manifestations of obsessive-compulsive neurosisin monozygotic twins. Am J Psychiatry. 1965;1211171- 1175
PubMed
Carey  GGottesman  II Twin and family studies of anxiety, phobia, and obsessive-compulsivedisorder. Klein  DRabkin  Jeds.Anxiety: New Researchand Changing Concepts. New York, NY Raven Press1981;117- 136
Andrews  GStewart  GAllen  RHenderson  AS The genetics of six neurotic disorders: a twin study. J Affect Disord. 1990;1923- 29
PubMed Link to Article
Karayiorgou  MSobin  CBlundell  MLGalke  BLMalinova  LGoldberg  POtt  JGogos  JA Family-based association studies support a sexually dimorphic effectof COMT and MAOA on genetic susceptibility to obsessive-compulsive disorder. Biol Psychiatry. 1999;451178- 1189
PubMed Link to Article
Karayiorgou  MAltemus  MGalke  BLGoldman  DMurphy  DLOtt  JGogos  JA Genotype determining low catechol-O-methyltransferaseactivity as a risk factor for obsessive-compulsive disorder. Proc Natl Acad Sci U S A. 1997;944572- 4575
PubMed Link to Article
Niehaus  DJKinnear  CJCorfield  VAdu Toit  PLvan Kradenburg  JMoolman-Smook  JCWeyers  JBPotgieter  ASeedat  SEmsley  RAKnowles  JABrink  PAStein  DJ Association between a catechol-O-methyltransferasepolymorphism and obsessive-compulsive disorder in the Afrikaner population. J Affect Disord. 2001;6561- 65
PubMed Link to Article
Schindler  KMRichter  MAKennedy  JLPato  MTPato  CN Association between homozygosity at the COMT gene locus and obsessivecompulsive disorder. Am J Med Genet. 2000;96721- 724
PubMed Link to Article
Kim  SJVeenstra-VanderWeele  JHanna  GLGonen  DLeventhal  BLCook  EH  Jr Mutation screening of human 5-HT(2B)receptor gene in early-onset obsessive-compulsivedisorder. Mol Cell Probes. 2000;1447- 52
PubMed Link to Article
Mundo  ERichter  MAZai  GSam  FMcBride  JMacciardi  FKennedy  JL 5HT1Dβ receptor gene implicated in the pathogenesis of obsessive-compulsivedisorder: further evidence from a family-based association study. Mol Psychiatry. 2002;7805- 809
PubMed Link to Article
Hanna  GLHimle  JACurtis  GCKoram  DQVeenstra-VanderWeele  JLeventhal  BLCook  EH  Jr Serotonin transporter and seasonal variation in blood serotonin infamilies with obsessive-compulsive disorder. Neuropsychopharmacology. 1998;18102- 111
PubMed Link to Article
Rosenberg  DRHanna  GL Genetic and imaging strategies in obsessive-compulsive disorder: potentialimplications for treatment development. Biol Psychiatry. 2000;481210- 1222
PubMed Link to Article
Mundo  ERichter  MASam  FMacciardi  FKennedy  JL Is the 5-HT(1Dβ) receptor gene implicated in the pathogenesisof obsessive-compulsive disorder? Am J Psychiatry. 2000;1571160- 1161
PubMed Link to Article
Walitza  SWewetzer  CWarnke  AGerlach  MGeller  FGerber  GGorg  THerpertz-Dahlmann  BSchulz  ERemschmidt  HHebebrand  JHinney  A 5-HT2A promoter polymorphism-1438G/A in children and adolescents withobsessive-compulsive disorders. Mol Psychiatry. 2002;71054- 1057
PubMed Link to Article
Cruz  CCamarena  BKing  NPaez  FSidenberg  Dde la Fuente  JRNicolini  H Increased prevalence of the seven-repeat variant of the dopamine D4receptor gene in patients with obsessive-compulsive disorder with tics. Neurosci Lett. 1997;2311- 4
PubMed Link to Article
Alsobrook  JP  IIZohar  AHLeboyer  MChabane  NEbstein  RPPauls  DL Association between the COMT locus and obsessive-compulsive disorderin females but not males. Am J Med Genet. 2002;114116- 120
PubMed Link to Article
Ohara  KNagai  MSuzuki  YOchiai  MOhara  K No association between anxiety disorders and catechol-O-methyltransferase polymorphism. Psychiatry Res. 1998;80145- 148
PubMed Link to Article
Kinnear  CNiehaus  DJSeedat  SMoolman-Smook  JCCorfield  VAMalherbe  GPotgieter  ALombard  CStein  DJ Obsessive-compulsive disorder and a novel polymorphism adjacent tothe oestrogen response element (ERE 6) upstream from the COMT gene. Psychiatr Genet. 2001;1185- 87
PubMed Link to Article
Cavallini  MCDi Bella  DCatalano  MBellodi  L An association study between 5-HTTLPR polymorphism, COMT polymorphism,and Tourette's syndrome. Psychiatry Res. 2000;9793- 100
PubMed Link to Article
Di Bella  DCavallini  MCBellodi  L No association between obsessive-compulsive disorder and the 5-HT(1Dβ)receptor gene. Am J Psychiatry. 2002;1591783- 1785
PubMed Link to Article
Boomsma  DVink  JBeijsterveldt  Cde Geus  EBeem  AMulder  ERiese  HWillemsen  ABartels  Mvan den Berg  MDerks  EGSKupper  HPolderman  JRietveld  MStubbe  JKnol  LStroet  TBaal  G Netherlands Twin Register: a focus on longitudinal research. Twin Res. 2002;5401- 406
PubMed Link to Article
Rietveld  MJHHudziak  JABartels  Mvan Beijsterveldt  CEMBoomsma  DI Heritability of attention problems in children, I: cross-sectionalresults from a study of twins, age 3-12 years. Am J Med Genet. 2003;117B102- 113
PubMed Link to Article
Rietveld  MJvan Der Valk  JCBongers  ILStroet  TMSlagboom  PEBoomsma  DI Zygosity diagnosis in young twins by parental report. Twin Res. 2000;3134- 141
PubMed Link to Article
Hudziak  JJHeath  ACMadden  PFReich  WBucholz  KKSlutske  WBierut  LJNeuman  RJTodd  RD Latent class and factor analysis of DSM-IV ADHD:a twin study of female adolescents. J Am Acad Child Adolesc Psychiatry. 1998;37848- 857
PubMed Link to Article
Heath  ACNyholt  DRNeuman  RMadden  PABucholz  KKTodd  RDNelson  ECMontgomery  GWMartin  NG Zygosity diagnosis in the absence of genotypic data: an approach usinglatent class analysis. Twin Res. 2003;622- 26
PubMed Link to Article
Achenbach  TM Manual for the Child Behavior Checklist/4-18 and1991 Profile.  Burlington Dept of Psychiatry, University of Vermont1991;
Achenbach  TMRescorla  LA Manual for the ASEBA School-Age Forms & Profiles.  Burlington Research Center for Children, Youth, & Families,University of Vermont2001;
Neale  MC Mx: Statistical Modeling.  Richmond Dept of Psychiatry, Medical College of Virginia1997;
Neale  MCCardon  LRNorth Atlantic Treaty Organization, Scientific Affairs Division, Methodology for Genetic Studies of Twins and Families.  Norwell, Mass Kluwer Academic Publishers1992;xxv496
Jöreskog  KGSörbom  DI PRELIS: A Preprocessor for LISREL.  Mooresville, Ind Scientific Software1998;
Bollen  Ked Structural Equations With Latent Variables.  New York, NY John Wiley & Sons Inc1989;
Neale  MCMiller  MB The use of likelihood-based confidence intervals in genetic models. Behav Genet. 1997;27113- 120
PubMed Link to Article
Swedo  SELeonard  HLGarvey  MMittleman  BAllen  AJPerlmutter  SLougee  LDow  SZamkoff  JDubbert  BK Pediatric autoimmune neuropsychiatric disorders associated with streptococcalinfections: clinical description of the first 50 cases. Am J Psychiatry. 1998;155264- 271
PubMed
Heyman  IFombonne  ESimmons  HFord  TMeltzer  HGoodman  R Prevalence of obsessive-compulsive disorder in the British nationwidesurvey of child mental health. Br J Psychiatry. 2001;179324- 329
PubMed Link to Article
Fireman  BKoran  LMLeventhal  JLJacobson  A The prevalence of clinically recognized obsessive-compulsive disorderin a large health maintenance organization. Am J Psychiatry. 2001;1581904- 1910
PubMed Link to Article
Kendell  RE Psychiatric diagnosis in Britain and the United States. Br J Psychiatry. 1975;Spec No 9453- 461
PubMed
Prendergast  MTaylor  ERapoport  JLBartko  JDonnelly  MZametkin  AAhearn  MBDunn  GWieselberg  HM The diagnosis of childhood hyperactivity: a US-UK cross-national studyof DSM-III and ICD-9. J Child Psychol Psychiatry. 1988;29289- 300
PubMed Link to Article
Hudziak  JJRudiger  LPNeale  MCHeath  ACTodd  RC A twin study of inattentive, aggressive, and anxious/depressed behaviors. J Am Acad Child Adolesc Psychiatry. 2000;39469- 476
PubMed Link to Article
Brown  RTFreeman  WSPerrin  JMStein  MTAmler  RWFeldman  HMPierce  KWolraich  ML Prevalence and assessment of attention-deficit/hyperactivity disorderin primary care settings. Pediatrics. 2001;107E43
PubMed Link to Article
March  JSMulle  KHerbel  B Behavioral psychotherapy for children and adolescents with obsessive-compulsivedisorder: an open trial of a new protocol-driven treament package. J Am Acad Child Adolesc Psychiatry. 1994;33333- 341
PubMed Link to Article
Rapoport  JLInoff-Germain  GWeissman  MMGreenwald  SNarrow  WEJensen  PSLahey  BBCanino  G Childhood obsessive-compulsive disorder in the NIMH MECA study: parentversus child identification of cases: methods for the Epidemiology of Childand Adolescent Mental Disorders. J Anxiety Disord. 2000;14535- 548
PubMed Link to Article

Figures

Place holder to copy figure label and caption
figure

Sex-genetic model. Additive genetic factors are correlated at 0.5in dizygotic (DZ) twins, because DZ twins share on average half of their genes,and at 1.0 in monozygotic (MZ) twins. The parameters a, c, and e are loadings of the observed phenotype (P) onthe latent additive genetic factors (A), common or shared environment factors(C), and nonshared environment effects (E) and indicate the degree of relationsbetween the latent factors and the observed P. The proportion of the varianceaccounted for by genetic and environmental influences is calculated by squaringthe parameters a, c, and e and dividingthem by the total variance (a2+c2+e2). In addition, in the univariate model,the effects of sibling interaction (path s) are also considered.Genotype×sex interaction effects (illustrated for the case of unlike-sexsibling pairs) may take the form of sex differences in the magnitude of geneticor environmental influences (paths am, cm, and em vs af, cf, and ef) or the form of an additionalgenetic or common environmental influence on only 1 of the unlike-sex siblingpairs (paths a′ and c′). OCS indicatesObsessive-Compulsive Scale.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 2. Percentage of Whole Sample Meeting CBCL OCS Cut Points
Table Graphic Jump LocationTable 3. Numbers and Ages of Twin Pairs
Table Graphic Jump LocationTable 4. Estimated Square Root–Transformed CBCL OCS Scores
Table Graphic Jump LocationTable 5. Observed Variance-Covariance Matrix for the Square Root–TransformedCBCL OCS Scores*
Table Graphic Jump LocationTable 6. Twin Correlations for Transformed CBCL OCS Syndrome
Table Graphic Jump LocationTable 7. Model-Fitting Results for Square Root–Transformed CBCLOCS Scores*

References

Flament  MFWhitaker  ARapoport  JLDavies  MBerg  CZKalikow  KSceery  WShaffer  D Obsessive compulsive disorder in adolescence: an epidemiological study. J Am Acad Child Adolesc Psychiatry. 1988;27764- 771
PubMed Link to Article
Costello  EJAngold  ABurns  BJStangl  DKTweed  DLErkanli  AWorthman  CM The Great Smoky Mountains Study of Youth: goals, design, methods, andthe prevalence of DSM-III-R disorders. Arch Gen Psychiatry. 1996;531129- 1136
PubMed Link to Article
Zohar  AH The epidemiology of obsessive-compulsive disorder in children and adolescents. Child Adolesc Psychiatr Clin N Am. 1999;8445- 460
PubMed
Karno  MGolding  JMSorenson  SBBurnam  MA The epidemiology of obsessive-compulsive disorder in five US communities. Arch Gen Psychiatry. 1988;451094- 1099
PubMed Link to Article
Kolada  JLBland  RCNewman  SC Epidemiology of psychiatric disorders in Edmonton: obsessive-compulsivedisorder. Acta Psychiatr Scand Suppl. 1994;37624- 35
PubMed Link to Article
Weissman  MMBland  RCCanino  GJGreenwald  SHwu  HGLee  CKNewman  SCOakley-Browne  MARubio-Stipec  MWickramaratne  PJWittchen  HUYeh  EKCross National Collaborative Group, The cross national epidemiology of obsessive compulsive disorder. J Clin Psychiatry. 1994;55suppl5- 10
PubMed
Barkley  RABiederman  J Toward a broader definition of the age-of-onset criterion for attention-deficithyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 1997;361204- 1210
PubMed Link to Article
Edelbrock  CCostello  AJDulcan  MKConover  NCKala  R Parent-child agreement on child psychiatric symptoms assessed via structuredinterview. J Child Psychol Psychiatry. 1986;27181- 190
PubMed Link to Article
Tsuang  MTFaraone  SVLyons  MJ Identification of the phenotype in psychiatric genetics. Eur Arch Psychiatry Clin Neurosci. 1993;243(special issue)131- 142
PubMed Link to Article
Jonnal  AHGardner  COPrescott  CAKendler  KS Obsessive and compulsive symptoms in a general population sample offemale twins. Am J Med Genet. 2000;96791- 796
PubMed Link to Article
Brown  FW Heredity in the psychoneuroses. Proc R Soc Med. 1942;35785- 790
McKeon  PMurray  R Familial aspects of obsessive-compulsive neurosis. Br J Psychiatry. 1987;151528- 534
PubMed Link to Article
Lenane  MCSwedo  SELeonard  HPauls  DLSceery  WRapoport  JL Psychiatric disorders in first degree relatives of children and adolescentswith obsessive compulsive disorder. J Am Acad Child Adolesc Psychiatry. 1990;29407- 412
PubMed Link to Article
Pauls  DLAlsobrook  JP  IIGoodman  WRasmussen  SLeckman  JF A family study of obsessive-compulsive disorder. Am J Psychiatry. 1995;15276- 84
PubMed
Swedo  SERapoport  JLLeonard  HLenane  MCheslow  D Obsessive-compulsive disorder in children and adolescents: clinicalphenomenology of 70 consecutive cases. Arch Gen Psychiatry. 1989;46335- 341
PubMed Link to Article
Black  DWNoyes  R  JrGoldstein  RBBlum  N A family study of obsessive-compulsive disorder. Arch Gen Psychiatry. 1992;49362- 368
PubMed Link to Article
Bellodi  LSciuto  GDiaferia  GRonchi  PSmeraldi  E Psychiatric disorders in the families of patients with obsessive-compulsivedisorder. Psychiatry Res. 1992;42111- 120
PubMed Link to Article
Nestadt  GSamuels  JRiddle  MBienvenu  OJ  IIILiang  KYLaBuda  MWalkup  JGrados  MHoehn-Saric  R A family study of obsessive-compulsive disorder. Arch Gen Psychiatry. 2000;57358- 363
PubMed Link to Article
Pauls  DLRaymond  CLStevenson  JMLeckman  JF A family study of Gilles de la Tourette syndrome. Am J Hum Genet. 1991;48154- 163
PubMed
Pauls  DLTowbin  KELeckman  JFZahner  GECohen  DJ Gilles de la Tourette's syndrome and obsessive-compulsive disorder:evidence supporting a genetic relationship. Arch Gen Psychiatry. 1986;431180- 1182
PubMed Link to Article
Hettema  JMNeale  MCKendler  KS A review and meta-analysis of the genetic epidemiology of anxiety disorders. Am J Psychiatry. 2001;1581568- 1578
PubMed Link to Article
Inouye  E Similar and dissimilar manifestations of obsessive-compulsive neurosisin monozygotic twins. Am J Psychiatry. 1965;1211171- 1175
PubMed
Carey  GGottesman  II Twin and family studies of anxiety, phobia, and obsessive-compulsivedisorder. Klein  DRabkin  Jeds.Anxiety: New Researchand Changing Concepts. New York, NY Raven Press1981;117- 136
Andrews  GStewart  GAllen  RHenderson  AS The genetics of six neurotic disorders: a twin study. J Affect Disord. 1990;1923- 29
PubMed Link to Article
Karayiorgou  MSobin  CBlundell  MLGalke  BLMalinova  LGoldberg  POtt  JGogos  JA Family-based association studies support a sexually dimorphic effectof COMT and MAOA on genetic susceptibility to obsessive-compulsive disorder. Biol Psychiatry. 1999;451178- 1189
PubMed Link to Article
Karayiorgou  MAltemus  MGalke  BLGoldman  DMurphy  DLOtt  JGogos  JA Genotype determining low catechol-O-methyltransferaseactivity as a risk factor for obsessive-compulsive disorder. Proc Natl Acad Sci U S A. 1997;944572- 4575
PubMed Link to Article
Niehaus  DJKinnear  CJCorfield  VAdu Toit  PLvan Kradenburg  JMoolman-Smook  JCWeyers  JBPotgieter  ASeedat  SEmsley  RAKnowles  JABrink  PAStein  DJ Association between a catechol-O-methyltransferasepolymorphism and obsessive-compulsive disorder in the Afrikaner population. J Affect Disord. 2001;6561- 65
PubMed Link to Article
Schindler  KMRichter  MAKennedy  JLPato  MTPato  CN Association between homozygosity at the COMT gene locus and obsessivecompulsive disorder. Am J Med Genet. 2000;96721- 724
PubMed Link to Article
Kim  SJVeenstra-VanderWeele  JHanna  GLGonen  DLeventhal  BLCook  EH  Jr Mutation screening of human 5-HT(2B)receptor gene in early-onset obsessive-compulsivedisorder. Mol Cell Probes. 2000;1447- 52
PubMed Link to Article
Mundo  ERichter  MAZai  GSam  FMcBride  JMacciardi  FKennedy  JL 5HT1Dβ receptor gene implicated in the pathogenesis of obsessive-compulsivedisorder: further evidence from a family-based association study. Mol Psychiatry. 2002;7805- 809
PubMed Link to Article
Hanna  GLHimle  JACurtis  GCKoram  DQVeenstra-VanderWeele  JLeventhal  BLCook  EH  Jr Serotonin transporter and seasonal variation in blood serotonin infamilies with obsessive-compulsive disorder. Neuropsychopharmacology. 1998;18102- 111
PubMed Link to Article
Rosenberg  DRHanna  GL Genetic and imaging strategies in obsessive-compulsive disorder: potentialimplications for treatment development. Biol Psychiatry. 2000;481210- 1222
PubMed Link to Article
Mundo  ERichter  MASam  FMacciardi  FKennedy  JL Is the 5-HT(1Dβ) receptor gene implicated in the pathogenesisof obsessive-compulsive disorder? Am J Psychiatry. 2000;1571160- 1161
PubMed Link to Article
Walitza  SWewetzer  CWarnke  AGerlach  MGeller  FGerber  GGorg  THerpertz-Dahlmann  BSchulz  ERemschmidt  HHebebrand  JHinney  A 5-HT2A promoter polymorphism-1438G/A in children and adolescents withobsessive-compulsive disorders. Mol Psychiatry. 2002;71054- 1057
PubMed Link to Article
Cruz  CCamarena  BKing  NPaez  FSidenberg  Dde la Fuente  JRNicolini  H Increased prevalence of the seven-repeat variant of the dopamine D4receptor gene in patients with obsessive-compulsive disorder with tics. Neurosci Lett. 1997;2311- 4
PubMed Link to Article
Alsobrook  JP  IIZohar  AHLeboyer  MChabane  NEbstein  RPPauls  DL Association between the COMT locus and obsessive-compulsive disorderin females but not males. Am J Med Genet. 2002;114116- 120
PubMed Link to Article
Ohara  KNagai  MSuzuki  YOchiai  MOhara  K No association between anxiety disorders and catechol-O-methyltransferase polymorphism. Psychiatry Res. 1998;80145- 148
PubMed Link to Article
Kinnear  CNiehaus  DJSeedat  SMoolman-Smook  JCCorfield  VAMalherbe  GPotgieter  ALombard  CStein  DJ Obsessive-compulsive disorder and a novel polymorphism adjacent tothe oestrogen response element (ERE 6) upstream from the COMT gene. Psychiatr Genet. 2001;1185- 87
PubMed Link to Article
Cavallini  MCDi Bella  DCatalano  MBellodi  L An association study between 5-HTTLPR polymorphism, COMT polymorphism,and Tourette's syndrome. Psychiatry Res. 2000;9793- 100
PubMed Link to Article
Di Bella  DCavallini  MCBellodi  L No association between obsessive-compulsive disorder and the 5-HT(1Dβ)receptor gene. Am J Psychiatry. 2002;1591783- 1785
PubMed Link to Article
Boomsma  DVink  JBeijsterveldt  Cde Geus  EBeem  AMulder  ERiese  HWillemsen  ABartels  Mvan den Berg  MDerks  EGSKupper  HPolderman  JRietveld  MStubbe  JKnol  LStroet  TBaal  G Netherlands Twin Register: a focus on longitudinal research. Twin Res. 2002;5401- 406
PubMed Link to Article
Rietveld  MJHHudziak  JABartels  Mvan Beijsterveldt  CEMBoomsma  DI Heritability of attention problems in children, I: cross-sectionalresults from a study of twins, age 3-12 years. Am J Med Genet. 2003;117B102- 113
PubMed Link to Article
Rietveld  MJvan Der Valk  JCBongers  ILStroet  TMSlagboom  PEBoomsma  DI Zygosity diagnosis in young twins by parental report. Twin Res. 2000;3134- 141
PubMed Link to Article
Hudziak  JJHeath  ACMadden  PFReich  WBucholz  KKSlutske  WBierut  LJNeuman  RJTodd  RD Latent class and factor analysis of DSM-IV ADHD:a twin study of female adolescents. J Am Acad Child Adolesc Psychiatry. 1998;37848- 857
PubMed Link to Article
Heath  ACNyholt  DRNeuman  RMadden  PABucholz  KKTodd  RDNelson  ECMontgomery  GWMartin  NG Zygosity diagnosis in the absence of genotypic data: an approach usinglatent class analysis. Twin Res. 2003;622- 26
PubMed Link to Article
Achenbach  TM Manual for the Child Behavior Checklist/4-18 and1991 Profile.  Burlington Dept of Psychiatry, University of Vermont1991;
Achenbach  TMRescorla  LA Manual for the ASEBA School-Age Forms & Profiles.  Burlington Research Center for Children, Youth, & Families,University of Vermont2001;
Neale  MC Mx: Statistical Modeling.  Richmond Dept of Psychiatry, Medical College of Virginia1997;
Neale  MCCardon  LRNorth Atlantic Treaty Organization, Scientific Affairs Division, Methodology for Genetic Studies of Twins and Families.  Norwell, Mass Kluwer Academic Publishers1992;xxv496
Jöreskog  KGSörbom  DI PRELIS: A Preprocessor for LISREL.  Mooresville, Ind Scientific Software1998;
Bollen  Ked Structural Equations With Latent Variables.  New York, NY John Wiley & Sons Inc1989;
Neale  MCMiller  MB The use of likelihood-based confidence intervals in genetic models. Behav Genet. 1997;27113- 120
PubMed Link to Article
Swedo  SELeonard  HLGarvey  MMittleman  BAllen  AJPerlmutter  SLougee  LDow  SZamkoff  JDubbert  BK Pediatric autoimmune neuropsychiatric disorders associated with streptococcalinfections: clinical description of the first 50 cases. Am J Psychiatry. 1998;155264- 271
PubMed
Heyman  IFombonne  ESimmons  HFord  TMeltzer  HGoodman  R Prevalence of obsessive-compulsive disorder in the British nationwidesurvey of child mental health. Br J Psychiatry. 2001;179324- 329
PubMed Link to Article
Fireman  BKoran  LMLeventhal  JLJacobson  A The prevalence of clinically recognized obsessive-compulsive disorderin a large health maintenance organization. Am J Psychiatry. 2001;1581904- 1910
PubMed Link to Article
Kendell  RE Psychiatric diagnosis in Britain and the United States. Br J Psychiatry. 1975;Spec No 9453- 461
PubMed
Prendergast  MTaylor  ERapoport  JLBartko  JDonnelly  MZametkin  AAhearn  MBDunn  GWieselberg  HM The diagnosis of childhood hyperactivity: a US-UK cross-national studyof DSM-III and ICD-9. J Child Psychol Psychiatry. 1988;29289- 300
PubMed Link to Article
Hudziak  JJRudiger  LPNeale  MCHeath  ACTodd  RC A twin study of inattentive, aggressive, and anxious/depressed behaviors. J Am Acad Child Adolesc Psychiatry. 2000;39469- 476
PubMed Link to Article
Brown  RTFreeman  WSPerrin  JMStein  MTAmler  RWFeldman  HMPierce  KWolraich  ML Prevalence and assessment of attention-deficit/hyperactivity disorderin primary care settings. Pediatrics. 2001;107E43
PubMed Link to Article
March  JSMulle  KHerbel  B Behavioral psychotherapy for children and adolescents with obsessive-compulsivedisorder: an open trial of a new protocol-driven treament package. J Am Acad Child Adolesc Psychiatry. 1994;33333- 341
PubMed Link to Article
Rapoport  JLInoff-Germain  GWeissman  MMGreenwald  SNarrow  WEJensen  PSLahey  BBCanino  G Childhood obsessive-compulsive disorder in the NIMH MECA study: parentversus child identification of cases: methods for the Epidemiology of Childand Adolescent Mental Disorders. J Anxiety Disord. 2000;14535- 548
PubMed Link to Article

Correspondence

CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 66

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections