Segregation Analysis of Obsessive-CompulsiveDisorder Using Symptom-Based Factor Scores

John P. Alsobrook II,1* James F. Leckman,1,2 Wayne K. Goodman,3 Steven A. Rasmussen,4 andDavid L. Pauls1,5

1Child Study Center, Yale University School of Medicine, New Haven, Connecticut2Departments of Psychiatry and Pediatrics, Yale University School of Medicine, New Haven, Connecticut3Department of Psychiatry, University of Florida College of Medicine, Gainesville, Florida4Department of Psychiatry, Butler Hospital, Brown University School of Medicine, Providence, Rhode Island5Department of Psychology, Yale University, New Haven, Connecticut

Obsessive-compulsive disorder (OCD) is acomplex psychiatric disorder characterizedby recurring obsessions or compulsions thatcause significant distress to the patient orsignificantly interfere with the patient’snormal home, work, or social activities [Di-agnostic and Statistical Manual of MentalDisorders, 4th Edition. Washington, DC:American Psychiatric Association, 1994].Twin and family studies have suggested thatOCD has a significant genetic component.We performed complex segregation analy-ses using POINTER with families ascer-tained through an OCD-affected proband. Inan attempt to resolve the phenotypic het-erogeneity observed among individualswith OCD these segregation analyses usedfour factor-analytic symptom dimensions tosubset the family sample based upon pro-bands’ symptom factor scores. Analysis ofthe entire sample allowed rejection of onlythe no transmission model; that model wasalso rejected in all subsequent analyses.Limiting the analyses to families with atleast one OCD-affected member in additionto the proband (the demonstrably familialform of OCD) allowed rejection of all modelsexcept the mixed model. Analyses limited tofamilies of high-factor-3 (symmetry and or-dering symptoms) probands led to rejectionof the polygenic model, indicating the in-volvement of a major locus. Additionally,the relative risk of OCD or subclinical OCDwas 1.7 for relatives of probands with a fac-

tor 3 score greater than zero compared withrelatives of probands with a low factorscore. The symptoms attributed to high fac-tor 3 scores (symmetry and ordering) mayconstitute a genetically significant symp-tomatic subtype of OCD. Am. J. Med. Genet.(Neuropsychiatr. Genet.) 88:669–675, 1999.© 1999 Wiley-Liss, Inc.

KEY WORDS: segregation analysis; factoranalysis; genetic heterogene-ity

INTRODUCTION

Obsessive-compulsive disorder (OCD) is estimated toaffect nearly 5 million U.S. citizens [Karno et al., 1988]with a resultant annual impact on the United Stateseconomy of $8.4 billion [DuPont et al., 1995], making ita public health issue of national scope; OCD has beencalled a hidden epidemic [Jenike, 1989]. Although re-search on the biology and treatment of OCD has in-creased greatly during the past decade, the etiology ofthis disorder remains largely unknown.

The key diagnostic feature of OCD in the Diagnosticand Statistical Manual of Mental Disorders, 4th Edi-tion (DSM-IV) [American Psychiatric Association,1994] is recurring obsessions or compulsions, with ad-ditional criteria based on how the patient experiencesthe thoughts or impulses. Obsessions are defined aspersistent thoughts, ideas, impulses, or images thatare initially experienced as intrusive and senseless.Compulsions are a physical corollary to obsessions;they are intentional, repetitive behaviors that are per-formed in response to obsessive thoughts, or in somestereotyped manner.

Twin and family studies have provided evidence forthe importance of genetic factors in the manifestationof OCD (reviewed in Alsobrook and Pauls [1997]). Datafrom the majority of studies completed over the past 60years suggest that OCD is familial; rates of illnessamong relatives reported in recent family studies also

Contract grant sponsor: NIH; Contract grant numbers: RO1ND16648, RSA MH00508, PO1 MH49351; Contract grant spon-sor: NARSAD.

*Correspondence to: John P. Alsobrook II, Ph.D., Yale ChildStudy Center / SHM I-274, 230 S. Frontage Rd., P.O. Box 207900,New Haven, CT 06520-7900. E-mail: john.alsobrook@yale.edu

Received 15 July 1998; Accepted 11 March 1999

American Journal of Medical Genetics (Neuropsychiatric Genetics) 88:669–675 (1999)

© 1999 Wiley-Liss, Inc.

demonstrate that OCD is familial [Lenane et al., 1990;Bellodi et al., 1992; Black et al., 1992; Pauls et al.,1995]. Rasmussen and Tsuang [1986] summarized theextant twin study literature before 1986 and reportedthat the concordance rates ranged from 53% to 87% formonozygotic twins and from 22% to 47% for dizygotictwins depending on the sample and the diagnostic cri-teria. Cumulatively, these data provide supportive evi-dence that some forms of OCD are familial and genetic,underscored by the potential of heterogeneity as a con-founding factor.

Two recent segregation analyses further examinedthe issue of inheritance of OCD, yielding results thatwere consistent with models that include genes of ma-jor effect. Nicolini et al. [1991] performed segregationanalyses on data collected from 24 OCD families, as-certained through the UCLA Child Psychiatry Clinic.All available first-degree relatives were directly inter-viewed, with family history information used for un-available relatives. Due to the small sample size, theinvestigators were unable to statistically reject eitheran autosomal dominant or autosomal recessive model.Their assertion that the dominant model provided abetter fit by assuming a penetrance of 0.8 was a posthoc determination; the likelihood of either model wasnot significantly different from the other. A more re-cent complex segregation analysis reported by Cavaliniet al. [1999] also provided support for a major geneeffect in a sample of 107 families of OCD probands.While the most parsimonious result of those analyseswas an autosomal dominant model, other major locussolutions (i.e., additive or recessive) could not be re-jected.

In those two samples of nuclear families, the precisemode of transmission for OCD was not discernable. Theresults do suggest that the inheritance pattern may beexplained by a relatively simple genetic model and isconsistent with the hypothesis that there are somegenes of major effect that contribute to the manifesta-tion of OCD.

Although the diagnosis of OCD is standardizedacross studies, it is clear that phenotypic and etiologi-cal heterogeneity confounds most studies of complexpsychiatric disorders. There is considerable phenotypicheterogeneity observed among individuals with OCD.Baer [1994] and Leckman et al. [1997] recently ad-dressed the issue of phenotypic heterogeneity in OCDusing a principal components factor analysis to identifysymptom-based subtypes. Baer identified three inde-pendent factors (symmetry/hoarding, contamination/cleaning, and pure obsessions) in a group of 107 pa-tients. Leckman et al. used two large sets of indepen-dently ascertained patients and identified fourseparate obsessive and compulsive symptom factors inboth groups (aggressive and sexual symptoms, hoard-ing, symmetry and ordering symptoms, and symptomsdealing with contamination). The factors identified byBaer are essentially the same as three of the four iden-tified by Leckman et al.

Given the lack of clear results from the two previousOCD segregation analysis studies, the analyses pre-sented here were based on symptom factor structuresin order to explore the possibility that these factors

represent homogeneous heritable components of OCD.A large sample of nuclear families was ascertainedthrough OCD-affected probands. The morbid risk ofOCD among first-degree relatives was calculated foreach factor type. Complex segregation analyses thenwere performed on the entire data set, the subset offamilies with an affected first-degree relative, and foursubsets based on the four factor scores.

MATERIALS AND METHODSData Collection

The sample for the analyses presented here is drawnfrom 100 OCD probands and 466 of their first-degreerelatives (191 parents, 217 siblings, and 58 offspring)described fully in Pauls et al. [1995]. Complete symp-tomatic information was not available for four of theprobands; therefore all analyses except those given forthe total data set were completed with the remaining96 probands and their 453 first-degree relatives.Briefly, 100 OCD probands were ascertained throughthe OCD clinics at the Connecticut Mental Health Cen-ter, New Haven, Connecticut, and Butler Hospital,Providence, Rhode Island. All probands were consecu-tively admitted to a double-blind treatment study ofOCD and met DSM-III-R [American Psychiatric Asso-ciation, 1987] criteria for full OCD; only psychotic in-dividuals were excluded from the sample of probands,and no relatives were excluded. Informed consent wasobtained from all probands and permission was ob-tained to contact all first-degree relatives; diagnosticinformation was obtained on 466 biological first-degreerelatives. Best estimate diagnoses of OCD were madeindependently by two investigators (J.F.L. and D.L.P.)using DSM-III-R criteria applied to data obtained by adirect structured interview and/or family history ques-tionnaire. An additional diagnostic category of sub-clinical OCD [Lenane et al., 1990] was utilized for sub-jects who met all DSM-III-R criteria for OCD exceptone of the following: their obsessions/compulsions con-sumed less than one hour per day, or they lacked in-sight into the unreasonable nature of their obsessionsand compulsions. The DSM-III-R differentiation of sub-clinical OCD from full OCD based on the lack of sig-nificant distress or interference presaged the adjust-ments made to the diagnostic criteria in the currentDSM-IV. Diagnostic ratings were completed with theraters blinded to the diagnosis of the proband. The di-agnosticians were never given a complete family toevaluate at one time and all diagnostic evaluations ofprobands were done separately from their relatives.

Statistical AnalysesThe factor analysis and the age-corrected risk to

relatives analyses were performed using SPSS (SPSS,Inc., 1996). The factor analysis is described more fullyin Leckman et al. [1997]. Briefly, a principal compo-nents factor analysis with a varimax rotation was per-formed on 13 a priori symptom categories from theYBOCS numeric obsessional scale [Goodman et al.,1989] for 96 OCD probands in our family study sample[Pauls et al., 1995]. Four symptom factors were ex-tracted that accounted for approximately 70% of thevariance. The primary symptomatic loadings of the fac-

670 Alsobrook et al.

tors were: factor 1, aggressive, checking, and sexualobsessions and compulsions; factor 2, hoarding obses-sions and compulsions; factor 3, symmetry, ordering,counting, and ritual obsessions and compulsions; andfactor 4, contamination obsessions and compulsions.The risk to relatives was calculated separately for thefour factors using Kaplan-Meier survival tables asimplemented by SPSS; significance was evaluated bythe log rank test. The combined rate of OCD and sub-clinical OCD in relatives of probands with a factorscore greater than zero was compared against the ratein relatives of probands with a factor score less than orequal to zero, for each of the four factors. The thresholdof zero was chosen because the factors are formulatedas a normal distribution with a mean of zero. The samefactor score dichotomizations were subsequently usedin complex segregation analyses described below. Pro-bands’ factor scores were compared between familieswith and without OCD-affected first-degree relatives(i.e., familial and nonfamilial cases, respectively) by aStudent’s t-test for equality of means on each factor.

Segregation Analyses

The segregation analyses of pedigree informationwere performed with the program POINTER [Lalouelet al., 1983]. This program is based upon a unifiedmixed model that encompasses a nested hierarchy ofMendelian and non-Mendelian models for transmis-sion of phenotypes. The transmission models tested us-ing POINTER were 1) a general mixed model; 2) a no-transmission model; 3) a single major locus generalMendelian model; 4) a polygenic model; 5) a dominantgenetic model; 6) an additive genetic model; and 7) arecessive genetic model.

All tests were done in a hierarchical fashion. Firstthe null hypothesis of no transmission was compared tothe alternative hypothesis that there was transmissiondue to a single major genetic locus with polygenic back-ground (the mixed model hypothesis). If there was sig-nificant evidence for transmission (i.e., no-trans-mission model could be rejected), the likelihood of themixed model was compared to the likelihoods of thehypotheses of 1) polygenic inheritance (no single locus),and 2) single gene inheritance (a general Mendelianmodel with no polygenic background). The polygenichypothesis specifies that transmission is due to segre-gation of alleles at multiple loci, each with equal andadditive effect. The single gene hypothesis specifiesthat transmission is due to segregation of alleles at onelocus. If polygenic transmission could not be rejected,further specific Mendelian models (dominant, additive,or recessive) were not tested.

Phenotypes for these analyses were the dichotomousqualitative trait of OCD or subclinical OCD affectedand unaffected. The underlying assumption of the di-chotomy is that affection status represents all individu-als above an “affected” threshold along a continuoustrait–liability axis. The continuous trait–liability vari-able × is defined by the equation ( × 4 g + c + e ) whereg is a major locus effect, c is a multifactorial (or poly-genic) contribution, and e is the environmental (nonge-netic) contribution. The POINTER algorithms assume

that g, c, and e are independent, and that c and e arenormally distributed.

POINTER requires that population prevalences bespecified. Age-specific prevalences defined three spe-cific liability classes: class 1, prevalence 4 0.005, ages2–12; class 2, prevalence 4 0.010, ages 13–18; andclass 3, prevalence 4 0.020, ages 19 and up. Becausethere are no significant differences in rates of illnessbetween males and females in this sample [Pauls et al.,1995], all analyses were done using identical preva-lences for males and females.

Potential heterogeneity in the sample was evaluatedby searching for differing modes of inheritance amongsubsets of the families. The first scheme limited thedata set to those families with a demonstrably familialform of OCD (at least one affected first-degree rela-tive); one affected relative was chosen at random fromeach family and assigned secondary proband status.The full data set was then subsetted according to fourdichotomous classification schemes based upon each ofthe probands’ factor scores from the previous factoranalysis of probands’ obsessive-compulsive symptom-atology [Leckman et al., 1997]. The factor dichotomiesused a threshold of zero because factor structures arecalculated as a normal distribution with a mean ofzero; segregation analyses were performed only onfamilies of probands with factor scores greater thanzero.

Ascertainment of families through an affected familymember can introduce a potential bias in estimates ofsegregation ratios. POINTER specifies the ascertain-ment probability p of an affected individual from thepopulation becoming a sampled proband. All affectedindividuals are assumed to have the same ascertain-ment probability, and all probands are assumed to beindependently ascertained. In the family sample pre-sented here, both assumptions were reasonable. Inap-propriate ascertainment correction has been reportedto cause spurious results [Kramer et al., 1989] there-fore analyses were replicated using several differentvalues of the ascertainment probability p. Results re-ported here are for the case p 4 0.01; this approxi-mates single selection wherein families are ascertainedfrom the population only once.

POINTER estimated four parameters in the fullmixed model: q (the affected or low allele frequency); d(the position of the mean of the heterozygous genotypedistribution relative to the means of the two homozy-gous genotype distributions along the liability axis; if d4 1.0, the trait gene is dominant, if d 4 0 it is reces-sive, and if d 4 0.5 it is additive or codominant); t (thedisplacement between the means of the two homozy-gous genotype distributions on the liability axis); and h(heritability, the additive genetic variance divided bythe total phenotypic variance). POINTER’s primaryoutput was an estimate of the likelihood of observingthe input pedigree samples under a particular model ofinheritance, obtained by a maximum likelihood itera-tive approach to estimate model parameters and ex-pressed as (−2 ln L). The mixed model iterates all fourparameters (d, t, q, and h), while the general Mende-lian model iterates three of those four (d, t, and q), andthe dominant, codominant, and recessive models each

Segregation Analysis of OCD Factors 671

iterate two of those three parameters (t and q). Thepolygenic model iterates one parameter (h, which is notiterated by the Mendelian models), and the model of notransmission performs no iterations, with all four pa-rameters set to zero.

The likelihood ratio used in these analyses is basedon Wilks’ theorem [Wilks, 1932]: the likelihood ratio isequal to the difference between the (−2 ln L) values forthe mixed model and any other model being compared.That difference is then used as a chi-squared statistic,with appropriate degrees of freedom.

RESULTS

The age-corrected rates of illness among the 453first-degree relatives of 96 probands for whom com-plete symptom information was available are shown inTable I. The rates were dichotomized by the probands’obsessive-compulsive symptom principal componentsfactor scores being greater than zero or less than orequal to zero. The rate of OCD or subclinical OCD inthe relatives of probands with a factor 1 score greaterthan zero (rate 4 0.236) was 1.70 times greater (p 40.006) than the rate in the relatives of probands with afactor 1 score less than or equal to zero (rate 4 0.139).The rate of OCD or subclinical OCD in the relatives ofprobands with a factor 3 score greater than zero (rate4 0.227) was 1.68 times greater (p 4 0.019) than therate in the relatives of probands with a factor 3 scoreless than or equal to zero (rate 4 0.227). The rate ofOCD or subclinical OCD was not significantly differentbetween the relatives of probands with high or low fac-tor 2 scores, nor was there a significant difference be-tween the relatives of probands with high or low factor4 scores.

The distribution of probands’ factor scores was com-pared between probands with a positive family historyof OCD and those with a negative OCD family historyby a Student’s t-test of means for each factor (Table II).

There was no significant difference between the twogroups of probands for factors 1, 2, and 4 (p 4 0.121, p4 0.842, and p 4 0.435 respectively). Scores for factor3, symmetry and ordering obsessions and compulsions,were significantly different between positive- andnegative-history probands (t 4 −1.98, p 4 0.051).

A summary of the segregation analysis results is pre-sented in Table III. Using the entire data set of 96probands and 453 first-degree relatives and an affectedclassification of DSM-III-R OCD or subclinical OCD,only the model of no transmission (NTR) was clearlyrejected. Segregation analysis of only those familieswith a positive history of OCD (at least one affectedfirst-degree relative) resulted in the rejection of theNTR, polygenic, and general Mendelian models, givingthe mixed model as the statistically best fit. Analysesperformed on families whose probands had factor 2scores or factor 4 scores greater than zero were able toreject neither the polygenic nor the general Mendelianmodel, but there was clear evidence for rejection of theno-transmission model. Analysis of families whose pro-bands had factor 1 scores greater than zero resulted inthe rejection of only the NTR model, with only a bor-derline rejection of the polygenic model. Analysis offamilies whose probands had factor 3 scores greaterthan zero resulted in the rejection of the NTR and poly-genic models; in that case none of the Mendelian sub-models (dominant, additive, or recessive) were rejected.

Detailed results of segregation analysis using the en-tire data set are presented in Table IV. Only the NTRmodel was rejected, at a p <10−6 significance level (x2

(4)4 135.49). The polygenic model (x2

(3) 4 2.94, p 4 0.40)and general Mendelian model (x2

(1) 4 1.43, p 4 0.23)were not significantly different from the mixed model.

Segregation analyses in families with a positive fam-ily history of OCD (Table V) rejected all models but themixed model. The NTR model was rejected at p <10−6

(x2(4) 4 117.57), the polygenic model was rejected at p

TABLE I. Age-Corrected Recurrence Risk in First-Degree Relatives by Probands’ Factor Scores*

Factor numberFactor score

1 2 3 4

Total sample# 4 10 >0 # 4 0 >0 # 4 0 >0 # 4 0 >0

Risk 0.139 0.236 0.177 0.182 0.135 0.227 0.184 0.175 0.182Standard error 0.022 0.031 0.022 0.033 0.022 0.029 0.025 0.026 0.018No. of affected probands 53 43 64 32 47 49 50 46 100No. of affected relatives 38/259 44/194 58/303 24/150 34/234 48/219 43/229 39/224 82/466p 0.006 0.900 0.019 0.671 —

*Affected status in relatives is a combined category of OCD or subclinical OCD. Factor 1, aggression, sexual, checking symptoms; factor 2, hoardingsymptoms; factor 3, symmetry, ordering, repeating symptoms; factor 4, contamination symptoms.

TABLE II. Comparison of Probands’ Factor Scores by Familial History of OCD*

Factornumber

Mean factor score +/− SE

t pNegative OC history Positive OC history

1 −0.169 0.153 0.149 0.134 −1.564 0.1212 −0.022 0.147 0.019 0.143 −0.200 0.8423 −0.212 0.150 0.187 0.135 −1.980 0.0514 −0.085 0.138 0.075 0.149 −0.785 0.435

*Fifty-one probands with positive family history, 45 probands with negative family history.

672 Alsobrook et al.

4 10−6 (x2(3) 4 35.56), and the general Mendelian

model was rejected at (p 4 0.009 (x2(1) 4 6.90).

Segregation analyses in families whose probandshad hoarding obsessions and compulsions character-ized by factor 2 scores greater than zero rejected onlythe NTR model (x2

(4) 4 32.48, p 4 2x10−6, data notshown). Similarly, analyses in families whose probandshad contamination obsessions and compulsions charac-terized by factor 4 scores greater than zero rejectedonly the NTR model (x2

(4) 4 62.53, p < 10−6, data notshown). The polygenic and general Mendelian modelswere not significantly different from the mixed model.

Results of separate segregation analyses in familieswith probands’ factor 1 scores and factor 3 scoresgreater than zero are presented in Table VI and VII,respectively. In the families whose probands hadchecking and aggression obsessions and compulsionscharacterized by factor 1 scores greater than zero(Table VI) the NTR model was clearly rejected (x2

(4) 489.38, p < 10−6). The polygenic model (x2

(3) 4 7.35, p 40.06) and recessive model (x2

(2) 4 5.10, p 4 0.08) bothapproached but did not reach p <0.05 significance andtherefore are not formally rejected. Neither the domi-nant model nor the additive model were rejected (p 40.82 and 1.00, respectively).

In the families whose probands had symmetry andordering obsessions and compulsions characterized byfactor 3 scores greater than zero (Table VII) both theNTR model (x2

(4) 4 73.90, p < 10−6) and polygenicmodel (x2

(3) 4 8.01, p 4 0.046) were rejected. The dom-inant, additive, and recessive Mendelian models werenot rejected (p 4 0.719, p 4 1.00, and p 4 0.178, re-spectively).

DISCUSSION

The segregation analyses presented here were com-pleted on data from 96 probands and their 453 first-degree relatives [Pauls et al., 1995]. Because evidence

suggests that OCD is clinically heterogeneous, poten-tially homogeneous subgroups were created basedupon the probands’ scores on four previously publishedsymptom-based principal component factors [Leckmanet al., 1997]. Two of these factor scores appear to berelated to morbid risk for OCD.

Relatives of probands with high scores for the ag-gression/sexual-obsession factor (factor 1) were at sig-nificantly higher risk of OCD than relatives of pro-bands with low factor scores; the relative risk ratio was1.7. The same significant difference, with a relativerisk ratio of 1.7, was found based on the symmetry/ordering/counting factor (factor 3) subsetting, althougha correction for multiple tests would make this differ-ence of borderline significance. This evidence suggeststhat aggression and sexual obsessive-compulsive symp-toms have a familial component, as do the symptoms ofsymmetry, ordering and counting.

The factor 1 and factor 3 symptom subsets, whileorthogonal in the empirical factor solution, may not begenetically independent: 24 of 96 probands had bothfactor 1 and factor 3 scores greater than zero. The riskof OCD in relatives of those 24 probands was comparedto the risk in all other relatives in the sample; therewas a significant relative risk ratio of 1.6, approxi-mately the same as when considering factors 1 and 3separately. It should also be noted that four familieswith 4 out of 19 affected relatives had probands withhigh scores on all four factors. It may be that scores forsymptom factors 1 and 3 constitute a continuous sever-ity index with a higher risk of illness in relatives ofmore severely affected probands. Future analysesshould explore the commonalities between the factor 1and factor 3 probands and their families.

High factor 2 or factor 4 scores (derived from hoard-ing and contamination symptoms, respectively) in pro-bands were not associated with an increased morbidrisk to relatives of OCD or subclinical OCD. The symp-toms that comprise these factors may be too pervasiveamong this sample of OCD patients to be useful fordiscriminatory analyses. While the factor-based group-ings represent distinct components of the OCD pheno-type, they do not necessarily constitute clinically rel-evant subtypes.

Given the increased risk of OCD to relatives of pro-bands with high factor 1 or factor 3 scores, we exam-ined the genetic transmission of OCD in factor-basedsubgroups of the family data. Segregation analysis ofthe total sample of 96 families allowed rejection of onlythe no-transmission model; while OCD appears to be

TABLE III. Segregation Analysis Summary*

Data subset Result

Total data set Reject No Transmission (NTR) modelPositive family history Reject NTR, Mendelian, and

polygenic modelsProband factor 1 >0 Reject NTR modelProband factor 2 >0 Reject NTR modelProband factor 3 >0 Reject NTR and polygenic modelsProband factor 4 >0 Reject NTR model

*Affected status is combined OCD or subclinical OCD.

TABLE IV. Complex Segregation Analysis of Total Family Sample*

Model −2ln(L) x2 df p d t q h

Mixed −480.82 — — — 0.685 3.39 0.076 0.207General Mendelian −479.39 1.43 1 0.23 0.392 5.53 0.020 0.0a

Dominant −478.34 2.48 2 0.29 1.0a 2.26 0.017 0.0a

Additive −478.44 2.38 2 0.30 0.5a 5.51 0.035 0.0a

Recessive −478.69 2.13 2 0.34 0.0a 3.47 0.206 0.0a

Polygenic −477.88 2.94 3 0.40 0.0a 0.0a 0.0a 0.996No transmission −345.33 135.49 4 <10−6 0.0a 0.0a 0.0a 0.0a

*Affected status in relatives is OCD or subclinical OCD.aValue fixed by model conditions.

Segregation Analysis of OCD Factors 673

genetically transmitted the cumulative data do not fit aspecific transmission model. Because recent familystudy data indicate OCD is heterogeneous [Pauls et al.,1995], it is not unexpected that both a single locusmodel and an amorphous multiple-additive-loci modelcan separately and simultaneously explain the data.There are likely to be many molecular paths to what iscurrently classified as a unitary psychiatric outcome. Itis possible that one subset of the 96 families has a formof OCD caused by mutation at a single locus, whileanother subset has a form caused by the action of dif-ferent multiple loci.

The results of the analysis of families who have atleast one affected member in addition to the probandalso indicates an underlying molecular complexity. Inthis case all models except the mixed model were re-jected. Rather than explaining the data with separategroups of families having distinct modes of inheritancethat then form a conglomerate sample, the rejection ofall but the mixed model indicates that the clearly fa-milial form of OCD may result from the combined ac-tions of multiple loci. In such a model a large propor-tion of the contributing loci each have a small impacton the end phenotype while at least one locus has alarger impact. This is POINTER’s closest approxima-tion to an oligogenic model.

The rejection of the no-transmission and polygenicinheritance models in high proband-factor-3 families,coupled with the increased risk of OCD in relatives ofhigh-factor-3 probands and the significant associationof probands’ high factor 3 scores with a positive familyhistory of OCD, all point to factor 3 as a significantgenetically transmitted symptomatic subtype of OCD.

The segregation analyses of high-factor-1 probands’

families were not as definitive as for high-factor-3 pro-bands’ families. The polygenic inheritance modelreached only a borderline rejection at p 4 0.06, withoutcorrection for multiple testing.

The dichotomization of family samples using a pro-band factor score threshold of zero may allow signifi-cant inheritance patterns to remain undetected. Thefactor score distributions were constructed as a normaldistribution with a mean of zero; hence zero is a rea-sonable starting value for a threshold. Further analy-ses using higher or lower thresholds (or combinationsthereof) may reveal specific Mendelian inheritancemodes, in essence maximizing the segregation resultsby iterating the threshold value. This approach wouldrequire additional corrections for the multiple tests in-volved.

Segregation analysis using additional biological in-formation available for these families (e.g., probands’age at onset; data not shown) did not improve discrimi-nation among transmission models; for families withearly-onset probands only the no-transmission modelwas rejected. Other biologically relevant informationthat might add power to the analyses includes a phar-maceutical treatment response classification, or a con-tinuous quantitative trait such as the YBOCS numericobsessional scale. Based on the findings presentedhere, an informative continuous quantitative traitmight be constructed from the factor 1 and factor 3scores. In the present sample, however, the necessarysymptom information was not available for all diag-nosed relatives. That lack of information also pre-vented a more direct analysis of the inheritance of fac-tor scores by performing within-family correlations.

OCD as seen in this large clinical sample appears to

TABLE V. Complex Segregation Analysis of Families With Positive Familial History of OCD*

Model −2ln(L) x2 df p d t q h

Mixed −278.26a — — — 0.727 3.34 0.106 0.0002General Mendelian −271.36 6.90 1 0.009 1.00b 3.60 0.022 0.0c

Dominant −271.36 6.90 2 0.032 1.0c 3.62 0.022 0.0c

Additive −270.57 7.69 2 0.021 0.5c 7.27 0.021 0.0c

Recessive −260.95 17.31 2 <2 × 10−4 0.0c 3.75 0.194 0.0c

Polygenic −242.70 35.56 3 <10−6 0.0c 0.0c 0.0c 0.927No transmission −160.69 117.57 4 <10−6 0.0c 0.0c 0.0c 0.0c

*Affected status in relatives is OCD or subclinical OCD.aSolution did not converge; this value is the best likelihood obtained, replicated from multiple starting parameter spaces.bValue set to bound by POINTER.cValue fixed by model conditions.

TABLE VI. Complex Segregation Analysis of Families With Probands’ Factor 1 Score >0*

Model −2ln(L) x2 df p d t q h

Mixed −195.08 — — — .547 4.90 0.021 0.017General Mendelian −195.08 0.00 1 1.00 .483 5.51 0.021 0.0b

Dominant −194.67 0.41 2 0.82 1.0b 2.64 0.019 0.0b

Additive −195.08 0.00 2 1.00 0.5b 5.32 0.021 0.0b

Recessive −189.98 5.10 2 0.08 0.0b 3.76 0.190 0.0b

Polygenic −187.73a 7.35 3 0.06 0.0b 0.0b 0.0b 0.998No transmission −106.00 89.38 4 <10−6 0.0b 0.0b 0.0b 0.0b

*Affected status in relatives is OCD or subclinical OCD.aSolution did not converge; this value is the best likelihood obtained, replicated from multiple starting parameter spaces.bValue fixed by model conditions.

674 Alsobrook et al.

be genetically heterogeneous. While it appears that atleast one single locus has an appreciable impact, OCDis not a single-gene disease. The analyses describedhere represent a relatively limited range of geneticmodels that were examined. For example, no two locusor oligogenetic models are implemented by POINTER,nor were they tested by other means. An oligogenicmodel of inheritance tested with these family data mayhave revealed significant roles of multiple discrete loci.The significant polygenic component cannot be dis-counted; its amorphous summation of genetic effectsreminds us that there are very likely many molecularpaths to a single observable disease outcome. The find-ings reported here may prove useful in discovering atleast one of those paths.

ACKNOWLEDGMENTS

We thank all of the families for their participation inthis study. We gratefully acknowledge Colin Bondi andCharles Hurst for their assistance with the symptomdata. This work was supported by NIH grants RO1ND16648 and RSA MH00508 to D.L.P., PO1 MH49351to J.F.L., and a NARSAD Young Investigator award toJ.P.A. (the NARSAD Maltz Investigator).

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TABLE VII. Complex Segregation Analysis of Families With Probands’ Factor 3 Score >0*

Model −2ln(L) x2 df p d t q h

Mixed −229.99 — — — 0.726 3.99 0.028 0.006General Mendelian −230.05 −0.06 1 1.000 0.757 4.20 0.028 0.0a

Dominant −229.33 0.66 2 0.719 1.0a 3.17 0.027 0.0a

Additive −229.99 0.00 2 1.000 0.5a 6.31 0.028 0.0a

Recessive −226.54 3.45 2 0.178 0.0a 3.53 0.312 0.0a

Polygenic −221.98 8.01 3 0.046 0.0a 0.0a 0.0a 0.882No transmission −156.09 73.90 4 <10−6 0.0a 0.0a 0.0a 0.0a

*Affected status in relatives is OCD or subclinical OCD.aValue fixed by model conditions.

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