(Am J Psychiatry 1997; 154: )

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1 KENDLER, PSYCHOTIC Am J Psychiatry KARKOWSKI-SHUMAN, SYMPTOMS 154:2, February AND SYNDROMES 1997 O NEILL, ET AL. Resemblance of Psychotic Symptoms and Syndromes in Affected Sibling Pairs From the Irish Study of High-Density Schizophrenia Families: Evidence for Possible Etiologic Heterogeneity Kenneth S. Kendler, M.D., Laura Karkowski-Shuman, Ph.D., F. Anthony O Neill, M.D., Richard E. Straub, Ph.D., Charles J. MacLean, Ph.D., and Dermot Walsh, M.B., F.R.C.P.I. Objective: The authors sought to determine whether the clinical manifestations of schizophrenia and other psychotic disorders are correlated in affected sibling pairs. Method: They examined, in 256 sibling pairs concordant for DSM-III-R schizophrenia and 457 sibling pairs concordant for all nonaffective psychoses ascertained in the Irish Study of High-Density Schizophrenia Families, similarity for 1) symptoms, course, and outcome; 2) symptom factors; and 3) syndromes, defined by latent class analysis. Results: Global course and outcome, as well as all major symptoms except hallucinations, were modestly but significantly correlated in sibling pairs concordant for schizophrenia. Three symptom factors negative symptoms, positive symptoms, and affective symptoms were all significantly correlated in concordant sib pairs. Latent class analysis suggested five schizophrenic syndromes. Class membership was significantly correlated in concordant sibling pairs. Similar results were found for sibling pairs concordant for nonaffective psychoses. Conclusions: The clinical manifestations of the schizophrenic syndrome (both narrowly and broadly defined) are moderately influenced by familial factors. From a familial/genetic perspective, schizophrenia as currently defined may be etiologically heterogeneous. (Am J Psychiatry 1997; 154: ) I call dementia praecox schizophrenia.... I use the word in the singular although it is apparent that the group includes several diseases.... [However,] so far, we have been unable to discover any natural lines of division within the described clinical picture... the subdivision of the group of schizophrenias is a task for the future. E. Bleuler (1, pp. 8, 280) Received Jan. 29, 1996; revision received Aug. 14, 1996; accepted Aug. 16, From the Virginia Institute for Psychiatric and Behavioral Genetics, Departments of Psychiatry and Human Genetics, Medical College of Virginia, Virginia Commonwealth University, Richmond; the Department of Psychiatry, Queens University, Belfast, Northern Ireland; and the Health Research Board, Dublin, Ireland. Address reprint requests to Dr. Kendler, Psychiatric Genetics Research Program, Virginia Institute for Psychiatric and Behavioral Genetics, P.O. Box , Richmond, VA ; kendler@gems.vcu.edu ( ). Supported by NIMH grants MH and MH-45390, and by a NIMH Research Scientist Award MH (Dr. Kendler). The authors thank S. Humphries, M. Healy, and A. Finnerty for supervision of data collection; J. Burke, B. Murphy, F. Duke, R. Shinkwin, M. Ni Nuallain, F. McMahon, J. Downing, T. Hebron, B. Hanratty, E. Crowe, M. Doherty, J. Bray, and L. Lowry for additional interviews; the families and the staffs of the many psychiatric hospitals and units in Ireland and Northern Ireland for their cooperation; and L. Thacker, B. Duke, and R. McClelland for their assistance. S ince its inception as a diagnostic category (1, 2), clinicians have commented on the clinical diversity of the schizophrenic syndrome. Can this clinical variability be used to understand the etiologic heterogeneity of this syndrome? Or, alternatively, are symptoms in schizophrenia too ephemeral or too susceptible to the influence of transient, unpredictable factors to usefully reflect etiologic processes? Given the importance of familial/genetic factors in the etiology of schizophrenia (3, 4), a powerful method to address this question is to examine pairs of affected relatives. If familial/genetic factors influence the liability to individual schizophrenic symptoms or syndromes, then the clinical features of pairs of relatives affected with schizophrenia should resemble one another. The earliest attempts to address this question examined whether the classic Kraepelinian subtypes (paranoid, hebephrenic, and catatonic [5]) run true in families. Results of earlier studies were conflicting (6), although three more recent studies have been negative (7 9). Efforts at examining whether specific clinical features of schizophrenia are correlated in pairs of affected relatives have been fewer but more successful. In a reanalysis of earlier case reports of 92 sibling pairs with Am J Psychiatry 154:2, February

2 PSYCHOTIC SYMPTOMS AND SYNDROMES a diagnosis of schizophrenia (10), Slater noted significant pair resemblance for poor, feeble affect, excitement, depressive colouring, and paranoia. In a subsequent study of concordant twin, sibling, and parentoffspring pairs (11), Slater noted significant resemblance for catatonic symptoms, delusions of passivity, depressive symptoms, and course. In the largest sample of which we are aware, M. Bleuler (12) observed significant resemblance for both course and outcome in 228 sibling pairs concordant for psychosis. More recently, DeLisi and colleagues (13) examined 53 sibling pairs concordant for schizophrenia or schizoaffective disorder and found significant resemblance for visual hallucinations and depressive episodes. Evidence for familial heterogeneity in the schizophrenic syndrome is of potential significance in the search for susceptibility loci for schizophrenia. The most widely used linkage tests for heterogeneity (14, 15) are a posteriori they divide families into linked and unlinked subgroups solely on the basis of the family-by-family evidence for linkage. This test has only modest power, particularly when applied to the relatively small families most commonly ascertained in schizophrenia linkage studies (16 19). If it is possible, on clinical grounds, to divide the sample before linkage into etiologically distinct subgroups, a great gain in power is possible. This a priori heterogeneity test has, for example, been successfully applied in linkage studies of Alzheimer s disease (20) and breast cancer (21) on the basis of early- versus late-onset of illness. In this report, we examined sibling pairs ascertained in the Irish Study of High-Density Schizophrenia Families (22) who were concordant either for DSM-III-R schizophrenia (N=256) or all nonaffective psychosis (N= 457). We examined sibling resemblance for 1) symptoms, 2) symptom factors, and 3) syndromes, as defined by latent class analysis (23). METHOD Sample The Irish Study of High-Density Schizophrenia Families is a collaborative project involving the Medical College of Virginia, Richmond, the Health Research Board, Dublin, and the Queen s University, Belfast, Northern Ireland (22). Families containing a high density of schizophrenia and related disorders were ascertained through 39 separate public psychiatric hospitals in Ireland and Northern Ireland. No exclusion criteria were used in our selection of families (22). Compared with relatives of the epidemiologically sampled schizophrenic probands from the Roscommon Family Study, relatives in the Irish Study of High-Density Schizophrenia Families had similar risks for affective illness, anxiety disorder, and alcoholism (22). In this paper, we report results from what we have termed the phenotypic Irish Study of High-Density Schizophrenia Families sample (22), including all relatives on whom high-quality clinical information was available (personal interview or hospital record or both), regardless of whether DNA samples were also available. For all individuals for whom DNA samples were available (about 80% of the sample), genetic relationships were confirmed by using data from 25 microsatellite markers, a process that required reclassifying 13 putative full sibling affected pairs as half-siblings. Interviews were conducted by Irish psychiatrists and social scientists with a background in mental health or survey work after consent was obtained through use of procedures approved by the ethical review panels at the Health Research Board and the Queens University. Our assessment instruments consisted of modified sections of the Structured Clinical Interview for DSM-III-R (24) for selected axis I disorders and the Structured Interview for Schizotypy for putative schizophrenia spectrum personality disorders (25). In 98.6% of subjects diagnosed with schizophrenia or schizoaffective disorder, we obtained psychiatric inpatient or outpatient records or both. A detailed abstract of these records was dictated, and a specially developed case record rating scale was completed. No attempt was made, during the assessments of individual relatives in the Irish Study of High-Density Schizophrenia Families, to keep the interviewer blind to information about the psychiatric status of other relatives. All relevant diagnostic information for each relative was reviewed independently by two of us (K.S.K. and D.W.). These assessments were done blind to pedigree assignment and knowledge of the psychopathologic status of other relatives. Diagnostic disagreements were resolved by consensus. The agreement rate and weighted kappa (26) for our main 10 diagnostic category system in the Irish Study of High-Density Schizophrenia Families (22) were 73.3% and 0.94 (SD= 0.05), respectively. In addition, one of these raters (K.S.K.), using all available information, assessed, in all cases with nonaffective psychosis, the following 11 key symptomatic and course variables on the Major Symptoms of Schizophrenia Scale: delusions (any), Schneiderian delusions, hallucinations, positive thought disorder (e.g., loosening of association), catatonic symptoms, affective deterioration (e.g., affective flattening), negative thought disorder (e.g., alogia), depressive symptoms, manic symptoms, chronicity of course (from single episode with recovery to chronic course without even partial remissions), and outcome (from full recovery to very poor outcome). These ratings reflected clinical judgment and incorporated the severity of the symptom, its duration, and its relative prominence over the entire course of the illness. While outcome was coded on a 4-point scale, all other variables were coded on 5-point scales with the following guidelines (details available from Dr. Kendler on request): 1=clearly not present, 2=possibly present but subthreshold, 3=clearly present but moderate, 4=clearly present and prominent, 5=clearly present and severe. Interrater reliability of the Major Symptoms of Schizophrenia Scale was tested on 47 subjects with psychotic illness from the Roscommon Family Study who were rated blindly by one of us (K.S.K.) and A. Gruenberg, M.D. Intraclass correlations ranged from 0.60 for catatonic symptoms to 0.91 for manic symptoms, with a mean of 0.77 (SD=0.11). We use here two diagnostic definitions: schizophrenia by DSM-III- R criteria and all nonaffective psychoses by DSM-III-R criteria for schizophrenia, schizoaffective disorder, schizophreniform disorder, delusional disorder, and psychosis not otherwise specified. In addition, we included a small number of individuals (N=25) that we diagnosed with simple schizophrenia through use of criteria outlined elsewhere (27), since individuals meeting these criteria in the Roscommon Family Study appeared to suffer from a disorder that was related to schizophrenia, from both a clinical and familial perspective (27). Statistical Methods Before examining sibling resemblance for symptoms, we explored three variables that might be both substantially correlated in siblings and strongly related to symptoms: age at onset, gender, and duration of illness. The resemblance for age at onset was modest for siblings concordant for schizophrenia (r=0.08, n.s.) and nonaffective psychoses (r=0.17, p<0.001), as was resemblance for gender (schizophrenia: phi=0.12, χ 2 =3.91, df=1, p=0.02; nonaffective psychoses: phi=0.09, χ 2 =4.00, df=1, p=0.02). However, the correlations in duration of illness were quite substantial (schizophrenia: r=0.64, p<0.0001; nonaffective psychoses: r=0.59, p<0.0001). We then compared the observed symptom correlation in sibling pairs by using raw symptom scores versus scores with the effect of age at onset, gender, or duration of illness removed by linear regression. While controlling for gender or age at onset had no substantial impact on symptom resemblance in siblings, controlling for duration of illness substantially altered sibling correlations for several variables. 192 Am J Psychiatry 154:2, February 1997

3 KENDLER, KARKOWSKI-SHUMAN, O NEILL, ET AL. For all analyses in this article, therefore, we examine measures of symptoms, course, and outcome after removing, by regression analysis, the linear effects of duration of illness. To quantify the similarity in clinical features of illness in affected sibling pairs, we used a Spearman rank correlation (28). Because these sibling pairs were not independent, we tested the significance of sibling resemblance by a Wilcoxon nonparametric one-way analysis of variance (29). Because we had a clear directional hypothesis (that sibling resemblance exceeds chance expectation), one-tailed p values are presented for these and similar analyses in this report. Factor analysis with VARIMAX rotation (through use of the PROC FACTOR procedure in SAS [29]) was used on the Major Symptoms of Schizophrenia Scale to define symptom factors. The number of meaningful factors was determined by the scree test. We used latent class analysis (30) a categorical analog of factor analysis to define empirically syndromes that could then be tested for resemblance in siblings. While in factor analysis the observed and latent variables are assumed to be continuously distributed, in latent class analysis these variables are assumed to be categorical. Latent class analysis attempts to explain the association in a population between many categorical variables on the basis of a few latent classes (analogous to the factors of factor analysis). In addition to estimating the number of latent classes and their frequency in the population, latent class analysis assigns a probability of endorsement for each variable for each latent class (analogous to factor loadings in factor analysis). Latent class analysis was performed by using a FORTRAN program written by Lindon Eaves, Ph.D., the basic model of which is widely used by others (31 33) and implemented in several widely available programs (reference 34, for example). The program, details of which have been outlined elsewhere (35), accepts data in raw form and uses the NAG FOR- TRAN library subroutine E04UCF (36) for minimization of a function subject to nonlinear constraints to find the maximum likelihood estimates of the estimated parameters. Maximum likelihood methods were used to estimate a vector of probabilities for class membership as well as a vector of item probabilities for each class conditional on class membership. We dichotomized scores on the Major Symptoms of Schizophrenia Scale by a median split. In addition, to aid the latent class analysis program in identifying stable syndromes, we added two variables: gender (percent females) and early versus late age at onset (again, through use of a median split). Once each individual was assigned to his or her most likely class, class resemblance in concordant pairs was examined by a chi-square analysis of the resulting N N contingency table, where N equals the number of classes. We also report the phi coefficient (28) as a measure of resemblance in contingency tables that is independent of sample size. Since this table contains nonindependent sibling pairs from sibships containing three or more affected individuals, we also repeated these analyses, picking one pair at random from sibships with three affected (N=27 for schizophrenia) and two independent pairs from sibships with four affected (N=6). While factor analysts have the problem of choosing the best number of factors, the analogous problem in latent class analysis is selecting the optimal class number. In these analyses, the best stable solution included five classes. RESULTS Sample The Irish Study of High-Density Schizophrenia Families contained 256 full sibling pairs concordant for a diagnosis of DSM-III-R schizophrenia. These individuals, of whom 65.7% were male, had a mean age at onset and evaluation of 24.8 (SD=6.8) and 45.6 years (SD=13.5), TABLE 1. Resemblance of Clinical Features of Psychosis in Siblings Concordant for Schizophrenia and Concordant for All Nonaffective Psychosis Item From Major Symptoms of Schizophrenia Scale Schizophrenia a respectively. These pairs came from 139 sibships with two affected, 27 with three affected, and six with four affected. This sample also contained 459 full sibling pairs concordant for nonaffective psychoses. The individuals in these pairs, of whom 66.4% were male, had a mean age at onset and evaluation of 25.1 (SD=7.6) and 44.6 years (SD=13.7), respectively. The 459 pairs came from 189 sibships with two affected, 44 with three affected, 16 with four affected, and four with five affected. Sibling Pairs Concordant for Schizophrenia All Nonaffective Psychosis b Spearman r p c Spearman r p c Psychotic symptoms over entire course of illness Hallucinations Delusions, any Delusions, Schneiderian Positive thought disorder Catatonic symptoms Affective deterioration Negative thought disorder Depressive symptoms Manic symptoms Course Outcome a N= pairs. b N= pairs. c One-tailed; p value from Kruskal-Wallis nonparametric one-way ANOVA. Resemblance for individual symptoms and symptom factors. Sibling pairs concordant for schizophrenia significantly resembled one another for eight of nine individual symptoms and for global course and outcome (table 1). Only the intensity of hallucinations was not significantly correlated. The significant correlations were generally modest, ranging from 0.11 for catatonic symptoms to 0.43 for manic symptoms. Three orthogonal factors were extracted from the Major Symptoms of Schizophrenia Scale from individuals with schizophrenia (results available from Dr. Kendler on request). The first or negative symptom factor had highest loadings on affective deterioration, poor outcome, chronic course, and negative thought disorder. The second or positive symptom factor had high loadings on hallucinations, any delusions, and Schneiderian delusions. The third or affective/manic symptom factor had a high loading only on manic symptoms and a more moderate loading on positive thought disorder. The Pearson correlations for these three factors in sibling pairs concordant for schizophrenia were r=0.21 (p=0.0007), r=0.16 (p= 0.005), and r=0.27 (p=0.0001), respectively. Latent class analysis of schizophrenia. We applied latent class analysis to the 11 items from the Major Symptoms of Schizophrenia Scale as well as age at onset and gender to the 580 individuals from the Irish Study of High-Density Schizophrenia Families with a DSM-III-R Am J Psychiatry 154:2, February

4 PSYCHOTIC SYMPTOMS AND SYNDROMES TABLE 2. Endorsement Frequencies for Items From the Major Symptoms of Schizophrenia Scale and for Age at Onset and Gender in the Five-Class Latent Class Analysis Solution a Endorsement Frequency for Class b Variable Items from Major Symptoms of Schizophrenia Scale Hallucinations Delusions, any Delusions, Schneiderian Positive thought disorder Catatonic symptoms Affective deterioration Negative thought disorder Depressive symptoms Manic symptoms Course Outcome Age at onset Gender Frequency a Items dichotomized by median split. b See text for description. diagnosis of schizophrenia and considered the five-class solution to be most satisfactory (table 2). Class 1 is characterized by moderate positive symptoms, low negative symptoms, and relatively high levels of affective symptoms. Individuals in this class demonstrate high levels of manic symptoms, late age at onset, and a very low rate of poor outcome. Class 2 contains individuals with quite high levels of negative symptoms and low levels of both positive and affective symptoms. Individuals in this class have especially high levels of flat affect, negative thought disorder, catatonic symptoms, and poor course and outcome. The third class is characterized by high levels of both positive and negative symptoms and early age at onset. Individuals in this class have particularly prominent delusions, flat affect, and thought disorder. The tendency toward a chronic course and poor outcome is only slightly less pronounced than that seen in class 2. Individuals in class 4 are characterized by very low levels of negative symptoms, low levels of positive and affective symptoms, late age at onset, and a relatively good outcome. Class 5 contains individuals with pronounced catatonic symptoms, negative thought disorder, and flat affect. They demonstrate very low levels of positive symptoms and have a remitting-relapsing course. Sibling resemblance for latent classes. Table 3 presents the latent class analysis assignments of the 256 sibling pairs concordant for schizophrenia from the Irish Study of High-Density Schizophrenia Families. It presents the observed number of pairs, the expected number under the null hypothesis of no association, and the chi-square for each class. Overall, sibling resemblance for class assignment far exceeded chance expectation (χ 2 =53.22, df=16, p<0.0001, phi=0.46.). The excess of observed over expected pairs was greatest for classes 5 (individual cell χ 2 =9.1) and 1 (cell χ 2 = 8.3). A substantial excess of pairs was also observed that was concordant for class 2 (cell χ 2 =4.3) and class 3 (cell χ 2 =3.1). We repeated this analysis after removing nonindependent sib pairs. The results were very similar (N=179 pairs, χ 2 =30.34, df=16, p=0.001, phi=0.48). Sibling Pairs Concordant for All Nonaffective Psychoses To examine whether sibling resemblance for the clinical features of psychosis extended beyond narrowly defined schizophrenia, we repeated the previous analyses for pairs of siblings in the Irish Study of High-Density Schizophrenia Families concordant for nonaffective psychoses (N=457 pairs). As seen in table 1, the correlations for symptoms, course, and outcome were similar in pairs concordant for schizophrenia and concordant for nonaffective psychoses. A factor structure for individuals with nonaffective psychoses (N=785) revealed negative and positive symptom factors very similar to those seen in schizophrenia. The third factor here called an affective symptom/good prognosis factor differed somewhat for that seen in schizophrenia, as high positive loadings were now seen for both depressive and manic symptoms and high negative loadings for course and outcome. The magnitude of resemblance for the three symptom factors in siblings concordant for nonaffective psychoses was similar to that seen in siblings concordant for schizophrenia: r=0.16 (p=0.005), r=0.14 (p= 0.001), and r=0.27 (p=0.0001), respectively. The results of latent class analysis in cases of nonaffective psychoses are available from Dr. Kendler on request. We again preferred a five-class solution which produced classes that bore substantial similarities to classes 1, 2, 3, and 5 from the latent class analysis of schizophrenia. The final class was characterized by intermediate levels of positive, negative, and affective symptoms. Resemblance in sib pairs for class assignment was less pronounced than that seen in pairs concordant for schizophrenia (χ 2 =26.40, df=16, p=0.047, phi=0.24). DISCUSSION Since the time of Bleuler (1), a central question in research on schizophrenia has been whether the syndrome is etiologically homogeneous. Prior attempts to address the question by using familial/genetic strategies have yielded conflicting results (7 13, 37). In the Irish Study of High-Density Schizophrenia Families, we found, at the level of individual symptoms, symptom factors, and latent class analysis-defined syndromes, significant resemblance in sibling pairs concordant for DSM-III-R-defined schizophrenia. The Irish Study of High-Density Schizophrenia Families differs in four ways from most previous studies that address this question. First, the sample size is considerably larger, providing greater statistical power to detect modest correlations. Eighty percent power to detect a 194 Am J Psychiatry 154:2, February 1997

5 KENDLER, KARKOWSKI-SHUMAN, O NEILL, ET AL. TABLE 3. Resemblance in Latent Class Assignment in Sibling Pairs Concordant for Schizophrenia (N=257) Latent Class Assignment, Sib 1 Latent Class Assignment, Sib 2 Class 1 Class 2 Class 3 Class 4 Class 5 of Pairs χ 2 of Pairs χ 2 of Pairs χ 2 of Pairs χ 2 of Pairs χ 2 Class Observed Expected a Class Observed Expected a Class Observed Expected a Class Observed Expected a Class Observed Expected a a Under the null hypothesis of no sib resemblance. correlation significantly different from zero (with p< 0.05, one-tailed) requires over 140 and 600 pairs, respectively, if the true population correlation is 0.20 and 0.10 (38). Second, the Irish Study of High-Density Schizophrenia Families was ascertained by using systematic sampling rules from treatment facilities serving the great majority of an entire population (22). Therefore, this sample is likely to be representative of concordant pairs in the population at least where one member has sought psychiatric care. Third, we used systematic data collection instruments of demonstrated reliability for both personal interviews and hospital records. We are aware of only one study of affected sibling pairs that used modern instrumentation (13), and that sample examined only 53 sibships. Fourth, this is the first study to examine sibling resemblance in schizophrenia, controlling for potential covariates. Duration of illness in this sample was both highly correlated in sibling pairs and significantly related to many clinical variables. If not controlled for, duration of illness might cause spurious clinical correlations in sibling pairs concordant for schizophrenia. Similarity of Symptoms In 256 pairs of siblings concordant for DSM-III-R schizophrenia, we found statistically significant resemblance for global course and outcome and the frequency/intensity of all major symptoms except auditory hallucinations. Our results are generally consistent with previous studies of this question. For example, Slater (10, 11) reported evidence that affective symptoms were significantly correlated in schizophrenic sibling pairs in two samples, and DeLisi et al. (13) reported a highly significant correlation for prior history of depressive episodes. Both Slater (11) and Bleuler (12) noted significant sibling resemblance for course or outcome. Our results agreed with those reported by Slater (10), but not by DeLisi et al. (13), in finding sibling resemblance for negative symptoms such as flat affect and poverty of speech. Our findings contrasted most strongly with previous reports in regard to sibling resemblance for thought disorder, which we found but which was observed neither by Slater (10, 11) nor by DeLisi et al. (13). Of interest, our results are congruent with previous findings in showing little sibling resemblance for hallucinations (10, 11, 13). Latent Class Analysis Since the classic work of Lorr et al. (39), many attempts have been made, by using a range of statistical methods, to define objective subtypes of schizophrenia (40 49). In subjects from the Irish Study of High-Density Schizophrenia Families who met DSM-III-R criteria for schizophrenia, we found evidence, by using latent class analysis applied to the 11 items from the Major Symptoms of Schizophrenia Scale plus age at onset and gender, for at least five distinct syndromes. Several of these bore close resemblance to prior clinical or statistical subtypes. In particular, class 2 closely resembled core or negative symptom schizophrenia, class 4 defined a syndrome similar to paranoid schizophrenia, and class 5 resembled remitting/relapsing catatonic schizophrenia. Class 1 bore some resemblance to schizoaffective disorder, although all these subjects met narrowly defined criteria for schizophrenia. Our study design permitted us not only to define putative subtypes of schizophrenia, but also to validate them by observing resemblance in affected relative pairs. Class membership of affected sibling pairs resembled one another substantially more frequently than would be expected by chance. Prior attempts to demonstrate the breeding true of the traditional Kraepelinian subtypes of schizophrenia have produced mixed results (7 9, 37). Several methodological features of Am J Psychiatry 154:2, February

6 PSYCHOTIC SYMPTOMS AND SYNDROMES our study particularly the large sample size and the use of empirically rather than clinically defined subtypes may be responsible for our positive findings. All Nonaffective Psychoses We also examined resemblance for symptoms, factors, and syndromes in sibling pairs from the Irish Study of High-Density Schizophrenia Families who were concordant for nonaffective psychoses. Despite the much larger sample size (N=457 pairs), the results were generally quite similar to those found examining pairs concordant for schizophrenia only. Consistent with several prior studies (50 52) (including the companion Roscommon Family Study [53, 54]), these results suggest that the familial factors influencing schizophrenia are unlikely to be qualitatively different from those that affect nonaffective psychoses. Resemblance for Gender and Age at Onset We found only modest resemblance for age at onset in sibling pairs from the Irish Study of High-Density Schizophrenia Families who were concordant for schizophrenia or nonaffective psychoses. The observed correlations were toward the lower end of the range (usually 0.15 to 0.30) previously found in sibling pairs concordant for schizophrenia (55 57). However, our results are consistent with those in the Roscommon Family Study (58). These low age at onset correlations do provide, indirectly, evidence about ascertainment bias (56). Given the substantial correlation in ages of siblings in a heterogeneous sample (r=0.91 in the Irish Study of High-Density Schizophrenia Families for pairs concordant for schizophrenia), if the ascertainment procedure had a short memory (e.g., could find only pairs whose onset of illness occurred within a few years of one another), this would induce a substantial correlation in age at onset. The low observed correlation in age at onset in affected sibling pairs from the Irish Study of High-Density Schizophrenia Families suggests that our ascertainment had a long memory ; that is, the probability of detection of a sibling pair was not substantially related to the proximity in time of the onset of their illnesses. Although long a subject of interest (59, 60), relatively recent attention has focused on gender similarity in pairs of schizophrenic relatives as a way of evaluating hypotheses of X-linkage (61 64). This hypothesis predicts an excess of same-sex affected sibling pairs. While such an excess was observed in the Irish Study of High- Density Schizophrenia Families, it was slight and provided meager support, at best, for hypotheses of X-linkage of schizophrenia. Interpretation Prior attempts to develop valid subtyping systems in schizophrenia based solely on symptoms have had only modest success (references 65 and 66, for example). Symptoms are only moderately stable over time and are influenced by a range of idiosyncratic features that may diminish substantially their value as the basis for etiologic theories. Since the observed resemblance for symptoms, factors, and syndromes in sibling pairs in this sample is relatively modest, it could be argued that they are of little overall significance. Four facts might suggest otherwise. First, we have assessed symptoms over the entire disease course through use of both hospital records and personal interviews. These measures may be a more valid index of an individual s overall symptom pattern than could be obtained from any single cross-sectional assessment. Second, while our symptom assessments were carefully performed, their reliability was far from perfect. Correcting for the attenuation due to measurement error at only the final stage of symptom assessment at blind review would increase the correlations around 30%. Additional error at the stage of primary data collection and summation would only add to this attenuation. Third, full siblings share only 50% of their genes in common identical by descent from their parents. Our sample cannot address whether symptom similarity was due to environmental or genetic factors. However, if sibling resemblance was entirely genetic in origin, and these symptom dimensions in schizophrenia had a heritability of 100%, the expected correlations in siblings would be only If due solely to genetic factors, our results would suggest that the symptom factors in schizophrenia might have a heritability as high as 50%. Fourth, although we have used lifetime assessments, many idiosyncratic factors might still attenuate an underlying sibling correlation. Sibling pairs concordant for schizophrenia might differ in their exposure to environmental factors (e.g., obstetrical complications, treatment, stressful life events) or treatment regimens that influence the pattern of symptoms and course of their illness. What mechanisms might explain these sibling correlations? We would suggest three that particularly merit further consideration. First, familial-environmental factors, such as socioeconomic class and access to and compliance with psychiatric care, might play a role in sibling resemblance. The direct influence of illness characteristics of one sibling on another cannot be ruled out. Second, sibling resemblance might be due to genetically influenced multifactorial characteristics such as temperament (67) or intellect (68). For example, individuals high in emotionality may be particularly prone to depressive symptoms during a schizophrenic illness, while those low in intelligence might be more prone to a poor outcome. Third, sibling resemblance might result from genetic heterogeneity within the schizophrenic syndrome. This heterogeneity might be interlocus (i.e., two or more single genes that predispose to schizophrenia) or intralocus (i.e., two or more pathogenic alleles at the same locus). If these varied genetic causes for schizophrenia differed in their clinical manifestations, then affected siblings would tend to have the same genetic cause of illness and would also tend to be similar in their clinical features. 196 Am J Psychiatry 154:2, February 1997

7 KENDLER, KARKOWSKI-SHUMAN, O NEILL, ET AL. The magnitude of sibling resemblance in this model would be a complex product of the specific genes involved (e.g., number, gene frequency, mode of expression), the magnitude of clinical difference between the different forms of schizophrenia, and the magnitude of error involved in their assessment. If schizophrenia were due to several different rare genes, whose manifestations were clinically distinct, the symptomatic correlations in siblings would probably be substantially greater than those observed here (69). However, if the different genes were relatively common, and the clinical differences between syndromes moderate, the predicted correlations in symptoms could easily be of the magnitude seen here. A fourth hypothesis might also merit consideration that certain of these symptom dimensions (e.g., negative symptoms) are simply measures of the genetic severity of schizophrenia (70). However, this hypothesis predicts that in representative probands, these clinical characteristics should predict risk of schizophrenia spectrum illness in relatives, a pattern that was not observed in the Roscommon Family Study (71). Given the rapid advances recently seen in mapping susceptibility genes for complex human traits (reference 72, for example), the ultimate validation of putative subtypes for schizophrenia might occur when individual susceptibility genes for schizophrenia are successfully identified. It will then be possible to determine whether the clinical heterogeneity in schizophrenia is due to genes at different loci, to different alleles at the same locus, or to other causes. Limitation In the Irish Study of High-Density Schizophrenia Families, the same field worker often prepared hospital abstracts and conducted interviews on ill members in the same family. 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