Manic-Depressive Illness

Transcription

1 Am J Hum Genet 26: , 1974 Morbidity Risk and Genetic Transmission in Manic-Depressive Illness JULIEN MENDLEWICZ1 AND JOHN D. RAINER2 INTRODUCTION Twin and family studies of manic-depressive (bipolar) illness strongly suggest the presence of a genetic factor in the etiology of this disease. Concordance rates for the illness in monozygotic twins are consistently greater than the rates found in dizygotic twins [1]. Several studies [2-4] on morbidity rates in the families of manic-depressive probands indicate that the lifetime risk for this disease in relatives of manicdepressive probands is significantly higher than the risk in the general population. The mode of inheritance of manic-depressive illness, however, is still not understood. Among the types of transmission suggested are single-gene autosomal [5, 6], sexlinked [7, 8], and polygenic inheritance [9, 10]. Several family studies [3, 11] have indicated that manic-depressive illness is genetically different from unipolar depressive illness. However, most of these studies have found rather high risks for unipolar illness in the relatives of bipolar probands. In our own linkage studies, we have previously hypothesized that the bipolar and unipolar phenotypes may be expressions of the same genotype in the families of bipolar probands [8]. This report summarizes our findings in a systematic morbidity risk study of first-degree relatives of manic-depressive (bipolar) probands. SUBJECTS AND METHODS The sample consists of 134 manic-depressive probands (56 males and 78 females) and all 781 of their first-degree relatives. The probands represent all those patients admitted between 1968 and 1972 to the Lithium Clinic (New York State Psychiatric Institute) who had been independently diagnosed as manic-depressive by two investigators. Most of these bipolar patients were referred by private physicians, outpatient clinics, and hospitals. The 76 patients suffering from depression alone (i.e., unipolar patients) who were referred to Received February 19, 1974; revised June 6, Presented at the annual meeting of the American Society of Human Genetics, Atlanta, Georgia, October This work was supported by General Research Support Grant no. 303-E-165F to the New York State Psychiatric Institute. 1 Departments of Medical Genetics and Internal Medicine, New York State Psychiatric Institute, and Department of Psychiatry, Columbia University, 722 West 168th Street, New York, New York Department of Medical Genetics, New York State Psychiatric Institute, and Department of Psychiatry, Columbia University, 722 West 168th Street, New York, New York i 1974 by the American Society of Human Genetics. All rights reserved. 692

2 GENETICS OF MANIC-DEPRESSIVE ILLNESS our clinic for treatment during the same period are not included in the present study. The existence of secondary cases in the patients' families was not a criterion for referring a patient to the Lithium Clinic. The referral sources were unaware of our ongoing family studies, and prospective study patients were referred to our clinic for the sole purpose of lithium treatment. The probands' diagnoses were made independently of the family study data. There were 22 patients excluded from our study either because the two screening psychiatrists could not agree on the diagnosis (N = 9) or because they both agreed that the patient was not suffering from bipolar manic-depressive illness (N = 13). The diagnostic criteria used were similar to those of Leonhard et al. [2], Perris [12], and Winokur et al. [4]. Bipolar illness was diagnosed in probands and relatives who had a history of clear-cut manic behavior and of depressive episodes severe enough to require treatment or hospitalization or to cause a disruption in everyday activities for at least 3 weeks. The depressive episodes are characterized by depressed mood along with symptoms of a physiological shift, such as a decrease in appetite, sleep, and energy level, often accompanied by guilt, decreased concentration, and suicidal thoughts. Manic episodes include such symptoms as euphoria, hyperactivity, decreased need for sleep, pressure of speech, flight of ideas, and irritability. Periodicity of illness (two or more episodes of manic or depressive symptoms) with symptom-free intervals was also among the criteria used for the diagnosis of bipolar illness. A diagnosis of unipolar depression was made for those relatives who had never experienced mania or hypomania but had experienced one or more depressive episodes severe enough to require treatment or hospitalization. For both bipolar and unipolar illness, there had to be no personality disintegration before or following psychotic episodes, nor could there be other preexisting psychiatric or medical disease which might be associated with an affective symptomatology. In studying psychiatric disturbances among the first-degree relatives, the family-study method (interviewing relatives personally) was used whenever possible in preference to the family-history method (collecting data about relatives from the proband). When interviewing a proband's relative, the examiner was kept blind with respect to whether the proband was unipolar or bipolar. All available relatives were interviewed using the Current and Past Psychopathology Scale [13] and a clinical semistructured interview for screening with respect to psychopathology. At least one relative in each family was seen by one of two investigators, and information about unavailable relatives was gathered from the proband, interviewed relatives, and questionnaires. A total of 82% of all living relatives were personally interviewed. Information about each proband and relative was coded, punched on IBM cards, and run on an IBM 1130 computer. The frequency of affective illness among first-degree relatives was investigated in terms of morbidity risks using the Strbmgren method [14]. The morbidity risk for a disease is an estimate of the probability that a person will develop the disease at some time during his life if he survives the risk period for the disease. A description and extensive discussion of the Strdmgren method has been published [15]. The following formula is used: MR = avbjc&, where aj is the number of affected individuals in the age group i to i + 1; bi is the total number of persons who have disappeared from observation in the age group i to i + 1; and ci is the probability that an affected person will become affected by the midpoint of age group i to i + 1 (ct ranges from 0 to 1). The numerator becomes the total number of affected persons, and the denominator is known as the Bezugsziffer (BZ), which is the total number of persons corrected for age. The weights cl are sometimes taken from data obtained in other populations. In the present study, however, these cumulative probabilities for both bipolar and unipolar illness were determined by analyzing the distribution of ages of onset in our own probands, which is a more reliable method. A modification of a computer program developed by Kidd and Cavalli-Sforza [16] was 693

3 694 MENDLEWICZ AND RAINER used to test the single-gene hypothesis for mode of transmission. Using the conditional probability matrices of Li and Sacks (see [16]), the program calculates as a function of four parameters the probability that a particular type of relative (e.g., sib, parent) of a proband is also affected. The parameters are q = gene frequency; h' = mean liability value of the heterozygote, where 0 is completely recessive and 2 is completely dominant; E2 = variance due to environment; and T = threshold on a liability scale for affected individuals. The following values were examined in all possible combinations: 0.05 c q c 0.25 in increments of 0.01; 0.0Ch' in increments of 0.25; 0.1.e in increments of 0.10; and 0.8. T in increments of In addition, the general incidence was allowed to range from 0.4% to 2.0% in increments of 0.2%. The predicted risk values for parents and sibs yielded by each parameter combination were tested against the observed values. Those combinations considered most likely were those which gave risks that agreed with the observed values + 2 SE. RESULTS Morbidity risks (Str6mgren method) for bipolar illness, unipolar illness, and for all affective disorders (either bipolar or unipolar) among all first-degree relatives of bipolar probands are presented in table 1. Table 1 clearly indicates that affective TABLE 1 MORBIDITY RISKS* FOR AFFECTIVE ILLNESS AMONG 781 FIRST-DEGREE RELATIVES OF 134 BIPOLAR PROBANDS Morbidity Type of Illness No. Ill BZt Risk (%) SE (%) All affective Bipolar Unipolar * Stromgren method [14] for age correction. t BZ = Bezugsziffer. disorders are highly prevalent among first-degree relatives of bipolar probands and that the affective disorder is not restricted to bipolar illness alone: the risk for unipolar illness (22.4%) is even greater than the risk for bipolar illness (17.7%o). Morbidity risks for affective illness calculated separately for parents, sibs, and children of bipolar probands appear in table 2. The data in table 2 show that the overall rate for affective disorder among sibs is similar to that among parents (39.2%o and 33.7%o, x2 1.34, P >.05). However, sibs are significantly more likely to manifest bipolar illness than parents (21.2%o compared to 12.1%o; x2 = 7.34,P <.01). The elevated risks found in children are probably due to methodological artefacts in applying the Strbmgren method to limited samples of young relatives where small differences can be given great weight and hence magnified. The finding of equal risks in parents and sibs is consistent with dominant major-gene inheritance; with the rates in first-degree relatives below the expected 50%o, the penetrance would be of the order of 70%o. It should be reiterated that while all probands are bipolar, relatives may be

4 GENETICS OF MANIC-DEPRESSIVE ILLNESS TABLE 2 MORBIDITY RISKS FOR AFFECTIVE ILLNESS AMONG PARENTS, SIBS, AND CHILDREN OF 134 BIPOLAR PROBANDS 695 Morbidity Illness No. Ill BZ Risk (%) SE (%) Parents (N = 268) All affective Bipolar Unipolar Sibs (N = 327) All affective Bipolar Unipolar Children (N = 186) All affective Bipolar Unipolar phenotypically either unipolar or bipolar; therefore observed and expected rates in the above analysis are presented separately for bipolar and unipolar relatives to make our data comparable with previous studies [2-4]. In view of our hypothesis that bipolar and unipolar relatives of bipolar probands have the same genotype, the "all affective" category in the various classes of relatives should be given primary consideration in tables 1 and 2. In order to investigate further the major-gene hypothesis, the rates for affective illness found among parents and sibs of bipolar probands were tested for consistency with a major-gene mode of transmission using a modification of a computer program developed by Kidd and Cavalli-Sforza [16] which simulates a single-gene threshold model. Table 3 presents the results of this analysis. All combinations of parameters that yield expected morbidity risks within 1 SE of those observed are included. Since such combinations of parameters indeed exist, the observed morbidity risks for all affective illness among parents and sibs of our bipolar probands are consistent with the single-gene mode of transmission. The set of values yielding expected rates closest to the observed appears in boldface type and corresponds with an essentially dominant gene (1h = 1.5, q = 0.01). It should be noted that the program was used to test the hypothesis of single-gene dominant inheritance regardless of whether the inheritance was autosomal or X linked. This was done by not taking into account the sex of index cases and relatives, but rather considering overall rates in each class of relatives for males and females combined.

5 696 MENDLEWICZ AND RAINER TABLE 3 MORBIDITY RISKS EXPECTED WITH A SINGLE-GENE MODE OF TRANSMISSION* GENERAL PARAMETERSt INCIDENCE PARENTS (S.) SIBS (c/c) (%)t T q E NOTE.-Observed morbidity risks for parents and sibs are 33.7%,, 2.9% and 39.2% ± 3.0%, respectively. The set of values yielding expected risks closest to observed risks appears in boldface type. * Kidd and Cavalli-Sforza [16] threshold model. t Range, 0.4%-2.0%. t h' = mean liability value of heterozygote, range 0-2.0; T = threshold, range ; q = gene frequency, range ; e2= variance due to environment, range To test the hypothesis of polygenic inheritance, our data were analyzed to provide an estimation of the heritability of bipolar illness under the conditions of that hypothesis. According to Falconer [17], a heritability estimate (I2) can be derived from data on the frequency of a trait in relatives of affected individuals and the frequency in the general population. This method is based on the assumption that liability to the trait studied is continuously distributed in the general population, an assumption which cannot be proven for manic-depressive illness. If h2 is found to be too high (e.g., h2 > 1), a dominant gene can be considered as a more probable mode of transmission. Falconer's approach is an approximation, as shown by Cavalli-Sforza and Bodmer [18], and it has been improved by Edwards [ 19] who uses tetrachoric correlation coefficients. Edwards also provides an empirical formula to estimate p (phenotypic correlation on Pearson's model) from qy and qr, where q, is the population rate for a given trait and q, is the rate observed in relatives of affected patients: p 0.57 log k/(- log qg log k ), k = q,./qg. The heritability estimate h2 can be obtained by dividing p by the theoretical correlation coefficient, which is.5 for first-degree relatives. If 1.5% is taken as the rate for manic-depressive illness in the general population (table 3) and 39.1% (SE 2%7) as the observed rate of all affective illness in first-degree relatives of manic-depressive patients (table 1), h2-1.72, with range according to the above standard error. If we take 0.5% as a general population rate, a value near the lower limit of our range for this variable (table 3), the heritability estimate is 1.78.

6 GENETICS OF MANIC-DEPRESSIVE ILLNESS According to Newcombe [20], a value of h2> 1 for a trait is not compatible with polygenic inheritance and is suggestive of simple Mendelian inheritance. A more complete analysis of heritability estimates would require further data on the incidence of manic-depressive illness in monozygotic and dizygotic twins, as well as in second- and third-degree relatives of patients with affective disorders. In view of the finding that a single-gene model can adequately account for the rates of affective illness observed among parents and sibs, and in light, moreover, of several studies showing evidence that bipolar manic-depression may be linked on the X chromosome to colorblindness [8, 21] and to the Xg locus [7, 22], an investigation was made into possible differences in morbidity risk due to sex of relatives. Table 4 presents the results of this investigation. TABLE 4 MORBIDITY RISKS AMONG FIRST-DEGREE RELATIVES OF BIPOLAR PROBANDS BY SEX OF RELATIVES Morbidity Illness No. Ill BZ Risk (%) SE (%) Male Relatives (N = 422) All affective Bipolar Unipolar Female Relatives (N = 359) All affective Bipolar Unipolar Under conditions of an X-linked dominant gene, one would expect a preponderance of affective disease in female relatives. From table 4, it is clear that female relatives have a significantly greater risk for affective illness than male relatives (48.2% compared to 30.7%o, x2 = 18.12, P <.001). Although this sex difference is not present in the bipolar relatives, it is significant in unipolar relatives. This may possibly be accounted for by some of the unipolar females later becoming bipolar. As discussed previously, data for bipolar and unipolar illness in relatives are provided separately for the purpose of comparison with previous studies [2-4]. In any event, the sex distribution of all affective illness observed in relatives is compatible with an X-linked dominant mode of transmission. A classic means of determining whether an X-linked dominant gene is involved in the transmission of an illness is to investigate the rate of illness among various classes of first-degree relatives by sex of the proband. The results of such an analysis appear in table 5.

7 698 MENDLEWICZ AND RAINER TABLE 5 MORBIDITY RISKS FOR ALL AFFECTIVE ILLNESS AMONG FIRST-DEGREE RELATIVES OF BIPOLAR PROBANDS BY SEX AND CLASS OF RELATIVE AND BY SEX OF PROBAND Morbidity No. Relative Risk (%) SE (%) Ill BZ Male Probands (N = 56) Fathers, N = Mothers, N = Brothers, N = Sisters, N = Sons, N = Daughters, N = Female Probands (N = 78) Fathers, N= Mothers, N = Brothers, N = Sisters, N = Sons, N = Daughters, N = It will be noted that the rates of all affective illness among fathers and sons of male probands are consistently and significantly lower than those found among the mothers and daughters of male probands. The overall rate of affective illness among these mothers (61.0%o) is almost three times that among fathers (18.3%), again a significant difference (X , P <.001). The rate of all affective illness among daughters of males (100o) is also significantly greater than that among sons (15.8%,o x2 = 13.04, P <.001). In our families, there are, to be sure, some instances of father-to-son transmission which would not be expected with an X-linked dominant gene. The risk for all affective illness in fathers of males is 18.3%o and in sons of males is 15.8%. If families with assortative mating are omitted, the risk for all affective illness among fathers of males decreases to 8.3%o while that among sons remains the same. While mothers and fathers of males show significant differences in risk for affective illness, mothers and fathers of females do not. The morbidity risk is 22.3%o among fathers and 36.8%o among mothers (X2 = 3.15, nonsignificant). These results are consistent with X-linked dominant transmission, since affected parents of female probands are male and female in equal proportion. The X-linked dominant hypothesis also predicts equal proportions of ill sons and ill daughters of females, a result not obtained in this study. A total of 96.7% of the daughters of females are affectively ill compared to only 47.5%o of sons of females (X2-9.74, P <.01). It should be emphasized again, however, that morbidity risk

8 GENETICS OF MANIC-DEPRESSIVE ILLNESS data in children should be interpreted with caution since the numbers are very small, as can be seen from table 5. This caution would apply as well to the unlikely 100%o rate found in daughters of male probands. Table 5 also provides data on morbidity in brothers and sisters of probands according to the probands' sex. In X-linked dominant transmission, brothers and sisters of males should be ill in the same proportion, while the ratio of ill sisters and brothers of female probands should be 3:1. The observed overall rate for affective illness is practically the same for brothers and sisters of males (44.6%o and 40.7%o, respectively). Although sisters of females are more likely to be affectively ill (41.3 %0) than brothers of females (31.1%), the difference is not statistically significant. DISCUSSION The results of our family studies of manic-depressive patients confirm previous studies [2-6] indicating an increase of morbidity risk for affective disorder in various classes of relatives of manic-depressive patients. Our results show high risks for affective illness (close to 40%o) in the first-degree relatives of the probands. These rates are close to those expected for dominant inheritance with a high penetrance. The morbidity risks in parents and sibs are similar, a fact which would be expected under a single-gene dominant model. Our data are based on the hypothesis [4, 8] that affective illness can be expressed phenotypically either as unipolar or bipolar disease in the relatives of manic-depressive patients. A computer program developed by Kidd and Cavalli-Sforza [16] allowed us to compare the observed morbidity risks in parents and sibs with those expected under a single-gene threshold model. The analysis shows that our risk data for all affective illness in relatives of manic-depressive patients fit those expected under a single-gene threshold model with an essentially dominant mode of transmission. Polygenic inheritance appeared less likely since our data gave a heritability estimate greater than one. The sex distribution among secondary cases is in the direction of an X-linked dominant pattern of inheritance. In particular: (1) there is a significant excess of female relatives with affective illness; (2) male probands have significantly more mothers and daughters affected compared to fathers and sons; (3) female probands have as many mothers affected as fathers, although there are more affected daughters than sons; (4) sibs of male probands have similar risks regardless of sex; and (5) there is a slight excess (nonsignificant) of ill female sibs of female probands, although we did not find the expected 3:1 ratio of affected sisters to brothers. It is equally clear from the data that heterogeneity of etiology and pattern of inheritance may be complicating the analysis. Most strikingly, even omitting families with assortative mating, there remain 10 families in which male-to-male transmission of affective illness is present. In these families, X linkage can obviously be ruled out; extensive pedigree analysis is in progress to determine other possible types of inheritance. 699

9 700 MENDLEWICZ AND RAINER SUMMARY Morbidity risks are presented for parents, sibs, and children of a successive series of 56 male and 78 female probands with manic-depressive (bipolar) illness. Both unipolar (recurrent depression) and bipolar illness are found to cluster among these first-degree relatives, with a significantly greater risk for the combined distribution in female relatives than in male ones. While fathers of male probands have risks comparable to those of fathers of female probands, mothers of male probands are three times as likely to be affected as fathers. Daughters, particularly of male probands, have a much higher risk than sons, although there are 10 father-son pairs in the entire material not accounted for by assortative mating. The data were tested for consistency with a single-gene threshold model using a modification of a program developed by Kidd and Cavalli-Sforza [16]. Observed values for sibs and parents were compatible with various forms of single-gene inheritance, with dominant inheritance most likely. Previous work from this institute and elsewhere substantiated an X-linked dominant pattern for manic-depressive illness, with linkage to colorblindness and Xg loci likely in informative families. The present data are consistent with this pattern as a preponderant mode of inheritance in an overall heterogeneity model. ACKNOWLEDGMENTS Acknowledgment is gratefully made to Dr. Ronald R. Fieve for his collaboration in this study. We are also indebted to Ms. M. Cataldo, Ms. J. Klotz, and Mr. A. Aversa for their assistance in the interviews and data compilation. REFERENCES 1. ZERBIN-RUDIN E: Zur Genetik der depressiven Erkrankungen, in Das depressive Syndrom, edited by Hippius H, SELBACH H, Munich, Urban & Schwarzenberg, 1969, pp LEONHARD K, KORFF I, SCHULZ H: Die Temperamente in den Familien der monopolaren und bipolaren phasichen Psychosen. Psychiatr Neurol 143: , ANGST J, PERRIS C: Zur Nosologie endogener Depression: Vergleich der Ergebnisse der Untersuchungen. Arch Psychiatr Z Neurol 210: , WINOKUR G, CLAYTON PJ, REICH T: Manic-Depressive Illness. St. Louis, Mosby, STENSTEDT A: A study in manic-depressive psychosis. Acta Psychiatr Neurol Scand [Suppl] 79:1-111, KALLMANN FJ: Genetic principles in manic-depressive psychoses, in Depression, edited by HOCH P, ZUBIN J, New York, Grune & Stratton, 1954, pp WINOKUR G, TANNA VL: Possible role of X-linked dominant factor in manic-depressive disease. Dis Nerv Syst 30:89-94, MENDLEWICZ J, FLEIss JL, FIEvE RR: Evidence for X-linkage in the transmission of manic-depressive illness. J Am Med Assoc 222 : , PERRIS C: Abnormality on paternal and maternal sides: observations in bipolar (manic-depressive) and unipolar depressive psychoses. Br J Psychiatry 118: , SLATER E, MAXWELL J, PRICE JS: Distribution of ancestral secondary cases in bipolar affective disorders. Br J Psychiatry 118: , WINOKUR G, CLAYTON PJ: Family history studies. 1. Two types of affective disorders

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