I close relatives of schizophrenics, although the reason for the increase

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1 THE LONGITUDINAL FAMILY DISTRIBUTION OF SCHIZOPHRENIA B~ J ~ LOVE N KARLSSON REYKJAVIK, ICELAND (Received April 20t11, 1964) INTKODUCTION T is generally recognized that the risk of schizophrenia is increased in I close relatives of schizophrenics, although the reason for the increase is debated (.JACKSON, 1960). Extensive data have been gathered on the rate of the disease in nionozygotic and dizygotic cotwins of index cases (KALLMAN, 1953) and on the empiric risk jn various relatives (LUXEN- BURGER, 1930; KALLMAN, 1938), but the total pattern of the distribution within families has received less attention. Certain relationships jn the transmission pattern would be required by the recognized principles of physical inheritance, which would differ from those expected in term of social heredity. Proponents of the genetic theory have suggested several modes of in- 1ierit:ince which might account for the family data. No unmodified single gene iiiechanism appears to fit, and a modified form of dominant inheritance seeins the most plausible (SLATER, 1958). According to one hypothesis the iiiodification results from incomplete penetrance, presumably influenced by the environment (BOOK, 1953) ; according to another the expression of the dominant gene is dependent mainly on a recessive iiiodifyiiig gene (KARLSSON, 1964). With any dominant hereditary mechanism it should be possible to trace the path of the gene as it travels along the family tree, establish a continuity of transmission, and show that segregation occurs so that the disorder persists in some segments while it disappears in others. On the basis of the two locus mechanism proposed by the author, an increased rate of schizophrenia would be expected in half the branches of descendants derived from carriers of the dominant gene. The disease would occur from this source in the rates of 1 in 16 in the chiidren of carriers, 1 in 32 in the grandchildren, and 1 in 64 in the great grand- 9 - Hercdilns 52

2 128 J6N LOVE KARLSSON children; after that it would be below the rate of one per cent which exists in the general population. The rate in the offspring of carriers would thus be diluted fairly rapidly, but high risk should persist in some segments of the family if these are followed. The possibility must, of course, always be considered that the gene may be brought in from a different source, as one person in fifteen would be a carrier. With respect to the recessive gene, which in combination with the dominant one produces schizophrenia according to the hypothesis, it could be followed only to the immediate offspring oc the person thought to possess it, as its frequency of 0.4 implies that it would constantly be derived from outside sources. The present report deals with a study of schizophrenia in a family in which it can be followed for many generations and attempis to illustrate the overall pattern of the disease as it travels along the various branches of the family. The distribution, assembled into pedigrees from previously recorded information, will in particular be evaluated in ternis of the two locus hypothesis. METHODS AND RESULT This study was carried out in Iceland because of the special local circumstances, which make it relatively easy to trace families for many generations. On the basis of preliminary work it was concluded that it should be possible to locate a published account of a kindred in which schizophrenia had occurred early and then persisted. Many books on the genealogy of specific families have been published in Iceland, and several of these start with one individual, perhaps 300 years ago, and list all his descendants. After a search in several such books one was located in which a person with documented mental illness had appeared in the second generation of descendants, and the entire family tree is accurately recorded from 1682 to 1930 (JONSSON, 1932). The author of the book is a professor of history at the University of Iceland who has made a careful study of this family, mainly in terms of genealogic relationships, but also to some extent in terms of social status, personal achievement, etc. It should be mentioned that this kindred does not appear to exhibit an increased rate of schizophrenia, but rather is of special interest because the disease shows up first at a stage which makes the family favorable for demonstrating the longitudinal pattern of transmission. It has been felt that many outstanding persons, both in cultural and social leadership, belong to this kindred, and it might be

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4 130 J6N LOVE KARLSSON P P of interest to make a further study of their precise location in the family in relationship to the occurrence of mental illness. In the case of individuals who lived before the time of medical documentation, decisions as to who had mental illness were based on the recorded history as well as on information obtained directly from the

5 FA31ILY I)ISTRIBUTION OF SCHlZOl llrl~nl~\ 131

6 Fig. 1 d. Descendants of individual marked with an asterisk in Fig. 1 c, showing generations IV through VI. Individual marked with an asterisk will be traced further in Fig. 1 e.

7 FAMILY DISTRIBUTION OF SCHIZOPHRENIA 133 Fig. 1 e. Descendants of individual marked with an asterisk in Fig. 1 d, showing generations V through VII. author of the book. Rather precise description is available for the two mentally ill individuals in generations I1 and IV; most physicians would agree that schizophrenia is the likely diagnosis. The first of these is a woman, born around 1735, who remained unmarried and is stated to have become insane; at the age of 54 she was further described as an indigent as a result of mental apathy. The other, a woman born in 1807, became insane and was divorced by her husband, a priest, after they had had two children; she is listed as insane in the 1860 census. TWO individuals in generation I11 were also considered mentally ill, but the nature of their disease is less definite. One of them, a man born around 1775, is described at the age of 40 as unable to manage his affairs because of mental confusion; the other, a man born in 1792, is said to have been a promising man initially, but later have become very strange in his conduct. Records of the Kleppur State Hospital in Reykjavik were the basis for diagnosis in cases subsequent to generation IV. The majority of the patients had been admitted with a diagnosis of schizophrenia, but it was decided to include also psychotic individuals with other diagnoses, such as psychogenic psychosis or manic depressive psychosis, as the clinical subdiagnoses assigned by physicians do not seem to follow the etiologic relationships suggested by the family data. In essence, this study may be said to deal with the family distribution of chronic psychotic reactions, but in the author s opinion it is probable that most of the individuals suffered from schizophrenia.

8 134 J6N L6VE KARLSSON The persons listed in the book number many thousands. It would be impractical to present such estensive data in pedigree form, but in the author s esperience it usually suffices for the purpose of deciding whether a particular individual appears to transmit the disorder to follow his descendants for three generations, the decision being dependent on a sufficient number of children. The pedigree in Fig. 1 a illustrates this. It shows the initial ancestors of tlie kindred in question and their offspring for three generations. The males in a family are in general shown before tlie females, because this approach was followed in the book, but the members of each sex are in chronologic order. Individuals who died before the age of 15 are omitted. The occurrence of mental disease within three generations in two of the sis branches, with a questionable case known in a third, is construed to indicate that the disorder most likely was transmitted by the initial ancestors. Only branches A and C of the Pumily will be traced further, one to illustrate how the disorder persists in some segments, the other to show how it may disappear. Schizophrenia has also occurred in some of the other branches, for example in branch 13, but a decision is not possible, because of the small number of children in the first generations, as to whether the illness is likely to have originated from the same source or was carried in from elsewhere. Fig. 2 traces for three generations the descendants of the fourth son of tlie initial ancestors (branch C). It is interpreted to indicate that this son did not transmit the disorder. Mental illness has occurred later on in this branch, but shows up first in the seventh generation. A followup parallel to that described below for branch A is therefore not possible. Branch A is traced further in Figs. 1 b to 1 e. Each pedigree shows for three generations the descendants of tlie chosen member of the first generation of descendants, marked with an asterisk, in the preceding pedigree. Just the last generation in each pedigree is coniposed of new members. For example, Fig. 1 b shows the descendants of the first son of the initial ancestors, who is marked with an asterisk in Fig. 1 a. Some of the cases of mental illness appear in two or three of the pedigrees. This form of presentation was chosen so as to include as much as possible of the overall pattern, although only certain segments of tlie family tree could be shown. The sectors which are followed are chosen to demonstrate the persistence of the disorder. Sectors in which the disease disappears are not included, and different lines with continued disease, besides the one shown, could have been selected. It will be noted that the total pattern reniains similar in all the pedigrees; this is the type of

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10 136 J6N L6VE KARLSSON distribution which the author has seen in many other families. Schizophrenia appeared first in generation I1 of branch A and has persisted since, appearing in each subsequent generation through generation 1 11, which is the last one traced. Only a total of 9 cases of mental illness fall into the pedigrees which are shown, but 7 others have occurred in branch A of the family. For comparison it may be iiientioned that in generations I to VII, G cases are known in branch B, 2 in branch C, 5 in branch D, and none in branches E or F. It must be realized that these branches are not of equal size. DISCUSSION On first inspection of a pedigree showing the typical family distribution of schizophrenia, such as in Figs. 1 a or 1 b, one is impressed with how scaltered the cases are and how the pattern does not offhand suggest any known hereditary mechanism. However, the contrast bclween the rate of the disorder in branches A and C of the family seems to suggest that the disease may have been carried in one and not in the other. The continuity of transmission for an apparently unlimited number of generations with segregation into affected and unaffected family segments is also consistent with heredity. These are fundanienlal relationships expected in terms of Mendelian inheritance. If one accepts that a hereditary basis exists, several possible mechanisnis must be considered. No sex differences are apparent, so that sex linked forms of inheritance can be disregarded. Recessive inheritance with a fairly frequent gene could lead to reappearance in successive generations, similar to that observed, but clustering in specific areas of the family would be expected more frequently if the risk in the sibs of a schizophrenic was one in four or one in two, depending upon whether or not one parent was affected. Modified dominant inheritance seems more likely. If dominant inheritance is responsible, the skipping of generations might be caused by incomplete penetrance, but one would then not expect direct passage for as many as three generations :is frequently as this is observed. Other arguments against peiietrmce of a very low order have been presented (KARLSSON, 1964). The distribution does, on the other h:ind, fit the two gene mechanism recently proposed by the author, in which the expression of a dominant gene is dependent on a recessive modifying factor, with the disease being diagnosed in 80 per cent of those with the full genotype. According to this hypothesis the average risk in the children of a carrier of the dominant gene would be

11 FAMILY DISTRIBUTION OF SCHIZOPHRENIA in 15, the risk in his grandchildren 1 in 26, and in his great grandchildren 1 in 43, when the risk of independent occurrence is taken into account. From inspection of the pedigrees it is apparent that a relationship of this order is present. If all the members of each generation in pedigrees 1 a to 1 e are added together and the rate of mental illness computed, the rates are 1 in 11, 1 in 22, and 1 in 49 respectively in generations one, two, and three. The following characteristics of the overall pattern have also been noted: The disease arises in most instances from unaffected parents, may then persist for two or sometimes three generations, but generally tends to disappear in one area, only to reappear elsewhere in the family. The total risk seems to be only slightly increased in the children of unaffected relatives of schizophrenics. In occasional families, usually with one parent schizophrenic, the risk appears to approach 50 per cent, although the average risk in children of schizophrenics is about 16 per cent. All these observations are consistent with the two locus hypothesis. Evidence obtained through an entirely different approach by McCo- NAGHY (1959) supports the participation of a dominant gene in the etiology of schizophrenia and suggests that by itself the gene may have an influence on basic patterns of thought. The present data are consistent with its expression as schizophrenia being dependent on a recessive modifying gene. Acknowledgements. - This work was carried out in Iceland, sponsored by the University of California and supported by grant number MH from the National Institute of hlental Health, United States Public Health Service. The author is indebted to Dr. GUDNI JONSSON for information about certain members of the family and to the staff of the Kleppur State Hospital for access to their records. SUMMARY The occurrence of schizophrenia is traced for six generations in a family in which the first case was described shortly after the middle of 18th century. It is demonstrated that the disorder has persisted in some segments of the family, apparently being transmitted indefinitely, while it has disappeared in others. The results are discussed in terms of Mendelian inheritance and specifically compared to predictions based on a mechanism involving two separate genes, one dominant and the other recessive.

12 138 J ~ LOVE N KARLSSON Literature cited Biiii~, J. A A genetic and neuropsychiatric investigation of a north-swedish population. - Acta Genet. 4: JACKSON, D. D The etiology of schizophrcnia. - New York: Basic Bool~s, Inc. JONSSON, G Bergsztt. - Reykjavik: lsafoldarprentsmidja. KALLMAN, F. J The genetics of schizophrenia. - New York: J. J. Augustin Heredity in health and mental disorder. - New York: W. \V. Norton. KARLSSON, J. L A hereditary niechanisni for schizophrenia based on two scparate genes, one dominant, the other rcccssive. - Hereditas 51 : LUXENBURGER, H Psychiatriscli-ncurologisclie Zwillingspathologie. - Zbl. 612s. Neurol. Psychiat. 56: hfcconaghy, N The use of an ohject sorting test in elucidating the hereditary factor in schizophrenia. - d. Neurol. Neurosnrg. and Psychiat. 22: SLATER, E The monogenic theory of schizophrenia. - Acta Genet. 8: