A Contribution to The Aetiology of Manic-Depressive Insanity (1940)

 The Inheritance of Manic‑Depressive Insanity

     On the basis of my figures and of all those available in the literature, nothing very certain can be said on the inheritance of manic‑depressive insanity. Almost insuperable difficulties lie in the way of any single investigator's accumulating sufficient data to provide a firm foundation for a theory of inheritance. These difficulties have not always been held in mind by previous authors. More recent workers, such as Röll and Entres, and Wein­berg and Lobstein, have shown a commendable caution in speculation. Earlier workers, however, have on an insufficient factual basis produced a number of complicated theories of inheritance. Before one can judge these theories, it is necessary to examine the work on which they are based, and I would suggest that such works should attempt to fulfil the following criteria:‑

   (1) In the gathering of the material there should be no process of selection that is not scientifically justified, and clearly understood and stated by the author. (2) The original material should be, as regards the character investigated, genetically uniform. (5) The numbers of relatives investigated should be sufficiently large to reduce the errors of random sampling within reasonable limits. (4) All persons covered by the terms of reference should be included, and exhaustive, up‑to‑date, and reliable information should be obtained about each and all of them. (5) The diagnosis of presence or absence of the character examined for should be sufficiently well founded to command general agreement among those qualified to judge. (6) The statistical working out should be free from objection.

    Judged by these criteria there is no family investigation in psychiatry known to me that passes the test. Certain grave difficulties lie in the nature of the material itself. It is impossible to assure oneself of the genetic similarity of the material, but it is quite possible to attempt as close as possible a phenotypic similarity. Most authors do not take this nearly far enough. It is in the nature of work on human material, particularly in psychiatry, that exhaustive information about any one individual is really only to be obtained when he has been observed by experts over many years in a .hospital. Anything less than this is only an approximation to what would. be scientifically desirable. Nevertheless many authors are contented with much less information than would be available with more intensive work, and are ready to publish figures on such a basis, with the implicit assiption that their material is complete. When one considers that in only a minority of cases is the investigator lucky enough to obtain what knowledge he can in a short interview, and that in the often great majority he is compelled to rely on secondhand information, one is in a position to appreciae how shaky are the "facts" on which the grandiose superstructure of psychiatric genetic theory has been built. These are what one might call the genetic difficulties. To them must be added the difficulties that arise from our lack of knowledge of what is fact and what is theory in psychiatry. We have little ground for supposing that the clinical entity, which is a matter of conception and convenience, and the supposed underlying genetic entity correspond. To all these difficulties, genetic and psychiatric, must be added the practical difficulties of the investigation itself, the necessity for the investigator to reach a diagnosis on inadequate material, the im­possibility of excluding the influence of preconceptions on judg­ment, the highly inadequate and often frequently slipshod statistical methods so often employed. The criteria I have outlinedabove would be difficult to satisfy in their entirety, but much of the unsatisfactory character of family investigations in psychiatry hitherto is due to the investigators either having little idea that these requirements should be filled, or in any case making but a poor approach to their fulfilment.

    Hoffmann in 1921¹ published an investigation into the children of manic‑depressives and based a theory on his findings. His theory briefly is that there are three independent genetic factors, each as it were carrying different weights, a total weight being necessary to precipitate the individual into a psychosis. This theory was put forward to explain the very heavy incidence of manic‑depressives he found among the children of his propositi. Judged, however, by the criteria I have suggested above, his work fails to satisfy one of them. There is no sign that Hoffmann made any attempt to secure uniformity of material; his numbers are small and unsatisfactory for statistical working out; not more than one member of the family was seen in any case; the amount of information obtained, at least that which he prints, is very in­adequate; above all, his diagnosis of manic‑depressive insanit, among the children he investigated is such as to command general disagreement. Apparently led by a Kretschmerian psychiatry, he includes among manic‑depressives all persons in any way subject to swings of mood, however socially well adapted and unremarkable they may be, and he includes among slighter degrees of hypomanic and depressive temperaments such persons as he describes as "quiet humorists'. It is possible that such people as quiet humorists are found more frequently among the relatives of manic‑depressives than in the general population; this remains to be proved; but it gives no right to rank them with persons showing well‑marked cyclic character traits as carriers of manic‑depressive hereditary elements. The very heavy incidence of manic‑depressive insanity among the children of manic‑depressives found by Hoffmann seems to me to be largely explained by his tendency to exaggerate normals into abnormals, and mild character deviations into psychoses. The most cogent criticisms on psychiatric grounds have been made on Hoffmann's work by Wilmanns² and Mayer‑Gross³ and I will not go into the matter further. Finally, Hoffmarin did not attempt any adequate statistical evaluation of his material, and though Luxenburger⁴ has subsequently attempted to treat his figures so as to make them comparable with the figures obtained by others, I do not think that Hoffmann's material can stand the strain.

    Rüdin in 1925⁵ put forward a theory of inheritance involvingone autosomal dominant and. two autosonial recessive factors. This was a hypothesis for which the statistician Weinberg was responsible, and was based on Rüdin's work, which has never yet been published, and cannot be criticised. At that time much was still unknown in the field of general animal genetics, which has since discovered; but it is remarkable that a statistician like Weinberg should not have advocated caution in interpretation, when the practical difficulties of investigation were well known.

    Luxenburger in 1932⁶ advanced the theory of a single auto­somal dominant and an autosomal recessive factor being responsible for the inheritance of the tendency to manic‑depressive insanity. This theory ias based on the work of Hoffmann and of Rüdin and certainly did not take account of all the complicating and disturb­ing factors that may cause empirical findings to deviate from Men­delian expectations.

    The latest investigators to advance theories of inheritance in manic‑depressive insanity are Rosanoff, Handy, and Plessett,⁷ based on their work on manic-depressive insanity twins. They have put forward the theory of an additional sex-linked factor in order to explain the fact that the female sex is more frequently subject to manic-depressive illnesses than the male. Rüdin⁸ long ago pointed out how frequently, among the relatives of manic‑depressives, suicide in the male sex appeared to be a substitute for the develop­ment of a recognizable psychosis. Weinberg and Lobstein have also discussed this question at length and arrived at the conclusion that the overloading of the female sex is more apparent than actual. The greater frequency of the female sex among hospital patients cannot here be advanced as an argument against this view. In the samples of the general population which have been analysed here, there was only the most trifling difference of frequency of manic­depressives (who did not need to be hospital patients) in the two sexes, and that not of the slightest statistical significance.

    According to Rosanoff's theory, a dominant autosomal "cyclethyraic factor C must be combined with a dominant sex‑linked "activating" factor A, before the psychosis can appear. From the six different male and nine different female genotypes, fifty‑four possible crossings can be worked out, and all these are detailed by Rosanoff. This theory demands, of course, a frequency of manic‑depressive psychoses among women double that among men, which is not found empirically. One can, however, make another test. On the assumption of universal unselected mating and a more or lessequal frequency of the genes A and C one can calculate that the frequency of these genes must be in the neighbourhood of 0.03 to 0.04 in order to give a frequency of 0.0036 to 0.0039 manic‑depressives in the general population. On this assumption all homozygotes must be exceedingly rare; only those crossings pro­ductive of manic‑depressives which are cited in Rosanoff's formulae: 24, 26, 27, 28, 32, 41, 47, 49, and 50, will be comparatively frequent. One would therefore have to expect that male propositi would have manic‑depressive mothers but practically no manic‑depressive fathers; the propositae, however, manic‑depressive mothers and fathers in more or less equal proportions. In the same way, the propositi would produce for the most part manic‑depressive daughters; the propositae approximately equal numbers of manic‑depressive sons and daughters, with the daughters perhaps in slight excess. In other words, one would expect the sex distributions closely to resemble those of a simple sex‑linked dominance. My material provides the following figures:

In this table one can see how little my figures correspond to the numerical relations demanded by the Rosanoff hypothesis.

    Is it possible on the basis of the recent additions to knowledge made by Röll and Entres and by myself to advance any more satisfying theory of inheritance? I think not. It is necessary to point out that my own investigation fails in a number of particulars to fulfil the requirements I have laid down above.

     It cannot be claimed that thoroughly adequate information has been obtained about all the persons investigated. Their number is really inadequate to base any certain figures on my findings. It is on this account that I have given the standard deviation of all the percentages. It is generally assumed that the true fig­ure will lie within the limits given by the observed figure, plus or minus twice its standard deviation. Thus the frequency of manic‑depressives among the children of the "A"‑propositi was probably between 23.6% ± 2 x 5.1%, i.e. between 13.4% and 33.8'o. Such a large possible margin of error indicates the rather unsat­isfactory character of this type of investigation. Further points of possible criticism are that my diagnosis of manic‑depressive insanity in parents and children might well be questioned in many cases by competent psychiatrists, usually on the grounds of in­sufficiency of information. To this the only reply is that to class such persons statistically under such titles as "mental ill­ness, of unknown nature, but with affective features" would really understate the probabilities, and that it is sufficient if one ac­cepts the figures with the proviso that in a high proportion of cases the diagnosis has not been certainly established. Finally, it cannot be claimed for this work that the statistical working out is free from all source of objection.

    In our knowledge of the genetics of manic‑depressive insanity only two things stand out as fairly certainly established, firstly that it is inheritable, and secondly that the inheritance follows a dominant type. The simplest possible theory to account for the facts is that the inheritance depends on a single dominant autosomal gene. Once dominance is assumed, this theory must be shown to be inadequate before any other is even provisionally ac­cepted. There are not sufficient facts at present to reject this theory.

    On this theory the expectation of manic‑depressive insanity Long the parents, brothers and sisters, and children of manic­depressives would be 50%. The empirical findings are given in the following table:

In this table the results obtained by Weinberg's shorter method have been quoted, in order to keep results comparable.

    In the above table, all the results are seen to be confirma­tory of each other, with the exception of Luxenburger's figures for the children. These figures have been based on Hoffmann's work and have to be discarded. All the figures in the above table are far below the expected 50% level, and it is obvious that if we are to retain the simplest possible theory of inheritance, namely that of a single dominant factor, some explanation of the discrepancy must be possible.

    From the work of Rosanoff and co‑workers on the incidence of manic‑depressive insanity in uniovular twins, it appears that only about 70 of those supplied rith the necessary genetic factors actually develop the disease. The remaining 3 do not meet a sufficiently favourable environment, and escape. If this is cor­rect, our expectation of 5 incidence of manic‑depressive insanity among the parents, sibs, and children of manic‑depressives falls to 35. This is still a long way from the empirical finding of 10 ‑ l, and any explanation of the remaining discrepancy must remain highly speculative. It does, however, seem to me justi­fiable to draw attention to a further possible disturbing factor. There are theoretical grounds which make it possible that a part also of the difference between theory and expectation is itself genetically determined. These genetic influences are conveni­ently included under the term “genotypic milieu".

    The gene or genes responsible for the appearance of any character have to work not only in an external environment, which as Rosanoff's work has shown, may have a very large influence, but also in the internal environment of all the other genes which go to make up the hereditary structure of the individual. This geno­typic milieu is the same for both individuals in the case of uni­ovular twins, and so does not find expression in Rosanoff's figures. That it can be very important is shown by recent work on Drosophila. Timofeeff-Ressovsky⁹ has shown that the recessive gene "vena tranaversa interrupta", which brings about an interruption in the transverse vein; shows itself normally in homozygotic culture in only 1 to 5% of the flies, all of whom should exhibit the change. This percentage is raised to 40 to 100% if a second recessive gene is present also homozygotically, which by itself has no effect on the transverse vein, but shortens one of the long­itudinal veins. This is a good example of a "weak" gene,¹⁰ and weak genes are so common, that in spite of difficulties of investigation in their case, they are already held to be more frequent than the "strong". ones. Timofeeff remarks that it is absurd to speak of one gene as being the only one affecting a given change. Every single gene known in Drosophila can be shown to have an influence on several different qualities; and there is no change which is not affected by several different genes. In any single quality one is not dealing with a single gene, but with the totality of genes. Dominance and recessivity are not absolute but quantitative characters. All genes can be ranged on a scale passing from almost complete recessivity to almost complete dominance, and on quite another scale passing from very bad to very good manifestation. The two scales are not, however, related, and weakly manifesting dominant genes are very common.

    These considerations are important for human genetics. It seems possible that we are dealing in manic‑depressive insanity with just such a weak dominant gene, that manifests itself in only a proportion of its carriers. To say that the degree of manifestation of such a weakly dominant manic‑depressive factor is also affected by other genetic factors, is an entirely different thing from saying that manic‑depressive insanity is governed by two or three or more separate factors. The latter is a statement that the psychosis does not appear without all the factors being present, when 100% manifestation results. It seems quite possible that only one gene is responsible for the change, but the degree to which it mnifests itself will be governed by a variety of circumstances, genetic and environmental.

    There are, however, other criticisms of a theory of simple dominance. How on this basic are we to explain the bewildering variety of clinical syndromes? In the present state of our know­ledge this criticism has no weight. Apart from the predominant mood change, we have no idea what are the primary and what the secondary and inessential features of this illness. The great symptomatic variety is likely to be caused in part by the inclusion of what are not really manic‑depressive psychoses. Further, it is probable that in such a oonit ion, in which the uhole psyche is involved, many of the varying features are due to other qualities of temperament and character, which are conditioned by other and independent genetic factors. There is no convincing clinical reason for rejecting the theory of one single factor, as the main one responsible for this type of psychic breakdown.

    Before leaving this aspect of the subject, there is an impcrt­ant observation to make. Geneticists have shown that in the majority of known heritable abnormalities, of Drosophila for inetance, the same change may be brought about by a number of quite differ­ent and independent genetic factors. Similarly in man it has been shown that there are a number of different genetic types of syndactyly, polydactyly, etc. It may well be that the same holds for manic‑depressive insanity. All that I would assert at present is that in the typical recurrent manic‑depressives there is sufficient evidence to believe that this is governed in the majority of cases by a dominant type of inheritance, and that there is insufficient evidence to show that the hypothesis of a single dominant auto­somal factor as the main responsible agent is insufficient. I do not wish to assert that in the long run this theory will be found satisfying, nor to claim for it the least degree of originality. It is, however, a theory that will require disproving before other hypotheses can be usefull advanced.

(1)"Die Nachkommenschaft bei endogenen Psychosen” Berlin, 1921.
(2) Z. ges. Neurol. Psychiat. (1922) 78 : 351.
(3) Z. ges. Neurol. Psychiat. (1925) 100 : 467.
(4) Nervenarzt. (1932) 5 : 505.
(5) Z. ges. Neurol. Psychiat. (1923) 81 : 459.
(6) op. cit.
(7) Amer J. Psychiat. (1935) 91 : 725
(8) op. cit.
(9) Wissenschaftliche Woche. zu Frankfurt a/M. (1934) Leipzig, 1 : 92.
(10) "Weak" genes and low manifestation rates are famllir also in human genetics: for instance, modern authorities consider epiloiato be determined by a single dominant gene which is only manifested in a low propotions of carriers, and then often incompletely.