1. American Psychiatric Association. (1980): Diagnostic and Statistical Manual of Mental Disorders, 3rd ed. American Psychiatric Association, Washington, D.C. 2. Clerget-Darpoux, F., Bonaiti-Pellie, C, and Feingold, N. (1984): In: Hystocompatibility Testing, edited by E. D. Albert et al., pp. 664-665. Springer Verlag, Berlin. 3. Goldin, L. R., Gershon, E. S., Targum, S. D., Sparkes, R. S., and McGinnis, M. (1983): Am. J. Hum. Genet., 35:274-287. 4. Heimbuch, R. C, Matthysse, S., and Kidd, К . К . (1980): Am. J. Hum. Genet., 32:564-574. 5. Kidd, К . К . (1983): Paper presented at The Aino Hospital Foundation International Conference on Genetic Aspects of Human Behavior. November 5-6, Kobe, Japan. 6. Kruger, S. D., Turner, W. J., and Kidd, К . К . (1982): Biol. Psychiatry, 17:1081-1099. 7. Ott, J. (1984): Am. J. Hum. Genet., 26:588-597. 8. Smeraldi, E., and Bellodi, L. (1981): Am. J. Psychiatry, 138:1232-1234. 9. Smeraldi, E., Negri, F., Melica, A. M., Scorza-Smeraldi, R., Fabio, G., Bonara, P., Bellodi, L., Sacchetti, E., Sabbadini-Villa, M. G., Cazzullo, С L., and Zanussi, С (1978): Neuropsychobiology, 4:344-352. 10. Smeraldi, E., Petroccione, A., Gasperini, M., Macciardi, F., and Orsini, A. (1984): J. Affective Disord., 7:99-107. 11. Smeraldi, E., Petroccione, A., Gasperini, M., Macciardi, F., Orsini, A., and Kidd, К . К . (1984): J. Affective Disord. ,6:139-151. 12. Smeraldi, E., Scorza-Smeraldi, R., and Cazzullo, С L. (1979): In: Biological Psychiatry Today, edited by J. Obiols et al., pp. 90-95. Elsevier, Amsterdam. 13. Suarez, В . К , and Reich, T. (1984): Arch. Gen. Psychiatry, 41:22-27. 14. Targum, S. D., Gershon, E. S., Van Eerdewegh, M., and Rogentin, N. (1979): Biol. Psychiatry, 14:615-636. 15. Tiwari, J. L., and Terasaky, P. I. (1985): Hla and Disease Associations. Springer Verlag, New York.
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Institute of Clinical Psychiatry, Milan Medical School, Ospedale S. Paolo, 20142 Milan, Italy
The linkage problem and linkage studies in recent years are a great focus in genetic research, because of their potential importance in giving us the oppor­tunity to better understand the inner genetic mechanisms at the chromosomal level, and thus allowing us to direct our attention to the hypothetical biological basis of the etiological processes of the disease. Segregation analysis may also give us reliable hypotheses about the genetic structure underlying affective dis­orders (10), but in any case the strongest evidence that they are primarily inherited (as opposed to culturally inherited), short of identifying a specific biochemical gene product, is to demonstrate genetic linkage to a well-defined marker (5). Ideally, the marker is itself an inherited characteristic that is polymorphic (i.e., it exists in two or more discrete forms that could be commonly found in the population), has a well-established and clearly understood mode of inheritance, is stable over time (not state dependent), is reliably detectable, and has been localized to a particular chromosomal region. Genetic linkage, then, is present when two or more loci are in close proximity on the same chromosome, so that genes residing at these loci fail to obey Mendel’s law of independent random assortment, and the degree of linkage is expressed in terms of recombination fraction (THETA). In a simplified way, THETA is a measure of the frequency that homologous chromosomes recombine in the region bounded by the two loci during meiosis. In this chapter we are particularly interested in the possible existence of a linkage between the Manic Depressive Illness (MDI) and the HLA system. The rationale of choosing the HLA system as a marker rests on two main points: (a) the HLA complex satisfies the requirements for a marker system probably better than any other potential marker (15), and (b) different investigators have suggested that one or more loci in the proximity of the HLA complex are capable of increasing susceptibility to affective disorders (13). There is at present a great debate about this point, and we will discuss later the effective role of the HLA complex in eliciting susceptibility to different diseases. (more…)

We studied the segregation pattern of MDI and HLA antigens combined in eight families, whose probands were diagnosed as having Major Affective Dis­orders, Recurrent, according to DSM-III (1), not taking into account the polarity of the disease. We investigated the first- and second-degree relatives of each proband with the Family Study Method using the same diagnostic criteria; for third- and fourth-degree relatives, as well as second-degree, when a personal interview was not possible, we used the Family History Method. All the probands and some of their first- and second-degree relatives were typed for their HLA structure, blind of their clinical diagnosis. For untyped subjects their HLA patterns were reconstructed when enough information allowed. To verify the hypothesis of a linkage between MDI and HLA, we applied the LIPED model (7). Parameters describing the MDI susceptibility locus were de­rived by the application of the multiple threshold models of transmission to a large sample of subjects and then experimentally tested (10). The result was a dominant SML with a reduced penetrance for the heterozygotes (q = 0.013, f(AA) = 0/0,f(Aa) = 0.923/0.926,f/(aa) = 1/1). Gene frequencies for HLA antigens were derived by a control population.
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Looking at our present data we can see the total lod-score values as a function of THETA for the hypotheses of a linkage with HLA В locus and A and В loci together (haplotypes). Figure 1 shows the findings that we observed for all our families tested. The
two curves each represent the sum of the lod-scores at the given THETA values obtained by the various families represented in the sample, so that the two curves are a graphical representation of total mean values. It should be noted that both the hypotheses of random assortment of the two loci (THETA = 0.5) and complete identity (THETA = 0.0) are unlikely, whereas the best lod-scores are comprised in a range of THETA values from 1.5 to 3.0, therefore indicating a mild to moderate physical genetic distance of the two loci (MDI and HLA) on the same chromosome. Even though numerical analysis does not offer exciting results (we lie in a sort of uncertainty zone where linkage could neither be strongly confirmed nor be ruled out), it can be seen that the hypothesis of a linkage with the В locus is better than with the haplotypic structure. Nevertheless, peaks of the two curves, corresponding to a kind of maximization of the test, are not too far from each other, thus corroborating a biological re­semblance of the two different hypotheses. We are still using a model of para-metrical analysis in which parameters are the genetic determinants of the marker locus and of the susceptibility (=MDI) locus. Consequently, when we look at the results obtainable for single families, we can observe a more complex pattern: The different behavior of the three families presented in Fig. 2 reveals the presence of heterogeneity that in this particular case is mainly, or exclusively, genetic in origin since it is based only on genetic parameters (such as gene frequency, penetrance variability). The exclusion of families with the worst results (for example, the dotted line family) may improve the total lod-score because it is likely that such families behave as having no linkage with the HLA complex. Moreover, among the various parameters we used, penetrance reveals the higher influence on linkage estimates. In fact, we know that a widely accepted way of measuring the penetrance defect of a complex character is to correlate the penetrance defect itself with the variability in age at onset distribution and to use this distribution for deriving, in a function too complex for description here, an age-corrected weight of every subject involved in the analysis (4). Figure 3 describes the effect of varying the ranges of age at onset distribution over the THETA estimates and also over the Log-Likelihoods values that represent the absolute probabilistic value for a given family. Thus, we must pay careful attention to treating and modifying the genetic parameters, and it should be remembered that the linkage models we used were originally built to study the simplest Mendelian all-or-none traits. When we modify these models to analyze non-Mendelian characters, methodological problems, as we pointed out earlier, may lower the reliability of the lod-score method. Finally, we used only data and genetic parameters strictly derived by experi­mental approaches without any modified simplification in order to obtain better results. In spite of all this, a comparison of our experimental data with the simulation data of Kruger et al. (6) shows a higher level of absolute probabilistic value that can be seen as an indirect proof of the good reliability of our results (Fig. 4). (more…)