ANNUAL REVIEWS
Further
Quick links to online content Copyright 1975. All rights reserved
X-LINKAGE IN
+7127
Annu. Rev. Med. 1975.26:21-25. Downloaded from www.annualreviews.org Access provided by University of Toronto Library on 01/26/15. For personal use only.
MANIC-DEPRESSIVE ILLNESS Remi J. Cadoret, MD. and George Winokur, MD. Department of Psychiatry, University of Iowa College of Medicine, Iowa City, Iowa 52242
.,
Affective disorders comprise a large proportion of psychiatric illnesses, with morbid risk estimates in the general population running as high as 6-8% (1). These condi'\ tions primarily involve severe mood changes, and their characteristic course, as shown long ago by Kraepelin (2), is episodic with remission to the person's usual personality and psychological state between episodes. Mood changes take 'two direc tions: depressive, by far the most common, and manic, which is considerably rarer. In recent years considerable evidence has separated affective disorders into two separate illnesses: bipolar and unipolar (3-5). In the bipolar condition, mania occurs sometime during the course of the affective illness; in the unipolar, only depressive episodes occur. Evidence supporting this differentiation is of two kinds: (a) clinical data, which show differences between unipolar and bipolar iJlnesses in such variables as length of episode, number of episodes, and age of onset of the condition (4, 6, 7), and (b) familial data, which show that bipolar families have higher rates of psychosis, (3, 8-11) especially manic episodes (4, 6). Most important to the present paper, bipolar families have shown in some series a pattern 0/ inheritance of affective iJlness suggestive of X-linked dominance (12, 13). Dominant X-linked transmission should manifest itself in a number of ways. One consequence is that more females than males should be affected; in the general population this is found in two large epidemiological studies (1, 14). Most series of bipolar patients do shQw an excess of iJI females (4, 6, 12). Also, in the families of bipolar probands more females than males should be affected. In a comprehensive study of depressive illness, Winokur, Clayton & Reich found this to be true (15). If the sex ratio (Jiving males: living females) in families with bipolar illness shows a preponderance of females, findings such as this would be questionable. In a small study, Brown et al (16) showed an excess of all female relatives over male relatives, but, in other studies, (4, 13) the number of female relatives equals the number of male relatives. Another consequence of X-linked dominant inheritance is that ill males should have equal numbers of affected brothers and sisters; ill females should 21
Annu. Rev. Med. 1975.26:21-25. Downloaded from www.annualreviews.org Access provided by University of Toronto Library on 01/26/15. For personal use only.
22
CADORET & WINOKUR
have more ill sisters than brothers. This too was found by Winokur, Clayton & Reich (15). No father-to-son transmission of illness is a crucial consequence of an X-linked dominant condition. This is such an important point that we discuss it more completely below. The strongest point in favor of X-linkage would be the finding of linkage of the illness with a known genetic marker on the X chromosome. The most direct evidence of X-chromosome involvement with bipolar illness has come from linkage studies. In situations where two genes on the same chromosome are close enough that crossing-over during meiosis is infrequent, it is possible to trace both genes through a number of generations because of that close linkage, and thus demonstrate that the two genes are on the same chromosome. Two objectively measured genetic traits have been found to be linked to bipolar illness. These markers, the Xga antigen and red-green color blindness (both protan and deutan types), are both located on the X chromosome (17, IS). Two groups of investigators have published studies involving these markers and all published data positively demonstrate linkage between one of these genetic markers and bipolar affective disorder. Results from these studies (17-20) appear in Table 1. By combining the data of studies 2 and 3, Mendlewicz et al (21) demonstrated linkage by estimating the recombination fraction 8 (the relative frequency of "recombinants," or offspring· demonstrating crossing-over to the number of nonrecombinants). A 8 near zero implies very close linkage; one at 50%, no linkage. Mendlewicz et al reported a 8 of .11 ± .08 (8 ± standard error) for protan color blindness and .19 ± .10 for deutan color blindness. Both these values are significantly different from 8 50% and are consistent with genetic linkage. These same investigators (22) have computed 8 .23 with a values for linkage of Xga with manic-depressive illness and report 8 standard error of .10. Again, this is consistent with linkage. Although Xga and the color blindness loci are on the X chromosome, they do not show linkage because the long distance between them allows for frequent crossing over (23). The manic-depressive locus shows linkage with both Xga and the color blindness loci and thus is unique in bridging the gap between Xga and its linked conditions (ocular albinism and ichthyosis) and deutan color blindness with its linked conditions (hemophilia, protan color blindness, g-6-pd). The genetic map distance between gc6-pd and Xga appears to be at least �50 map units (21) since linkage is not detectable, which suggests that the manic-depressive locus could well fit in the intervening space. 1 Inspection of pedigrees from studies in Table I suggests a dominant-type trans mission, although Reich, Clayton & Winokur (17) argue cogently for a modified sex-linked dominance involving either (a) diminished penetrance of one gene or (b) more than one dominant gene necessary for manifestation of the illness. At the present time the question of penetrance or a second gene is unresolved (13). =
=
'Recent weak evidence cited by McKusick (Joseph C. Wilson lecture, University of Roches ter, Nov.
I, 1973) suggests that the Xga locus may be on the short arm of the X chromosome.
If this is true, it is unlikely that manic-depressive illness could be linked both to Xga and color blindness loci. We must await more definitive data on the location of Xg".
X-LINKAGE IN MANIC-DEPRESSIVE ILLNESS Table I
Linkage studies in bipolar affective disorder Study
1.
23
Results
Genetic Marker
Winokur & Tanna (18)
Report 3 pedigrees informative for linkage. In these,
10 children were
compatible with X-linked trans mission, one was incompatible. This difference is significant (2 of
Annu. Rev. Med. 1975.26:21-25. Downloaded from www.annualreviews.org Access provided by University of Toronto Library on 01/26/15. For personal use only.
the 3 families suggest specific link age with Xga blood system. This was not significant, however). 2.
Reich, Clayton &
red-green color
Report 2 pedigrees, one with pro
Winokur (17)
blindness
tan, the other with deutan color blindness. In each pedigree signifi cant evidence of linkage with color blindness was found. Pedigrees suggest dominant inheritance.
3. Fieve et a! (19)
red-green color
Report 8a pedigrees-4 with pro
blindness
tan and 4 with deutan color blind ness. Total of protan and deutan families gave significant evidence for linkage. Pedigrees fit a domi nant inheritance.
4.
Mendlewicz, Heiss &
Report 12a pedigrees for Xg3. Sig
Fieve (20)
nificant linkage reported.
a Since publication of these results, 9 additional families with red-green color blindness and 11 more families informative for Xg and affective disorder have been examined, and the cumulative results found consistent with X-linkage (32).
While an X-linked dominant transmission appears to account for the pattern of bipolar illness in some families, it has become increasingly apparent that it is incompatible with some patterns of illness in others. As noted above, if an X-linked dominant gene is needed for illness, the pattern of inheritance should show no ill father-son combinations. Results from different series have varied on this critical point. Table 2 shows the published data bearing on father-son transmission (15, 19, 24-29). Of the eight series presented, six report ill father-son pairs. As a diathesis for illness could come from the maternal side and result in apparent father-to-son transmission, it is essential to examine the maternal side to rule out this possibility. In four series shown in Table 2, those of Green et al (27), Fieve et al (19), Helzer & Winokur (28), and Von Greiff et al (29), the distaff side of the pedigree was investigated and ill father-son pairs occurred in families in whom no illness could be found on the maternal side. The Fieve data reporting ill father-son pairs are especially interesting since this series of patients also contained the families positive for X-linkage. A reasonable genetic interpretation of these results is that transmission in bipolar illness is heterogeneous, as is the case in other illnesses such as retinitis pigmentosa
24
CADORET & WINOKUR
Table 2
Father-to-son "transmission" of bipolar affective disorder Results
Series Compatible with X-linked Transmission
1. Winokur, Clayton &
In 89 families
no
ill father-son pairs.
In 55 families
no
ill father-son pairs.
Reich (15) 2.
Taylor & Abrams (24)
Annu. Rev. Med. 1975.26:21-25. Downloaded from www.annualreviews.org Access provided by University of Toronto Library on 01/26/15. For personal use only.
Series Not Compatible with X-linked Transmission as the Sole Transmission Possibility In series of 138 bipolar probands, 13 ill father-son
1. Perris (25)
pairs. Dunner, Gershon &
In 23 bipolar male patients, 4 had affectively ill
Goodwin (26)
fathers.
3.
Green et al (27)
In 35 bipolar families, 4 ill father-son pairs (no illness
4.
Fieve et al
2.
on maternal side).
(19)
In 120 bipolar probands, 13 ill father-son pairs
(9 pairs
no evidence of illness on maternal side). 5. Helzer & Winokur (28)
Of 30 male manics, 8 affectively ill mothers (41 %),
and 1 affectively ill father (5%); in another ill father-ill son pair, considerable affective disorder existed on the maternal side of the family. 6.
no
Von Greiff, McHugh &
In 16 male probands, 4 ill father-son pairs with
Stokes (29)
illness on maternal side; 3 ill father-son pairs did have illness on maternal side.
which is inherited in some families in an X-linked fashion and in others as an autosomal type (30). The importance of the present linkage studies lies in the fact that a genetic etiology in some families has been demonstrated for a major psychiat ric illness. This has some limited practical application at present in genetic counsel ing (3 1). Literature Cited
I. Helgason, R. 1964. Acta Psychiat. Scand. 40 (Suppl. 173):258
2. Kraepelin, E. 1901. Psychiatrie;. ein Lehrbuch for Studierende und Artze. Leipzig: Barth. 9th ed. 3. Leonhard, K. 1966. Aufteilung der En dogenen Psychosen. Berlin: Akad-Ver lag 4. Perris, C. 1966. Acta Psychiat. Scand. SuppL 194:420 5. Winokur, G., Clayton, P. 1967. Recent Advances in Biological Psychiatry, Vol. 9. New York: Plenum 6. Angst, J. 1966. Monographien aus dem Gesamtgebiete der Neurologie und Psy chiatrie, Vol. 112. Berlin: Springer 7. Cadoret, R., Winokur G. 1972. Int. J. Ment. Health. 1:159-75
8. Asano, N. 1967. In H. Mitsuda, Ed. Clinical Genetics in Psychiatry. Tokyo: Igaku Shoin 9. Dorzab, J., Baker, M., Cadoret, R., Winokur, G. 1971. Am. J. Psychiat. 127: 1128-33 10. Kinkelin, M. 1954. Schweiz. Arch. Neu rol. Psychiat. 73:100--146 11. Neele, E. 1949. Die phasischen Psy chosen nach ihrem Erscheinungs und Erbbild. Leipzij!: Barth 12. Cadoret, R., Wmokur, G., Clayton, P. 1970. Brit. J. Psychiat. 116:625-35 13. Winokur, G., Reich, T. 1970. Compr. Psychiat. II :93-99 14. Fremming, K. H. 1951. The Expecta tion of Mental Infirmity in a Sample of the Danish Population. London: Cassell
Annu. Rev. Med. 1975.26:21-25. Downloaded from www.annualreviews.org Access provided by University of Toronto Library on 01/26/15. For personal use only.
X-LINKAGE IN MANIC-DEPRESSIVE ILLNESS 15. Winokur, G., Clayton, P., Reich, T. 1970. Manic Depressive Disease. St. Louis: Mosby 16. Brown, R., Elston, R. C., Pollitzer, W. S., Prange, A., Wilson, I. 1973. BioI. Psychiat. 6:307-9 17. Reich, T., Clayton, P., Winokur, G. 1969. Am. J. Psychiat. 125:1358-69 18. Winokur, G., Tanna, V. L. 1969. Dis. Nerv. Syst. 30:89-93 19. Fieve, R, Mendlewicz, J., Rainer, J., Fleiss, J. 1974. Linkage studies in affec tive disorders, II. Color blindness and manic-depressive illness. In Genetics and Psychopathology, ed. R. Fieve, D. Rosenthal, H. Brill. Baltimore: Johns Hopkins Univ. 20. Mendlewicz, J., Fleiss, J., Fieve, R. 1974. Linkage studies in affective disor ders, I. Xg blood group and manic depressive illness. In Genetics and Psy chopathology, ed. R. Fieve, D. Rosen thal, H. Brill. Baltimore: Johns Hopkins Univ. 21. Mendlewicz, J., Fleiss, J. L., Fieve, R. R. 1972. J. Am. Med. Assoc. 222:1624--27 22. Fieve, R. R., Mendlewicz, J., Fleiss, J. L. 1973. Am. J. Psychiat. 130:1355-59 23. Race, R. R., Sanger R. 1968. Blood
25
Groups in Man. Philadelphia: Davis. 5th ed. 24. Taylor, M., Abrams, R 1973. Arch. Gen. Psychiat. 28:656-58 25. Perris, C. 1971. Brit. J. Psychiat. 118:207-10 26. Dunner, D., Gershon, E., Goodwin, F. K. 1969. Heritable Factors in the Se verity of Affective Illness. Presented at 123rd Ann. Meet. APA, San Francisco 27. Green, R., Goetze, V., Whybrow, P., Jackson, R 1973. J. Am. Med. Assoc. 223:1289 28. Helzer, J., Winokur, G. W. 1974. Arch. Gen. Psychiat. 31:73-77 29. Von Greiff, H., McHugh, P. R., Stokes, P. 1973. The Familial History in Sixteen Males with Bipolar Manic-Depressive Disorder. Presented at 63rd Ann. Meet.
Am. Psychopathol. Assoc., New York 30. Stern, C. 1960. Principles ofHuman Ge netics. San Francisco:Freeman. 2nd ed. 31. Cadoret, R. 1973. The Genetics ofAffec tive and Genetic Counseling. Presented at Workshop on Genetic Counseling, Univ. Indiana, Indianapolis, Indiana 32. Mendlewicz, J., Fleiss, J. 1974. Linkage studies with X-chromosome markers in bipolar (manic-depressive) and unipolar (depressive) illness. Recent Advan. BioI. Psychiat. In press
Further
Quick links to online content Copyright 1975. All rights reserved
X-LINKAGE IN
+7127
Annu. Rev. Med. 1975.26:21-25. Downloaded from www.annualreviews.org Access provided by University of Toronto Library on 01/26/15. For personal use only.
MANIC-DEPRESSIVE ILLNESS Remi J. Cadoret, MD. and George Winokur, MD. Department of Psychiatry, University of Iowa College of Medicine, Iowa City, Iowa 52242
.,
Affective disorders comprise a large proportion of psychiatric illnesses, with morbid risk estimates in the general population running as high as 6-8% (1). These condi'\ tions primarily involve severe mood changes, and their characteristic course, as shown long ago by Kraepelin (2), is episodic with remission to the person's usual personality and psychological state between episodes. Mood changes take 'two direc tions: depressive, by far the most common, and manic, which is considerably rarer. In recent years considerable evidence has separated affective disorders into two separate illnesses: bipolar and unipolar (3-5). In the bipolar condition, mania occurs sometime during the course of the affective illness; in the unipolar, only depressive episodes occur. Evidence supporting this differentiation is of two kinds: (a) clinical data, which show differences between unipolar and bipolar iJlnesses in such variables as length of episode, number of episodes, and age of onset of the condition (4, 6, 7), and (b) familial data, which show that bipolar families have higher rates of psychosis, (3, 8-11) especially manic episodes (4, 6). Most important to the present paper, bipolar families have shown in some series a pattern 0/ inheritance of affective iJlness suggestive of X-linked dominance (12, 13). Dominant X-linked transmission should manifest itself in a number of ways. One consequence is that more females than males should be affected; in the general population this is found in two large epidemiological studies (1, 14). Most series of bipolar patients do shQw an excess of iJI females (4, 6, 12). Also, in the families of bipolar probands more females than males should be affected. In a comprehensive study of depressive illness, Winokur, Clayton & Reich found this to be true (15). If the sex ratio (Jiving males: living females) in families with bipolar illness shows a preponderance of females, findings such as this would be questionable. In a small study, Brown et al (16) showed an excess of all female relatives over male relatives, but, in other studies, (4, 13) the number of female relatives equals the number of male relatives. Another consequence of X-linked dominant inheritance is that ill males should have equal numbers of affected brothers and sisters; ill females should 21
Annu. Rev. Med. 1975.26:21-25. Downloaded from www.annualreviews.org Access provided by University of Toronto Library on 01/26/15. For personal use only.
22
CADORET & WINOKUR
have more ill sisters than brothers. This too was found by Winokur, Clayton & Reich (15). No father-to-son transmission of illness is a crucial consequence of an X-linked dominant condition. This is such an important point that we discuss it more completely below. The strongest point in favor of X-linkage would be the finding of linkage of the illness with a known genetic marker on the X chromosome. The most direct evidence of X-chromosome involvement with bipolar illness has come from linkage studies. In situations where two genes on the same chromosome are close enough that crossing-over during meiosis is infrequent, it is possible to trace both genes through a number of generations because of that close linkage, and thus demonstrate that the two genes are on the same chromosome. Two objectively measured genetic traits have been found to be linked to bipolar illness. These markers, the Xga antigen and red-green color blindness (both protan and deutan types), are both located on the X chromosome (17, IS). Two groups of investigators have published studies involving these markers and all published data positively demonstrate linkage between one of these genetic markers and bipolar affective disorder. Results from these studies (17-20) appear in Table 1. By combining the data of studies 2 and 3, Mendlewicz et al (21) demonstrated linkage by estimating the recombination fraction 8 (the relative frequency of "recombinants," or offspring· demonstrating crossing-over to the number of nonrecombinants). A 8 near zero implies very close linkage; one at 50%, no linkage. Mendlewicz et al reported a 8 of .11 ± .08 (8 ± standard error) for protan color blindness and .19 ± .10 for deutan color blindness. Both these values are significantly different from 8 50% and are consistent with genetic linkage. These same investigators (22) have computed 8 .23 with a values for linkage of Xga with manic-depressive illness and report 8 standard error of .10. Again, this is consistent with linkage. Although Xga and the color blindness loci are on the X chromosome, they do not show linkage because the long distance between them allows for frequent crossing over (23). The manic-depressive locus shows linkage with both Xga and the color blindness loci and thus is unique in bridging the gap between Xga and its linked conditions (ocular albinism and ichthyosis) and deutan color blindness with its linked conditions (hemophilia, protan color blindness, g-6-pd). The genetic map distance between gc6-pd and Xga appears to be at least �50 map units (21) since linkage is not detectable, which suggests that the manic-depressive locus could well fit in the intervening space. 1 Inspection of pedigrees from studies in Table I suggests a dominant-type trans mission, although Reich, Clayton & Winokur (17) argue cogently for a modified sex-linked dominance involving either (a) diminished penetrance of one gene or (b) more than one dominant gene necessary for manifestation of the illness. At the present time the question of penetrance or a second gene is unresolved (13). =
=
'Recent weak evidence cited by McKusick (Joseph C. Wilson lecture, University of Roches ter, Nov.
I, 1973) suggests that the Xga locus may be on the short arm of the X chromosome.
If this is true, it is unlikely that manic-depressive illness could be linked both to Xga and color blindness loci. We must await more definitive data on the location of Xg".
X-LINKAGE IN MANIC-DEPRESSIVE ILLNESS Table I
Linkage studies in bipolar affective disorder Study
1.
23
Results
Genetic Marker
Winokur & Tanna (18)
Report 3 pedigrees informative for linkage. In these,
10 children were
compatible with X-linked trans mission, one was incompatible. This difference is significant (2 of
Annu. Rev. Med. 1975.26:21-25. Downloaded from www.annualreviews.org Access provided by University of Toronto Library on 01/26/15. For personal use only.
the 3 families suggest specific link age with Xga blood system. This was not significant, however). 2.
Reich, Clayton &
red-green color
Report 2 pedigrees, one with pro
Winokur (17)
blindness
tan, the other with deutan color blindness. In each pedigree signifi cant evidence of linkage with color blindness was found. Pedigrees suggest dominant inheritance.
3. Fieve et a! (19)
red-green color
Report 8a pedigrees-4 with pro
blindness
tan and 4 with deutan color blind ness. Total of protan and deutan families gave significant evidence for linkage. Pedigrees fit a domi nant inheritance.
4.
Mendlewicz, Heiss &
Report 12a pedigrees for Xg3. Sig
Fieve (20)
nificant linkage reported.
a Since publication of these results, 9 additional families with red-green color blindness and 11 more families informative for Xg and affective disorder have been examined, and the cumulative results found consistent with X-linkage (32).
While an X-linked dominant transmission appears to account for the pattern of bipolar illness in some families, it has become increasingly apparent that it is incompatible with some patterns of illness in others. As noted above, if an X-linked dominant gene is needed for illness, the pattern of inheritance should show no ill father-son combinations. Results from different series have varied on this critical point. Table 2 shows the published data bearing on father-son transmission (15, 19, 24-29). Of the eight series presented, six report ill father-son pairs. As a diathesis for illness could come from the maternal side and result in apparent father-to-son transmission, it is essential to examine the maternal side to rule out this possibility. In four series shown in Table 2, those of Green et al (27), Fieve et al (19), Helzer & Winokur (28), and Von Greiff et al (29), the distaff side of the pedigree was investigated and ill father-son pairs occurred in families in whom no illness could be found on the maternal side. The Fieve data reporting ill father-son pairs are especially interesting since this series of patients also contained the families positive for X-linkage. A reasonable genetic interpretation of these results is that transmission in bipolar illness is heterogeneous, as is the case in other illnesses such as retinitis pigmentosa
24
CADORET & WINOKUR
Table 2
Father-to-son "transmission" of bipolar affective disorder Results
Series Compatible with X-linked Transmission
1. Winokur, Clayton &
In 89 families
no
ill father-son pairs.
In 55 families
no
ill father-son pairs.
Reich (15) 2.
Taylor & Abrams (24)
Annu. Rev. Med. 1975.26:21-25. Downloaded from www.annualreviews.org Access provided by University of Toronto Library on 01/26/15. For personal use only.
Series Not Compatible with X-linked Transmission as the Sole Transmission Possibility In series of 138 bipolar probands, 13 ill father-son
1. Perris (25)
pairs. Dunner, Gershon &
In 23 bipolar male patients, 4 had affectively ill
Goodwin (26)
fathers.
3.
Green et al (27)
In 35 bipolar families, 4 ill father-son pairs (no illness
4.
Fieve et al
2.
on maternal side).
(19)
In 120 bipolar probands, 13 ill father-son pairs
(9 pairs
no evidence of illness on maternal side). 5. Helzer & Winokur (28)
Of 30 male manics, 8 affectively ill mothers (41 %),
and 1 affectively ill father (5%); in another ill father-ill son pair, considerable affective disorder existed on the maternal side of the family. 6.
no
Von Greiff, McHugh &
In 16 male probands, 4 ill father-son pairs with
Stokes (29)
illness on maternal side; 3 ill father-son pairs did have illness on maternal side.
which is inherited in some families in an X-linked fashion and in others as an autosomal type (30). The importance of the present linkage studies lies in the fact that a genetic etiology in some families has been demonstrated for a major psychiat ric illness. This has some limited practical application at present in genetic counsel ing (3 1). Literature Cited
I. Helgason, R. 1964. Acta Psychiat. Scand. 40 (Suppl. 173):258
2. Kraepelin, E. 1901. Psychiatrie;. ein Lehrbuch for Studierende und Artze. Leipzig: Barth. 9th ed. 3. Leonhard, K. 1966. Aufteilung der En dogenen Psychosen. Berlin: Akad-Ver lag 4. Perris, C. 1966. Acta Psychiat. Scand. SuppL 194:420 5. Winokur, G., Clayton, P. 1967. Recent Advances in Biological Psychiatry, Vol. 9. New York: Plenum 6. Angst, J. 1966. Monographien aus dem Gesamtgebiete der Neurologie und Psy chiatrie, Vol. 112. Berlin: Springer 7. Cadoret, R., Winokur G. 1972. Int. J. Ment. Health. 1:159-75
8. Asano, N. 1967. In H. Mitsuda, Ed. Clinical Genetics in Psychiatry. Tokyo: Igaku Shoin 9. Dorzab, J., Baker, M., Cadoret, R., Winokur, G. 1971. Am. J. Psychiat. 127: 1128-33 10. Kinkelin, M. 1954. Schweiz. Arch. Neu rol. Psychiat. 73:100--146 11. Neele, E. 1949. Die phasischen Psy chosen nach ihrem Erscheinungs und Erbbild. Leipzij!: Barth 12. Cadoret, R., Wmokur, G., Clayton, P. 1970. Brit. J. Psychiat. 116:625-35 13. Winokur, G., Reich, T. 1970. Compr. Psychiat. II :93-99 14. Fremming, K. H. 1951. The Expecta tion of Mental Infirmity in a Sample of the Danish Population. London: Cassell
Annu. Rev. Med. 1975.26:21-25. Downloaded from www.annualreviews.org Access provided by University of Toronto Library on 01/26/15. For personal use only.
X-LINKAGE IN MANIC-DEPRESSIVE ILLNESS 15. Winokur, G., Clayton, P., Reich, T. 1970. Manic Depressive Disease. St. Louis: Mosby 16. Brown, R., Elston, R. C., Pollitzer, W. S., Prange, A., Wilson, I. 1973. BioI. Psychiat. 6:307-9 17. Reich, T., Clayton, P., Winokur, G. 1969. Am. J. Psychiat. 125:1358-69 18. Winokur, G., Tanna, V. L. 1969. Dis. Nerv. Syst. 30:89-93 19. Fieve, R, Mendlewicz, J., Rainer, J., Fleiss, J. 1974. Linkage studies in affec tive disorders, II. Color blindness and manic-depressive illness. In Genetics and Psychopathology, ed. R. Fieve, D. Rosenthal, H. Brill. Baltimore: Johns Hopkins Univ. 20. Mendlewicz, J., Fleiss, J., Fieve, R. 1974. Linkage studies in affective disor ders, I. Xg blood group and manic depressive illness. In Genetics and Psy chopathology, ed. R. Fieve, D. Rosen thal, H. Brill. Baltimore: Johns Hopkins Univ. 21. Mendlewicz, J., Fleiss, J. L., Fieve, R. R. 1972. J. Am. Med. Assoc. 222:1624--27 22. Fieve, R. R., Mendlewicz, J., Fleiss, J. L. 1973. Am. J. Psychiat. 130:1355-59 23. Race, R. R., Sanger R. 1968. Blood
25
Groups in Man. Philadelphia: Davis. 5th ed. 24. Taylor, M., Abrams, R 1973. Arch. Gen. Psychiat. 28:656-58 25. Perris, C. 1971. Brit. J. Psychiat. 118:207-10 26. Dunner, D., Gershon, E., Goodwin, F. K. 1969. Heritable Factors in the Se verity of Affective Illness. Presented at 123rd Ann. Meet. APA, San Francisco 27. Green, R., Goetze, V., Whybrow, P., Jackson, R 1973. J. Am. Med. Assoc. 223:1289 28. Helzer, J., Winokur, G. W. 1974. Arch. Gen. Psychiat. 31:73-77 29. Von Greiff, H., McHugh, P. R., Stokes, P. 1973. The Familial History in Sixteen Males with Bipolar Manic-Depressive Disorder. Presented at 63rd Ann. Meet.
Am. Psychopathol. Assoc., New York 30. Stern, C. 1960. Principles ofHuman Ge netics. San Francisco:Freeman. 2nd ed. 31. Cadoret, R. 1973. The Genetics ofAffec tive and Genetic Counseling. Presented at Workshop on Genetic Counseling, Univ. Indiana, Indianapolis, Indiana 32. Mendlewicz, J., Fleiss, J. 1974. Linkage studies with X-chromosome markers in bipolar (manic-depressive) and unipolar (depressive) illness. Recent Advan. BioI. Psychiat. In press
