ANNUAL REVIEWS
Annu.
Rev. Med. 1991. 42:151-58
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Annu. Rev. Med. 1991.42:151-158. Downloaded from www.annualreviews.org Access provided by George Washington University - Gelman Main Library on 01/29/15. For personal use only.
GENETICS OF MAJOR PSYCHIATRIC DISORDERS Roland D. Ciaranello, M.D., and Andrea L. Ciaranello
Division of Child Psychiatry, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California 94305 KEY WORDS:
affective disorders, bipolar illness, major depressive disorder, schizophrenia, linkage, RFLP, lad scores
ABSTRACT
We review recent studies on the inheritance of affective disorders and schizophrenia. Both groups of diseases have substantial genetic and non genetic components, and their inheritance does not fit simple Mendelian models. Linkage studies implicate the Xp28 and 11p15 regions as potential disease loci in' affective illness, and the 5ql l -q13 region in schizophrenia. These conclusions are highly controversial, however, and must be viewed as extremely tentative. MAJOR AFFECTIVE ILLNESS
The major affective disorders comprise a heterogeneous group of illnesses whose underlying commonality is a disturbance of mood. Individuals with affective illness display mood extremes from euphoria to despair. Associated with these are disturbances in cognition, sleep, appetite, psychomotor function, and sexuality. Affective disorders typically strike in early adulthood, but they have been reported with increasing regularity even in very young children. The major affective disorders are subdivided into bipolar (manic-depressive disorder) and unipolar (depression only) groups. Bipolar disorder is frequently subdivided into bipolar I (presence of mania) and bipolar II (hypomania with a history of major depression) subgroups, Unipolar illness can be either episodic or recurrent. 151 0066-4219/91/0401-0151$02:00
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Genetic Epidemiology of Affective Disorders
Family, twin, and adoption studies consistently support the contribution of genetic factors to the development of both bipolar and unipolar illness (reviewed in 1). Family studies show an increased risk to first-degree relatives of probands with either unipolar or bipolar illness (2-5). Ger shon's group (I) estimated the age-corrected lifetime risk of affective illness to be 24% for relatives of a bipolar proband, 20.2% for relatives of a unipolar proband, 37.5% for relatives of a proband with schizo-affective illness (a disorder characterized by mixed symptoms of affective illness and schizophrenia), 21.6% for relatives of a proband with anorexia (sometimes classed as an affective illness), and 6.8% for normal controls. Results from twin and adoption studies also indicate a substantial gen etic contribution to affective illness. These studies show an increased con cordance in monozygotic compared to dizygotic twins, 0.67 vs 0.20 (1). There was a slightly higher concordance among bipolar monozygotic probands than unipolar (0.79 vs 0.54). Analysis of the concordant pairs for polarity showed 11 unipolar/unipolar, 14 bipolar/bipolar, and 7 uni polar/bipolar. These data hint at some genetic distinction based on polarity, but also point out the extensive similarity between unipolar and
bipolar patients. Segregation analyses have not been helpful in elucidating a mode of transmission in affective illness. There has been little evidence supporting the involvement of a single major gene. Linkage Studies in Affective Disorders
Early studies reported linkage between affective disorder and loci on the X chromosome for protan and deutan color blindness (6, 7) and to the Xg blood group locus (8). Subsequently, linkage of affective illness to Xg was ruled out in at least one study (9). There have been a few reports of linkage between bipolar illness and the human leukocyte antigen (HLA) system located on chromosome 6 (10, 11). However, these reports were disputed in subsequent studies ( 12, 13). Egeland and coworkers (14) reported a linkage between affective illness and DNA markers for the Harvey ras oncogene (HRAS1) and insulin (INS) loci on chromosome 11 in an Old Order Amish pedigree. The prevalence of bipolar disorder in the Amish mirrors that in the general North American population, as do its clinical characteristics and respon siveness to treatment (15-17). Pairwise linkage analysis between probes for HRASl and bipolar illness on one large, multigenerational pedigree gave a maximum log of odds (LOD) score of 3.340 at a recombination frequency e 0 for penetrance =
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of 0.63, and 4.083 for penetrance of 0.85. By convention, a LOD score of 3.0 is the threshold value for accepting the hypothesis of linkage at the specified recombination frequency rather than independent segregation, while LOD scores less than -2 are taken to exclude linkage. Three-point analyses indicated a close linkage to HRASI (LOD score of 4.904). Among the more interesting observations in this study was that clinically diverse forms of affective disorder-embracing bipolar I, bipolar II, major depressive disease, and schizo-affective disorder-shared a common chromosomal haplotype. Thus this study seemed to confirm what many researchers had suspected and suggested, that despite the diverse clinical presentations among affective disorders, a common genetic etiology, and therefore a common biology, might underlie them. Simultaneously, however, two other groups reported their inability to observe linkage at the same loci in other pedigrees. Hodgkinson et al ( 18) used probes for the HRASJ and INS loci, as well as a probe for tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis, which maps to the same region of chromosome Il pl 5. Positive linkage of affective illness to the tyrosine hydroxylase marker would have been especially exciting because of the long-standing implication of cate cholamines in these disorders. However, linkage between the three markers and bipolar illness was ruled out in three Icelandic pedigrees. Detera Wadleigh et al (19) studied kindreds from the National Institute of Mental Health repository, and were similarly unable to establish linkage between the HRASI locus and bipolar illness. Their conclusions were unaffected by narrowing the diagnostic classification to include discrete subtypes of affective disorder. Egeland and coworkers recently published an updated report on their Amish study (20). They conducted their genotyping collaboratively at two independent centers in St. Louis and Bethesda. Repeat diagnoses of the original core pedigree led them to reclassify two individuals without chang ing the LOD scores. However, the addition of more complete genotyping on ten unaffected members (who had been typed with only a single marker in the original study), plus the inclusion of two family members who were clinically unaffected in the first study but developed affective illness during the follow-up period and several new family members, all combined to drastically reduce LOD scores to -9.31 for HRASI and -7.75 for INS. Both scores are highly significant for the exclusion of linkage. The possibility of linkage to markers on the X chromosome was revived by Baron et al (21), who studied bipolar illness in Jerusalem. This patient population had high rates of affective disorder, particularly bipolar illness. Among the selection criteria was exclusion of families with evidence of male-to-male transmission. Color blindness (CB) was determined by clini-
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cal examination, and glucose 6-phosphate dehydrogenase (G6PD) deficiency by erythrocyte enzyme assay. Maximum LOD scores of 4.75 for color blindness and 2.94 for G6PD deficiency were observed. Multipoint analysis with both markers and affective illness suggested the bipolar locus may lie between the color blindness and G6PD deficiency loci, closer to color blindness. Neiswanger et al (22) studied three large families with unipolar affective illness; they excluded linkage of this disorder to loci on chromosome 11 that were within 28 centi-Morgans (cM) around the HRASI-INS cluster on Ilp l 5, and up to 5 cM around the DXS52 locus on Xq28,a region that includes the G6PD locus. However, since ascertainment in this study was limited to unipolar disorder,these results cannot be said to refute the work of Baron et al (21). SCHIZOPHRENIA
Schizophrenia is a term used to describe a group of disorders in which the primary clinical deficit is a disturbance of thinking. Schizophrenic individuals exhibit disordered thought processes and thought content and
a looseness of cognitive associations. They may experience auditory hal lucinations and persecutory delusions. Schizophrenia is usually divided into several subtypes, based on clinical mariifestations and symptom pre sentations. In none of the genetic studies we reviewed,. however, was subtype assignment carried out. Genetic Epidemiology of Schizophrenia
There have been numerous reviews on the inheritance of schizophrenia (23, 24). These address many of the major problems and issues in great detail, so we simply highlight them here. The major points are as follows: 1. Diagnosis is a major problem. For many years, the diagnosis of schizophrenia was idiosyncratic among investigators, which resulted in widely disparate estimates of prevalence among centers worldwide. Diag nosis has been improved by the use of standardized criteria; nevertheless the schizophrenias remain a heterogeneous cluster of symptomatic entities [what Kety (25) termed "phenomenologic clusters"], unlinked in any measurable way to defined medical or biologic markers. 2. There is a distinct familial aggregation in schizophrenia. Many studies have shown a familial aggregation of schizophrenia, although precisely what is aggregating is not known. Kendler (23) argued that what is likely to be transmitted is a liability to impaired psychosocial functioning or a liability to psychosis, but not a liability to all forms of mental illness nor to a narrowly defined form of schizophrenia. Family studies (26),twin
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studies (27), and adoption studies (28, 29) all point to the heritability of schizophrenia, although these studies also indicate a substantial nongenetic component. There is some evidence (24) that the operation of genetic factors is not uniform; they may be highly active in one family and inactive in another. Thus, the problem of phenocopies is very real. 3. The inheritance of schizophrenia does not fit any simple Mendelian model. While there is some evidence for vertical transmission of schizo phrenia (24, 26, 30-32), single-gene models generally do not fit the data, while more complex models have been inconclusive. Multifactorial models have frequently been invoked, in which the aggregate contribution of several genes leads to crossing a threshold into clinical illness (23). Linkage Studies in Schizophrenia
Linkage studies in schizophrenia using conventional markers yield incon clusive results. In the past two years, studies with polymorphic DNA markers have appeared. Sherrin gton et al (33) identified a region of chro mosome 5q l l-q13 that showed linkage to schizophrenia in five Icelandic and two English families. Three models were tested: (a) only individuals with typical schizophrenia were classed as affected, (b) people with either schizophrenia or schizophrenic spectrum disorders were included, and (c) people with schizophrenia, with schizophrenic spectrum disorders, or with schizoid personality disorders, phobic disorder, and affective illnesses were classed as affected. The strongest evidence for linkage occurred in the third model. Multi point analysis gave a total LOD score of 6.49 at a penetrance of 0.86 for a dominant schizophrenia susceptibility allele and two markers in the 5ql1-q13 region. The observation that maximum linkage estimates were obtained in the most clinically diverse model suggests that clinical hetero geneity may overlie a common genotype. Although the data indicate a dominant inheritance pattern in this collection of families, they may not be applicable to other pedigrees. By using an Icelandic sample, Sherrington et al may have over-represented an otherwise rare allele (34). However, while this may limit the generalizability of their findings, it in no way minimizes the value of learning what that rare allele is doing biologically. Concurrent with this report, Kennedy et al (35) reported their inability to detect linkage of schizophrenia to an expanded set of restriction fragment length polymorphism (RFLP) markers that included the regions probed by Sherrington et al. Kennedy et al studied a northern Swedish kindred that has been extensively examined for many years. The Diagnostic and Statistical Manual III (DSM-III) and Research Diagnostic Criteria (RDC) were used; those with schizophrenia were classed as affected, while other diagnoses were excluded.
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Two subsequent reports also failed to detect linkage to the 5ql l-q13 region. St. Clair et al (36) studied fifteen Scottish families, while Detera Wadleigh et al (37) tested five North American families. In the latter study, linkage was excluded despite an attempt to test multiple models of clinically affected individuals, as had been done by Sherrington et al. The initial attempt at reconciling these results again invoked the prob lem of genetic heterogeneity. This possibility remains the default position until some group replicates the Sherrington et al study in the same popu lation. However, Byerley (38) raised some methodologic issues that merit consideration. First, he questioned the relatively high penetrance estimate used in the studies by Sherrington et al and Kennedy et aI, arguing that these may have given undue weight to the information derived from unaffected individuals. This same point could be raised about penetrance estimates in the affective illness studies. Second, the kindred in the Kennedy et al study apparently has no cases of bipolar disorder. In contrast, the families in the studies by St. Clair et al and Detcra-Wadleigh et al had numerous cases of bipolar disorder (8 of 15 and 2 of 5 bipolar-positive families, respectively). Although Byerley is troubled because this weighting of bipolar illness might imply the cosegregation of two genes, one for each major disorder, another cause for concern is diagnostic misclassification. Some effort should be made to explain the unusual loading of affective illness in these latter two pedigrees. CONCLUSIONS
A major problem in psychiatric genetics, perhaps the fundamental problem, is that there are no objective diagnostic criteria. This has led to confusion and disagreement among investigators. Although the problem has been improved by the use of standardized criteria, the lack of a defined biologic marker still makes accurate diagnosis problematic. Genetic heterogeneity has frequently been invoked to explain contra dictory results. However, this hypothesis cannot be tested in the absence of definitive illness markers. Thus, while it remains a predictive explanation, it is inherently unsatisfying. Wc have argued that diagnostic error is a major contributor to the apparent presence of genetic heterogeneity (H. C. Kraemer and R. D. Ciaranello, in preparation). Clinical heterogeneity should not be overlooked as an important source of confusion. In addition to variable clinical presentations, the major psychiatric illnesses have delayed temporal onsets, variable clinical courses, and extended ages of risk. "Nonaffected" individuals, particularly in affective illness, have a significant lifetime risk for developing clinical illness; thus reevaluation of their status is a necessary part of the experi-
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mental design. Further, there appear to be significant nongenetic con tributions to these illnesses, so that the presence of phenocopies poses a substantial problem. Despite the lack of definitive conclusions, psychiatric geneticists remain cautiously optimistic. The complexity of these disorders challenges the limits of genetic methodologies and creates pressure for geneticists to develop new tools and strategies to investigate diseases that may be multi factorial, exhibit reduced penetrance, and have a significant nongenetic component. AC KNOWLEDGMENTS Work cited from the authors' laboratory is supported by grants from the National Institute of Mental Health (NIMH) (MH39437), and the John Merck, Spunk, and Rebecca and Solomon Baker Foundations. RDC is the recipient of a Research Scientist Award from the NIMH (MH200 19). The authors thank Dr. Anne Bowcock for her thoughtful review of the manuscript. Literature Cited 1. Gershon, E. S., Berrettini, W., Nurn berger, J. Jr., Goldin, L. 1987. Genetics of affective illness. In Psychophar macology: The Third Generation of Pro gress, ed. H. Y. Meltzer, pp. 481�91.
New York: Raven
2. Weissman, M. M., et al. 1984. Psychiatric
disorders in the relatives of probands with affective disorders. Arch. Gen. Psy chiatry 41: 13�21 3. Bland, R. C., Newman, S. c., Om, H. 1986. Recurrent and nonrecurrent depression: A family study. Arch. Gen. Psychiatry 43: 1085�89 4. Andreasen, N. c., et al. 1987. Familial rates of affective disorder. A report from the National Institute of Mental Health collaborative study. Arch. Gen. Psy chiatry 44: 461�69 5. Goldin, L. R., Gershon, E. S., Targum, S. D., Sparkes, R. S., McGinniss, M. 1983. Segregation and linkage analyses in families of patients with bipolar, unipolar, and schizoaffective mood disorders. Am. J. Hum. Genet. 35: 27487 6. Reich, T., Clayton, P. J., Winokur, G.
1969. Family history studies. V. The gen etics of mania. Am. J. Psychiatry 125:
1358�69 7. Fieve, R. R., Mendelewicz, J., Rainer, J. D., Fleiss, J. L. 1975. A dominant X-
linked factor in manic-depressive illness: Studies with color blindness. In
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Research in Psychiatry, ed. R. R. Fieve, D. Rosenthal, H. Brill, pp. 241�58. Bal timore: Johns Hopkins Univ. Press Mendelewicz, J., Fleiss, J. L., Fieve, R. R. 1975. Linkage studies in affective dis orders: The Xg blood group and manic depressive illness. See Ref. 7, pp. 219�32 Risch, N., Baron, M. 1982. X-linkage and genetic heterogeneity in bipolar related major affective illness: reanalysis of linkage data. Ann. Hum. Genet. 46: 1 53�66 Smeriadi, E., Neari, F., Melica, A., Scor za-Smeraldi, R. 1978. HLA system and affective disorders: A sibship genetic study. Tissue Antigens 12: 270�74 Weitkamp, L., Stancer, H., Persad, E., Flood, c., Guttoromsen, C. 1981. De pressive disorders and HLA: A gene on chromosome 6 that can affect behavior. N. Engl. J. Med. 305: 1301�6 Goldin, L., Clerget-Darpoux, F., Ger shon, E. 1982. Relationship of HLA to majur alTective disorder not suppor ted. Psychiatr. Res. 7: 29-45 Suarez, B. K., Reich, T. 19R4. HLA and major affective disorder. Arch. Gen. Psy chiatry 41: 22�27 Egeland, J., Gerhard, D. S., Pauls, D. L., Sussex, J. N. 1987. Bipolar affective
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disorders linked to DNA markers on chromosome II. Nature 325: 783-86 Egeland, J. A. 1972. Descendants of Christian Fisher and other Amish and Mennonite Pioneer Families. Baltimore: Johns Hopkins Univ. Press Egeland, 1. A., Hostetter, A. M. 1983. Amish Study, I: Affective disorders among t he Amish, 1976-1980. Am. J. Psychiatry 140: 56-61 Egeland, 1. A., Kidd, 1. R., Frazer, A., Kidd, K. K., Neuhauser, B. S. 1984. Amish Study, V: Lithium-sodium coun tertransport and catechol O-methyl transferase in pedigrees of bipolar pro brands. Am. J. Psychiatry 141: 1049-54 Hodgkinson, S., Sherrington, R., Gur ling, H. 1987. Molecular genetic evi dence for heterogeneity in manic de pression. Nature 325: 805-6 Detera-Wadleigh, S. D., et al. 1987. Close linkage of c-Harvey-ras- I and the insuli n gene to affective disorder is ruled out in three North American pedigrees. Nature 325: 806-8 Kelsoe, J. R., et al. 1989. Re-evaluation of the linkage relationship between chro mosome IIp loci and the gene for bi polar affective disorder in the Old Order
Amish. Nature 342: 238-43 21. Baron, M., et al. 1987. Genetic linkage between X-chromosome markers and bi polar affective disorders. Nature 326: 289-92 22. Neiswanger, K., et al. 1990. Evidence against close linkage of unipolar affec tive illness to human chromosome I Ip markers HRASI and INS and chro mosome Xq marker DXS52. Bioi. Psy chiatry 28: 63-72 23. K endl er, K. S. 1987. The genetics of schizophrenia: A current perspective. See Ref. I, pp. 705-13 24. Matthysse, S., Kety, S. S. 1986. The gen etics of psychiatric disorders. In Ameri can Handbook of Psychiatry, Vol. 8: Biological Psychiatry, ed. P. A. Berger, H. K. H. Brodie, pp. 160-69. New York: Basic
25. Kety, S. S. 1981. Problems of genetic research on psychiatric illness. In Gen etic Research Strategies for Psycho biology and Psychiatry, ed. E. S. Ger shon, S. Matthysse, X. O. Breakefield, R. D. Ciarancllo, pp. 395-97. Pacific Grove: Boxwood Press
26. Tsuang, M. T., Winokur, G., Crowe, R. R. 1980. Morbidity risks of schizo phrenia and affective disorders among
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first degree relatives of patients with schizophrenia, mania, depression, and surgical conditions. Br. J. Psychiatry 137: 497-504 Kety, S. S., Rosenthal, D., Wender, P. H., Schulsinger, F., Jacobsen, B. 1975. Mental illness in the biological and adoptive families of adopted individuals who have become schizophrenic: A pre liminary report based on psychiatric interviews. See Ref. 7 Wender, P. H., Rosenthal, D., Kety, S. S. 1968. A psychiatric assessment of t he adoptive parents of schizophrenics. In The Transmission of Schizophrenia, ed. D. Rosenthal, S. S. Kety. New York: Pergamon Wender, P. H., Rosenthal, D., Rainer, J. D., Greenhill, L., Sarlin, M. B. 1977. Schizophrenics' adopting parents. Psy chiatric status. Arch. Gen. Psychiatry 34: 777-84 Risch, N., Baron, M. 1984. Segregation analysis of schizophrenia and related disorders. Am. J. Hum. Genet. 36: 103959 Carter, C. L., Chung, C. S. 1980. Seg regation analysis of schizophrenia under a mixed genetic model. Hum. Hered. 30: 350-56
R. c., Namboodiri, K. K., Spence, M. A., Rainer, ]. D. 1978. A genetic study of schizophrenia p edigr ees. II. One-locus models. Neuropsychobiol ogy 4: 193-206 33. Sherrington, R., et al. 1988. Localization of a susceptibility locus for schizo phrenia on chromosome 5. Nature 336 :
32. Elston,
164-67 34. Lander, E. S. 1988. Splitting schizo phrenia. Nature 336: 105-6 35. Kennedy, 1. L., et al. 1988. Evidence against linkage of schizophrenia to mar kers on chromosome 5 in a northern Swedish pedigree. Nature 336: 167-70 36. St. Clair, D., Blackwood, D., Muir, W., Baillie, D., Hubbard, A., et al. 1989. No linkage of chromosome 5ql l -q13 mar kers to schizophrenia in Scottish fami
lies. Nature 339: 305-9 37. Detera-Wadleigh, S. D., Goldin, L. R., Sherrington, R., Encio, I., de Miguel, C., et al. 1989. Exclusion of linkage to 5q1113 in families with schizophrenia and other psychiatric disorders. Nature 340: 391-93 38. Byerley, W. F. 1989. Schizophrenia: gen etic linkage revisited. Nature 340: 34041
Annu.
Rev. Med. 1991. 42:151-58
Copyright © 1991 by
Annual
Reviews
Inc. All righls reserved
Further
Quick links to online content
Annu. Rev. Med. 1991.42:151-158. Downloaded from www.annualreviews.org Access provided by George Washington University - Gelman Main Library on 01/29/15. For personal use only.
GENETICS OF MAJOR PSYCHIATRIC DISORDERS Roland D. Ciaranello, M.D., and Andrea L. Ciaranello
Division of Child Psychiatry, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California 94305 KEY WORDS:
affective disorders, bipolar illness, major depressive disorder, schizophrenia, linkage, RFLP, lad scores
ABSTRACT
We review recent studies on the inheritance of affective disorders and schizophrenia. Both groups of diseases have substantial genetic and non genetic components, and their inheritance does not fit simple Mendelian models. Linkage studies implicate the Xp28 and 11p15 regions as potential disease loci in' affective illness, and the 5ql l -q13 region in schizophrenia. These conclusions are highly controversial, however, and must be viewed as extremely tentative. MAJOR AFFECTIVE ILLNESS
The major affective disorders comprise a heterogeneous group of illnesses whose underlying commonality is a disturbance of mood. Individuals with affective illness display mood extremes from euphoria to despair. Associated with these are disturbances in cognition, sleep, appetite, psychomotor function, and sexuality. Affective disorders typically strike in early adulthood, but they have been reported with increasing regularity even in very young children. The major affective disorders are subdivided into bipolar (manic-depressive disorder) and unipolar (depression only) groups. Bipolar disorder is frequently subdivided into bipolar I (presence of mania) and bipolar II (hypomania with a history of major depression) subgroups, Unipolar illness can be either episodic or recurrent. 151 0066-4219/91/0401-0151$02:00
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Annu. Rev. Med. 1991.42:151-158. Downloaded from www.annualreviews.org Access provided by George Washington University - Gelman Main Library on 01/29/15. For personal use only.
Genetic Epidemiology of Affective Disorders
Family, twin, and adoption studies consistently support the contribution of genetic factors to the development of both bipolar and unipolar illness (reviewed in 1). Family studies show an increased risk to first-degree relatives of probands with either unipolar or bipolar illness (2-5). Ger shon's group (I) estimated the age-corrected lifetime risk of affective illness to be 24% for relatives of a bipolar proband, 20.2% for relatives of a unipolar proband, 37.5% for relatives of a proband with schizo-affective illness (a disorder characterized by mixed symptoms of affective illness and schizophrenia), 21.6% for relatives of a proband with anorexia (sometimes classed as an affective illness), and 6.8% for normal controls. Results from twin and adoption studies also indicate a substantial gen etic contribution to affective illness. These studies show an increased con cordance in monozygotic compared to dizygotic twins, 0.67 vs 0.20 (1). There was a slightly higher concordance among bipolar monozygotic probands than unipolar (0.79 vs 0.54). Analysis of the concordant pairs for polarity showed 11 unipolar/unipolar, 14 bipolar/bipolar, and 7 uni polar/bipolar. These data hint at some genetic distinction based on polarity, but also point out the extensive similarity between unipolar and
bipolar patients. Segregation analyses have not been helpful in elucidating a mode of transmission in affective illness. There has been little evidence supporting the involvement of a single major gene. Linkage Studies in Affective Disorders
Early studies reported linkage between affective disorder and loci on the X chromosome for protan and deutan color blindness (6, 7) and to the Xg blood group locus (8). Subsequently, linkage of affective illness to Xg was ruled out in at least one study (9). There have been a few reports of linkage between bipolar illness and the human leukocyte antigen (HLA) system located on chromosome 6 (10, 11). However, these reports were disputed in subsequent studies ( 12, 13). Egeland and coworkers (14) reported a linkage between affective illness and DNA markers for the Harvey ras oncogene (HRAS1) and insulin (INS) loci on chromosome 11 in an Old Order Amish pedigree. The prevalence of bipolar disorder in the Amish mirrors that in the general North American population, as do its clinical characteristics and respon siveness to treatment (15-17). Pairwise linkage analysis between probes for HRASl and bipolar illness on one large, multigenerational pedigree gave a maximum log of odds (LOD) score of 3.340 at a recombination frequency e 0 for penetrance =
Annu. Rev. Med. 1991.42:151-158. Downloaded from www.annualreviews.org Access provided by George Washington University - Gelman Main Library on 01/29/15. For personal use only.
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of 0.63, and 4.083 for penetrance of 0.85. By convention, a LOD score of 3.0 is the threshold value for accepting the hypothesis of linkage at the specified recombination frequency rather than independent segregation, while LOD scores less than -2 are taken to exclude linkage. Three-point analyses indicated a close linkage to HRASI (LOD score of 4.904). Among the more interesting observations in this study was that clinically diverse forms of affective disorder-embracing bipolar I, bipolar II, major depressive disease, and schizo-affective disorder-shared a common chromosomal haplotype. Thus this study seemed to confirm what many researchers had suspected and suggested, that despite the diverse clinical presentations among affective disorders, a common genetic etiology, and therefore a common biology, might underlie them. Simultaneously, however, two other groups reported their inability to observe linkage at the same loci in other pedigrees. Hodgkinson et al ( 18) used probes for the HRASJ and INS loci, as well as a probe for tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis, which maps to the same region of chromosome Il pl 5. Positive linkage of affective illness to the tyrosine hydroxylase marker would have been especially exciting because of the long-standing implication of cate cholamines in these disorders. However, linkage between the three markers and bipolar illness was ruled out in three Icelandic pedigrees. Detera Wadleigh et al (19) studied kindreds from the National Institute of Mental Health repository, and were similarly unable to establish linkage between the HRASI locus and bipolar illness. Their conclusions were unaffected by narrowing the diagnostic classification to include discrete subtypes of affective disorder. Egeland and coworkers recently published an updated report on their Amish study (20). They conducted their genotyping collaboratively at two independent centers in St. Louis and Bethesda. Repeat diagnoses of the original core pedigree led them to reclassify two individuals without chang ing the LOD scores. However, the addition of more complete genotyping on ten unaffected members (who had been typed with only a single marker in the original study), plus the inclusion of two family members who were clinically unaffected in the first study but developed affective illness during the follow-up period and several new family members, all combined to drastically reduce LOD scores to -9.31 for HRASI and -7.75 for INS. Both scores are highly significant for the exclusion of linkage. The possibility of linkage to markers on the X chromosome was revived by Baron et al (21), who studied bipolar illness in Jerusalem. This patient population had high rates of affective disorder, particularly bipolar illness. Among the selection criteria was exclusion of families with evidence of male-to-male transmission. Color blindness (CB) was determined by clini-
Annu. Rev. Med. 1991.42:151-158. Downloaded from www.annualreviews.org Access provided by George Washington University - Gelman Main Library on 01/29/15. For personal use only.
154
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cal examination, and glucose 6-phosphate dehydrogenase (G6PD) deficiency by erythrocyte enzyme assay. Maximum LOD scores of 4.75 for color blindness and 2.94 for G6PD deficiency were observed. Multipoint analysis with both markers and affective illness suggested the bipolar locus may lie between the color blindness and G6PD deficiency loci, closer to color blindness. Neiswanger et al (22) studied three large families with unipolar affective illness; they excluded linkage of this disorder to loci on chromosome 11 that were within 28 centi-Morgans (cM) around the HRASI-INS cluster on Ilp l 5, and up to 5 cM around the DXS52 locus on Xq28,a region that includes the G6PD locus. However, since ascertainment in this study was limited to unipolar disorder,these results cannot be said to refute the work of Baron et al (21). SCHIZOPHRENIA
Schizophrenia is a term used to describe a group of disorders in which the primary clinical deficit is a disturbance of thinking. Schizophrenic individuals exhibit disordered thought processes and thought content and
a looseness of cognitive associations. They may experience auditory hal lucinations and persecutory delusions. Schizophrenia is usually divided into several subtypes, based on clinical mariifestations and symptom pre sentations. In none of the genetic studies we reviewed,. however, was subtype assignment carried out. Genetic Epidemiology of Schizophrenia
There have been numerous reviews on the inheritance of schizophrenia (23, 24). These address many of the major problems and issues in great detail, so we simply highlight them here. The major points are as follows: 1. Diagnosis is a major problem. For many years, the diagnosis of schizophrenia was idiosyncratic among investigators, which resulted in widely disparate estimates of prevalence among centers worldwide. Diag nosis has been improved by the use of standardized criteria; nevertheless the schizophrenias remain a heterogeneous cluster of symptomatic entities [what Kety (25) termed "phenomenologic clusters"], unlinked in any measurable way to defined medical or biologic markers. 2. There is a distinct familial aggregation in schizophrenia. Many studies have shown a familial aggregation of schizophrenia, although precisely what is aggregating is not known. Kendler (23) argued that what is likely to be transmitted is a liability to impaired psychosocial functioning or a liability to psychosis, but not a liability to all forms of mental illness nor to a narrowly defined form of schizophrenia. Family studies (26),twin
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studies (27), and adoption studies (28, 29) all point to the heritability of schizophrenia, although these studies also indicate a substantial nongenetic component. There is some evidence (24) that the operation of genetic factors is not uniform; they may be highly active in one family and inactive in another. Thus, the problem of phenocopies is very real. 3. The inheritance of schizophrenia does not fit any simple Mendelian model. While there is some evidence for vertical transmission of schizo phrenia (24, 26, 30-32), single-gene models generally do not fit the data, while more complex models have been inconclusive. Multifactorial models have frequently been invoked, in which the aggregate contribution of several genes leads to crossing a threshold into clinical illness (23). Linkage Studies in Schizophrenia
Linkage studies in schizophrenia using conventional markers yield incon clusive results. In the past two years, studies with polymorphic DNA markers have appeared. Sherrin gton et al (33) identified a region of chro mosome 5q l l-q13 that showed linkage to schizophrenia in five Icelandic and two English families. Three models were tested: (a) only individuals with typical schizophrenia were classed as affected, (b) people with either schizophrenia or schizophrenic spectrum disorders were included, and (c) people with schizophrenia, with schizophrenic spectrum disorders, or with schizoid personality disorders, phobic disorder, and affective illnesses were classed as affected. The strongest evidence for linkage occurred in the third model. Multi point analysis gave a total LOD score of 6.49 at a penetrance of 0.86 for a dominant schizophrenia susceptibility allele and two markers in the 5ql1-q13 region. The observation that maximum linkage estimates were obtained in the most clinically diverse model suggests that clinical hetero geneity may overlie a common genotype. Although the data indicate a dominant inheritance pattern in this collection of families, they may not be applicable to other pedigrees. By using an Icelandic sample, Sherrington et al may have over-represented an otherwise rare allele (34). However, while this may limit the generalizability of their findings, it in no way minimizes the value of learning what that rare allele is doing biologically. Concurrent with this report, Kennedy et al (35) reported their inability to detect linkage of schizophrenia to an expanded set of restriction fragment length polymorphism (RFLP) markers that included the regions probed by Sherrington et al. Kennedy et al studied a northern Swedish kindred that has been extensively examined for many years. The Diagnostic and Statistical Manual III (DSM-III) and Research Diagnostic Criteria (RDC) were used; those with schizophrenia were classed as affected, while other diagnoses were excluded.
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Two subsequent reports also failed to detect linkage to the 5ql l-q13 region. St. Clair et al (36) studied fifteen Scottish families, while Detera Wadleigh et al (37) tested five North American families. In the latter study, linkage was excluded despite an attempt to test multiple models of clinically affected individuals, as had been done by Sherrington et al. The initial attempt at reconciling these results again invoked the prob lem of genetic heterogeneity. This possibility remains the default position until some group replicates the Sherrington et al study in the same popu lation. However, Byerley (38) raised some methodologic issues that merit consideration. First, he questioned the relatively high penetrance estimate used in the studies by Sherrington et al and Kennedy et aI, arguing that these may have given undue weight to the information derived from unaffected individuals. This same point could be raised about penetrance estimates in the affective illness studies. Second, the kindred in the Kennedy et al study apparently has no cases of bipolar disorder. In contrast, the families in the studies by St. Clair et al and Detcra-Wadleigh et al had numerous cases of bipolar disorder (8 of 15 and 2 of 5 bipolar-positive families, respectively). Although Byerley is troubled because this weighting of bipolar illness might imply the cosegregation of two genes, one for each major disorder, another cause for concern is diagnostic misclassification. Some effort should be made to explain the unusual loading of affective illness in these latter two pedigrees. CONCLUSIONS
A major problem in psychiatric genetics, perhaps the fundamental problem, is that there are no objective diagnostic criteria. This has led to confusion and disagreement among investigators. Although the problem has been improved by the use of standardized criteria, the lack of a defined biologic marker still makes accurate diagnosis problematic. Genetic heterogeneity has frequently been invoked to explain contra dictory results. However, this hypothesis cannot be tested in the absence of definitive illness markers. Thus, while it remains a predictive explanation, it is inherently unsatisfying. Wc have argued that diagnostic error is a major contributor to the apparent presence of genetic heterogeneity (H. C. Kraemer and R. D. Ciaranello, in preparation). Clinical heterogeneity should not be overlooked as an important source of confusion. In addition to variable clinical presentations, the major psychiatric illnesses have delayed temporal onsets, variable clinical courses, and extended ages of risk. "Nonaffected" individuals, particularly in affective illness, have a significant lifetime risk for developing clinical illness; thus reevaluation of their status is a necessary part of the experi-
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mental design. Further, there appear to be significant nongenetic con tributions to these illnesses, so that the presence of phenocopies poses a substantial problem. Despite the lack of definitive conclusions, psychiatric geneticists remain cautiously optimistic. The complexity of these disorders challenges the limits of genetic methodologies and creates pressure for geneticists to develop new tools and strategies to investigate diseases that may be multi factorial, exhibit reduced penetrance, and have a significant nongenetic component. AC KNOWLEDGMENTS Work cited from the authors' laboratory is supported by grants from the National Institute of Mental Health (NIMH) (MH39437), and the John Merck, Spunk, and Rebecca and Solomon Baker Foundations. RDC is the recipient of a Research Scientist Award from the NIMH (MH200 19). The authors thank Dr. Anne Bowcock for her thoughtful review of the manuscript. Literature Cited 1. Gershon, E. S., Berrettini, W., Nurn berger, J. Jr., Goldin, L. 1987. Genetics of affective illness. In Psychophar macology: The Third Generation of Pro gress, ed. H. Y. Meltzer, pp. 481�91.
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