The genetics of schizophrenia: past, present, and future concepts

SCHIZOPHRENIA RESEARCH ELSEVIER

SchizophreniaResearch 28 (1997) 163 175

The genetics of schizophrenia: past, present, and future concepts L y n n E. DeLisi * State University of New York at Stony Brook, Health Sciences Center, T-IO, Stony Brook, NYl1794, USA

Received 13 March 1997; accepted 7 July 1997

Abstract

Although a genetic susceptibility for schizophrenia has been long established and even noted by Kraepelin in 1907, the mechanisms for its inheritance remains unknown. No candidates have proven to be correct and while many weakly positive chromosomal linkages have been reported, none have yet been consistently replicated. The following review examines the present status of these findings. The conclusion is that the field must move on to finding a consistently replicable mutation segregating with schizophrenia in families, before any of the present linkage results can be resolved. © 1997 Elsevier Science B.V. Keywords: Genetics; Dementia praecox; Genome scans; Chromosome 6; Chromosome 22; Chromosome, X

Approximately 100 years ago, Emil Kraepelin, when describing 'dementia praecox' in his classical textbook on psychiatry, observed that 'defective heredity is a very prominent factor...and appears in about 70% of cases' (Kraepelin, 1907). Present calculations based on monozygotic versus dizygotic twin concordance rates show that he was not far from wrong (McGuffin et al., 1984). Kraepelin also characterized dementia praecox as an illness with clear anatomical 'damage to the cerebral cortex' (Kraepelin, 1899). This observation has also been followed by an extensive literature showing brain structural anomalies in chronic schizophrenic patients. Thus, it is likely that the genetic defect(s) underlying susceptibility for schizophrenia affect mechanisms involved in brain development, growth, and plasticity. These genes may be active during embryonic periods of neuronal * Tel: + 1 516 444 1612;Fax + 1 516 444 7536; e-mail: [email protected] 0920-9964/97/$17.00© 1997ElsevierScienceB.V. All rights reserved. PH S0920-9964(97)00111-4

migration into cortex, again during times of adolescent neuronal pruning and dendritic rebranching, and then in adulthood during the normal aging process and reduction of cortical neuronal number and size. Schizophrenia is clearly a lifetime disease process and, although not clearly elucidated, may also be a lifetime genetic brain disorder with crucial defective genes playing a role on and off throughout the life span of an individual (DeLisi, 1997). Since Kraepelin's observations, an extensive series of large family and twin studies consistently supported a genetic etiology for schizophrenia. The debate over environment versus genes tilted in favor of the latter when results of adoption studies were reported. These showed that the increased risk for schizophrenia was present in biologic relatives of schizophrenic probands and not in the members of adoptive families with whom they resided (e.g. Kety et al., 1994). However, the mode of inheritance is clearly non-Mendelian, with reduced penetrance, i.e.

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LE. DeLisi / Schizophrenia Research 28 (1997) 163 175

individuals who can be shown to carry the gene(s) do not necessarily express the illness. Probably, the two most important controversial questions relevant to the genetics of schizophrenia today are: (1) whether one major gene or several genes, each producing a form of illness in different families or interacting as a group to cause schizophrenia, are to be found; and (2) whether the diagnostic boundaries for the phenotype include a wide range of syndromes, only the core Kraepelinian type of schizophrenia, or a combination of both depending on the specific gene involved. No data to date support any of the above more strongly, and the arguments for and against these hypotheses have been reviewed elsewhere (Cardno and Farmer, 1995; Crow, 1995; DeLisi and Nasrallah, 1995; Goldberg and Weinberger, 1995; Tsuang and Faraone, 1995). The traditional approach for finding a gene for an illness has until recently been first to uncover a biological marker specific for, and characteristic of, the illness that in addition has underlying genetic control. If this marker segregated with illness within families, it would be further proof that it was related to the inheritance of the specific disorder. Candidate genes could then be screened, such as in the search for the gene for phenylketonuria in the early 1980s (Lidsky et al., 1985). However, the availability over the past decade of increasingly advanced methods to examine the genome directly with densely placed DNA sequence markers throughout all 23 chromosomes has enabled the use of an extensive genomic screening approach without an a priori hypothesis or strong candidate locus to examine. The first aim is to map a region of the genome on a specific chromosome with high probability of linkage of the disease to this region, and then eventually to isolate the genomic sequence and examine its function. Application of these methods to finding genes for major psychiatric disorders is now in progress at several research facilities internationally, independently and together in large collaborative efforts. This new approach to a genomic search is performed in two major ways:

(1) by examining large sets of families with multiple ill members and calculating linkage of markers to the disease with families, and (2) by typing alleles at different loci to determine whether an excess of any specific allele is associated with illness. The latter, if present, would signify that either a variation in the specific locus examined leads to increased susceptibility for the disease, the disease locus is very close in genetic distance along the chromosome to the locus being examined (and thus in linkage disequilibrium with it), or the association is an artifact of differences among populations being compared (population stratification). Unfortunately, these are not easily distinguished, except by consistent independent replications and further support from linkage studies. The hallmark statistic of linkage studies has become the 'lod score' (the log of the ratio of the relative likelihood that a given set of results is evidence of linkage over the likelihood that it does not represent linkage) (Ott, 1991). The lod score has undergone many modifications in recent years so that heterogeneity can be taken into account, as well as nonparametric methods of analysis (e.g. no assumption about mode of inheritance in pairs of ill siblings). Thus, while in previous years, a lod score of above 3.0 (a 1/1000 chance that linkage is present) was taken as the gold standard for having found a disease locus for Mendelian inherited disorders, the standards for the new analyses, such as heterogeneity lods and maximum likelihood scores (MLS, converted from sib-pair analyses), are still being debated. There are very few hypotheses for chromosomal regions to examine. One methodology, previously providing success in nonpsychiatric disorders, has been to explore regions of chromosomes previously found to have reported chromosomal translocations in individuals with that disease, suggesting that chromosomal breakpoints are natural accidents giving clues to the location of a disease gene. One such aberration was reported by Bassett et al. (1988). A family was found in which schizophrenia was associated with an unbalanced translocation of a region of chromosome 5q to chromosome 1, causing a trisomy of the 5q segment in the ill

L.E. DeLisi / Schizophrenia Research 28 (1997) 163-175

individuals. A flurry of subsequent analyses of this region in families with schizophrenia then ensued, culminating in a publication by Sherrington et al. (1988) finding linkage of schizophrenia to this region and then several others following failure to replicate this finding. This led to a reluctance among investigators to become excited about positive findings in relatively small groups of families until either the findings were replicated in other independent cohorts or a whole genome screen in the same families failed to produce any other regions of positivity of equal or greater magnitude. As of December 1996, four genomic scans of schizophrenia have been published, and several more have been completed with analyses in progress. In these, a total of 143 families have been studied, and positive suggestions of linkage have been found on approximately half the total number of chromosomes, with no consistencies thus far across studies. These include findings on chromosomes 3, 4, 6, 8, 9, ll, 13, 14, 15, 17, 20, and 22 (Table 1).

Table 1 Genome scans of schizophrenia published by December 1996 References

No. of families

No. of markers

Spacing

Positive findings

Pulver et al. ( 1994a,b); Antonarakis et al. (1996)

57

520

20 cM

3p26-p24

9cM

8p22-p211 13q32 22qll-q12 6p21

(70%)

Moises et al. (1995b)

I: 5

413

II: 65 Barr et al. (1994a,b)

Coon et al. (1994b)

Total

7

9

143

10-20 cM

9p23-p21 20p12 4

Unlisted

11 17 4pll-qll

(84%) 180

329

14q32 1522ql 1-qter 3,4,6,8,9, 11, 13, 14, 15, 17, 20, 22

165

Other reports of linkage come from random findings in the beginning of genomic surveys that subsequently led investigators to focus efforts within that respective region. These include the report of linkage to 5p14-p13 (Silverman et al., 1996) and the findings of linkage on chromosome 6p24-p22 (Straub et al., 1995), llq21-q22 (St. Clair et al., 1990; Maziade et al., 1995), 13q32 (Lin et al., 1995), and Xp (both pseudoautosomal region and pl 1; Collinge et al., 1991; DeLisi et al., 1994b). Many of these positive reports have been followed by publications of failures to replicate the original finding or attempts to replicate them that have found linkages to other loci a considerable distance from the original linkage. The details of some of the major findings are discussed below.

1. Chromosome 6 (see Fig. 1)

Susceptibility to loci on this chromosome has long been of interest because of the location of the series of histocompatibility (HLA) genes on 6p22. However, while many inconsistent associations to specific HLA loci have been found in subgroups of patients with schizophrenia, no linkages to this region have been found in family studies (McGuffin et al., 1983; Goldin et al., 1987). Recently Wang et al. (1995) reported a positive linkage in this region, highest at the locus D6S260. This was followed, however, by another report on the same cohort of Irish families, but expanded with more individuals and corrections of some genotypes (Straub et al., 1995). The latter showed a peak lod score several centimorgans (cM) distance away at the locus D6S296, and a much lower lod score at the original locus, D6S260, thus not replicating the original results. To confuse the status of this finding further, other groups have had small positive findings spanning a distance of approximately 40 cM (Antonarakis et al., 1995; Moises et al., 1995a; Schwab et al., 1995a), while others have had negative ones (Gurling et al., 1995; Mowry et al., 1995; Brzustowicz et al., 1996; Garner et al., 1996). To resolve this issue, D. Levinson, in a large multicenter collaboration that included the above positive and negative attempts to replicate, sought to corn-

166

L.E. DeLisi / Schizophrenia Research 28 (1997) 163-175 L I N K A G E TO 8 Z / S A

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6 Fig. 1. Diagram of C h r o m o s o m e 6 indicating a linkage m a p of markers in the region of interest (6p24-22.2). Negative studies are indicated with the n u m b e r of families studied. Positive studies are indicated with a 't' next to the peak marker.

bine a consistent set of marker data for this region. A total of 463 pairs of siblings not included in the original data set from Straub et al. were included. However, this larger data set did not yield more definitive lod scores in either a positive or negative direction, thus adding even more confusion to the literature (Levinson, 1996). Our own data set on 211 families failed to confirm a linkage to any portion of this region (Garner et al., 1996). It is doubtful that linkage data alone will resolve this

controversy. Only the finding of a mutation that segregates with schizophrenia within families will yield the answer.

2. Chromosome 8 (see Fig. 2) The original finding of Pulver et al. (1995) within 8p22-p21, using heterogeneity lod scores, was only weakly supported by the results in the

L.E. DeLisi / Schizophrenia Research 28 (1997) 163-I 75

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8 Fig. 2. D i a g r a m of C h r o m o s o m e 8 indicating a linkage m a p of the region of interest on 8p.

Levinson (1996) collaboration, again with a heterogeneity lod score that did not increase with the larger data set and peaked approximately 14cM distal to the Pulver linkage at D8S261. Kendler et al. (1996) also reported a finding in this region (maximal with marker D8S1715, just distal to D8S261). Interestingly, Kendler reports that within his families, the peak lod scores for

chromosome 6 correlated with the peak lod scores on chromosome 8, but the significance of this correlation disappeared when the number of affected individuals within families was controlled in the analysis. Thus, these data could be falsepositives based on the higher likelihood of obtaining higher positivity by chance on larger, more informative families.

L.E. DeLisi / Schizophrenia Research 28 (1997) 163-175

168

3. Chromosome 18 (see Fig. 3)

D18S53 showed excess sharing of markers at p<0.02. However, since these families were by chance those with maternal evidence of transmission, this study was not a true test of the finding by Berrettini et al. In another independent study, Wildenauer et al. (1996) showed a maximum lod score of greater than 2.0 at the same locus in a similar number of families with schizophrenia with unknown patterns of inheritance. At least two other studies are negative so far, not only for the pericentric region but for markers on 18q23 (Fang et al., 1995; Moises et al., 1995b). Further evidence from other groups will be needed prior to pursuing more extensive analysis of this region in schizophrenia.

Berrettini et al. (1994) reported a linkage to bipolar disorder pericentomeric on chromosome 18, but only suggestive when non-parametric tests of linkage were used and found to be relevant to only a proportion of families, particularly those having non-maternal transmission of illness (Stine et al., 1995). This finding remains controversial, with some confirmations and further linkages suggested by other groups in other locations on the distal long arm of chromosome 18 (q23) (Freimer et al., 1996), not linked to the Berrettini region. Any finding in bipolar disorder deserves follow-up in famiies with schizophrenia, since it is likely that the phenotypic expression of different genotypes will cross clinical diagnostic boundaries. In DeLisi et al. (1995a), we failed to find any evidence of linkage in 32 families to the pericentric region, although a sib-pair analysis at the locus LINKAGE

TO S Z / S A

cM

Berrettini

J

4. Chromosome 22 (see Fig. 4) Findings on this chromosome have received considerably more attention than many of the

et al.

1994

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ZMAX

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Wildenauer

DeLisi 112

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et al. 1995 et al 1995b

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0.29 Neg.

996 R e q i o n

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22

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23

18 Fig. 3. Chromosome 18 indicating two positive regions of interest and negative and positive studies.

L.E. DeLisi / Schizophrenia Research 28 (1997) 163-175

LINEAGE 13

TQ.

169

8S/SA

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orge 8yndrole (VCF)

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1994

199s.

Fig. 4. Diagram of Chromosome 22 indicated the linkage distance for markers in the region of 22ql 1.2-13.1. Positive ('t') and negative studies are linked.

others. First, velocardiofacial (VCF) syndrome, resulting from a deletion on 22ql 1, has suggestive associations to schizophrenia. Some patients known to have this syndrome have psychotic features, either schizophrenia-like or more bipolar in diagnosis. In addition, the enzyme COMT (catechol O-methyltransferase) is mapped not far from this deleted region, and when this locus is included in the deletion, known psychotic symptoms are reported to be present (Lachman et al., 1996). Although unlinked and much distal to this locus on 22q12-13, Pulver et al. (1994a) and Coon et al. (1994a) reported interesting linkages to 22q in schizophrenia families. However, Pulver et al. (1994b) failed to confirm this in a larger collaboration with two other research centers. Our examination of this region in over 100 families was negative (Polymeropoulos et al., 1994), as was that of Schwab et al. (1995b) and Kalsi et al. (1995) in smaller groups of families. Nevertheless, other

findings were weakly positive (Moises et al., 1995a; Vallada et al., 1995a,b) with markers 8-11 cM proximal to the original Pulver et al. finding, but still distal and unlinked to the VCF syndrome region. In an attempt to resolve the significance of this region, Gill et al. (1996) organized a large multicenter collaboration, including all the above (total of 11 centers and 620 sib-pairs), to determine whether excess sharing exists at the D22S278 locus. These results were equivocal with Z2=9.31 and p = 0.001. Thus, whether a gene for schizophrenia exists in this region is still not resolved.

5. The X chromosome(see Fig. 5) Several years ago, we hypothesized that it was likely that a susceptibility gene might be located on the X chromosome (Crow, 1987, 1988; DeLisi et al., 1988). This hypothesis, however, has evolved

L.E. DeLisi / Schizophrenia Research 28 (I 997) 163-175

170

LINKAGE TO BZ/BA

I

22.3 22 2 22 1

/

21 3 21.2 21 I 114

~

DXYS14 Collinge et al. 1 9 9 1 MIC-2 50 23 DMD

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I

113

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20

ti:

Androgen Receptor Crow et al. 1 9 9 4

122 13 211 21 2 213

23 24 25

26 2~

~ P e l t o n e n - BP Mendlewicz - BP 1974 B a r o n - BP 1981 ~Del Zompo - BP 1984

28

X Fig. 5. The X Chromosome with linkage map distances for Xp. The positive studies are listed. Negative ones are included in the text. DeLisi et al. (1991) was negative for Xq27-28. Okoro et al. (1995) was negative for DXS7.

from suggesting that it could be pseudoautosomal (Crow, 1987) to suggesting that it may lie outside the pseudoautosomal region to include an X-Y homologous locus (Crow and DeLisi, 1991). It has also been suggested that the gene function involves the development of cerebral lateralization (Crow et al., 1989a; Crow, 1990, 1993). The evidence that a brain growth factor (or

more than one) is produced by a gene on the X chromosome is indirect and implied from cognitive studies of anomalous lateralization in individuals with extra X chromosomes (XXY and XXX) and from the knowledge that cognition in general must be determined by X chromosome factors, since over half the genes for mental retardation are X-linked (reviewed in DeLisi and Crow, in press).

171

L.E. DeLisi / Schizophrenia Research 28 (1997) 163-175

It is also curious that XXY and XXX individuals are increased among hospitalized patients with schizophrenia (reviewed in DeLisi et al., 1994a). There is an excess of same-sex concordance for schizophrenia among pairs of psychotic siblings that cannot be accounted for by the sex distribution in each cohort (Crow et al., 1989b, 1990). There is a sex difference in risk to relatives of schizophrenic probands and also sex differences in the clinical manifestations of the illness, particularly age of onset, which is likely to be genetically determined (reviewed in DeLisi and Crow, 1989). Taken together, the above observations could be accounted for by a locus for illness on these chromosomes, although, undoubtedly, there are alternative explanations for each. Most investigators have avoided molecular studies of the sex chromosomes because there has never been any indication that a significant proportion of families have an X-linked pattern of inheritance. The above pseudoautosomal and X-Y hypotheses for inheritance, however, allow for male-to-male transmission in families. While initial studies of the fragile X region on Xq28 were negative (DeLisi et al., 1991), studies on the short arm were more positive. The first report of a pseudoautosomal linkage was for a marker in the distal pseudoautosomal region (DXYS14) showing a weakly positive result for excess sharing of alleles at this highly polymorphic locus by pairs of schizophrenic siblings (Collinge et al., 1991). This finding was confirmed by one group (D'Amato et al., 1992) but never repeated by others (Asherson et al., 1992; Barr et al., 1994a,b; Wang et al., 1993; Maier et al., 1995); and in the same cohort, Crow et al. (1994) eventually concluded (using other distributed markers and lod scores) that it was unlikely for a locus to be situated in this distal Xp pseudoautosomal region. Nevertheless, the same cohort consistently remains weakly positive for a locus farther down in the X specific proximal short arm or pericentromeric region of X, possibly extending into the proximal long arm (Crow et al., 1993; DeLisi et al., 1994b, 1995b). Another investigator also has evidence of a possible Xp locus, either close to the D M D gene or a variant of it (Zatz et al., 1993). These results need further confirmation but are similar to the

suggestive positive findings reported above on other chromosomes.

6. Examination of candidate loci Another approach has been to examine genes for neuroreceptors known to be abnormal in previous neuropathologic studies of schizophrenia, particularly those binding dopamine and serotonin. Their map locations remain of interest as reports accumulate from systematic genomic screens in case one of these candidates is located within a putative chromosome region. However, thus far, none of the examinations of regions for these interesting candidates has yielded consistent and replicable results (Table2). No study has yet shown a mutation in a receptor gene that is associated with schizophrenia and that cosegregates with it in families.

7. Newly understood mechanisms of interest It is now recognized that some familial neurodegenerative syndromes are due to unstable repeat sequences present in the gene that can expand and in some cases decrease when transmitted from one generation to the next. On a clinical level, the phenomenon of 'anticipation' is usually observed with a progressively earlier age of onset and increasingly severe illness from generation to generation (reviewed by Petronis et al., 1995). There are some observations of cohorts of families with schizophrenia that show anticipation (DeLisi et al., Table 2 Candidate receptor genes and their examination Receptor

Location Initialpositive study

Negative reports (?)

D1B and D1 D2 D3 D4 D5 5-HT2A 5-HTIA

4p16,5q35 None 11q23 None 3q13.3 Crocq et al. (1992) 1lp15.5 None 4p 16-15 None 13q14-21 Williamset al. (1996) 5q11.2-13 None

None Yes Yes Yes Yes Yes None

172

L.E. DeLisi / Schizophrenia Research 28 (1997) 163-175

1993; Bassett and Honer, 1994). However, several artifacts related to collection bias can show this effect and do n o t have an underlying genetic basis. These can be resolved only by examining genes with repeat sequences with expansion potential. Several independent groups are pursuing this direction, although no clearly positive findings have emerged. Two separate groups show significantly m o r e non-specific expansions in schizophrenic groups as a whole but have not localized this finding in any specific region o f the genome (Morris et al., 1995; O ' D o n o v a n et al., 1995). The observation o f considerable discordance for illness a m o n g m o n o z y g o t i c twins has usually been used as evidence that an environmental factor must be involved in the expression o f illness. However, it is also clear that both ill and well twins are carrying the susceptibility gene, since the risk o f illness to their offspring remains the same ( G o t t e s m a n and Bertelsen, 1989). Therefore, another epigenetic p h e n o m e n o n must provide some explanation for lack o f clinical expression in the seemingly unaffected twin. Perhaps, differential methylation m a y provide protection. A n o t h e r new mechanism m a y be recognized in the near future.

8. Conclusions It is clear that the heritability o f schizophrenia is high, but the m o d e o f inheritance is nonMendelian and complex. N o biological factor is a consistent and specific genetic marker. The review above describes statistically positive findings for gene locations spread over half the genome. Several or all o f these are likely to be false-positive chance findings. At present, there is no way to detect which is m o r e likely to be a true linkage and if more than one locus exists, as m a n y investigators currently interpret the evidence. Only finding a consistently replicated m u t a t i o n segregating with schizophrenia in families will uncover the truepositive linkages.

Acknowledgment This w o r k is supported by funding f r o m the N I M H ( R 0 1 M H 4 4 2 4 5 ) . Angela Boccio-Smith

aided the a u t h o r in gathering the information and constructing the illustrations.

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