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Clinical Variables and Genetic Loading
for Schizophrenia: Analysis of Published
Danish Adoption Study Data
by Alastair Q. Cardno, Katherine Thomas, and Peter McQuffin
be used to improve phenotypic definitions of schizophrenia in molecular genetic studies, for example; by including
the variables as covariates in linkage analyses (Greenwood
and Bull 1999).
Previous studies aimed at identifying clinical variables associated with high genetic loading for schizophrenia have generally been based on data from families or
pairs of monozygotic (MZ) twins and have sought to
determine whether clinical variables in affected probands
are associated with risk of schizophrenia or related disorders in their biological relatives. Greater familial risk has
been associated in some studies with earlier age of onset
(Kendler et al. 1987; Dworkin et al. 1988; Kendler and
MacLean 1990; Pulver and Liang 1991; Suvisaari et al.
1998), female sex (Goldstein et al. 1989, 1990; Sham et al.
1994a), poor premorbid adjustment (Dworkin et al. 1988),
the hebephrenic or nonparanoid subtype of schizophrenia
(Gottesman and Shields 1972; Kendler and Davis 1981;
Farmer et al. 1984; McGuffin et al. 1987), and severity of
negative (Dworkin and Lenzenweger 1984; McGuffin et
al. 1987, 1991; Van Os et al. 1997; Malaspina et al. 2000)
or disorganized (Cardno et al. 1997; Van Os et al. 1997)
symptomatology. However, such studies are unable to distinguish between genetic and shared environmental
effects.
In contrast, pairs of biological relatives from adoption
studies of schizophrenia do not share a family environment, which implies that variables in probands that are
associated with risk of schizophrenia in their relatives are
likely to be markers of genetic loading for schizophrenia.
The adoption studies of Kety and colleagues (1968,
1975, 1994) in Denmark provide vital evidence for the
role of genetic factors in the etiology of schizophrenia.
Furthermore, in the definitive report on the "provincial
sample" (Kety et al. 1994), covering adoptees in Denmark
Abstract
Schizophrenia shows considerable clinical variation,
but the relationship between clinical variables and
degree of genetic loading for schizophrenia is unclear.
We investigated this by analyzing published data from
the adoption study of Kety et al. (1994) in Denmark.
We sought to determine which clinical variables in
proband adoptees with chronic schizophrenia predicted risk of schizophrenia in their biological relatives, using logistic regression analysis. We found that
risk of chronic schizophrenia in relatives was predicted
by the presence of pervasive negative symptoms (odds
ratio [OR] = 9.44, 95% confidence interval [CI] =
1.98-45.01) and absence of pervasive positive symptoms (OR = 0.09, 95% CI = 0.01-0.78) in probands.
Pervasive negative symptoms were defined by the presence of all of the symptoms: social withdrawal, autistic
behavior, poverty of thought/speech, and flat affect.
Pervasive positive symptoms were defined by the presence of all of the symptoms: suspiciousness/ideas of reference, delusions, auditory hallucinations, and other
hallucinations. These clinical variables may be useful
for refining phenotypic definitions of schizophrenia in
molecular genetic studies.
Keywords: Schizophrenia, symptom, adoption,
genetic.
Schizophrenia Bulletin, 28(3):393-399,2002.
It is well established that genetic factors make an important contribution to the etiology of schizophrenia (Gottesman 1991; McGuffin et al. 1995) and that multiple genes
are involved in most, or all, cases (O'Rourke et al. 1982;
Risch 1990). This genetic complexity makes the process
of identifying specific susceptibility genes a formidable
task (Risch 2000); however, the endeavor may be considerably facilitated by identifying clinically relevant variables that are markers of particularly high genetic loading
(or liability) for schizophrenia. Such variables could then
Send reprint requests to Dr. P. McGuffin, Director and Professor of
Psychiatric Genetics, Social Genetic and Developmental Psychiatry
Research Centre, Institute of Psychiatry, Kings College London, De
Crespigny Park, London SE5 8AF, U.K.; e-mail: [email protected].
393
Schizophrenia Bulletin, Vol. 28, No. 3, 2002
A.G. Cardno et al.
outside Copenhagen, information is provided on the core
clinical features shown by each adoptee proband with
chronic schizophrenia, along with pedigree diagrams for
each proband giving details of the illness status of their
biological relatives.
The aim of the current study was, therefore, to determine which clinical features of adoptee probands from the
provincial adoption sample of Kety et al. (1994) are associated with the level of risk of schizophrenia in their biological
relatives and hence which clinical features are likely to be
markers of relatively high genetic loading for schizophrenia.
variables shown by each adoptee proband with chronic
schizophrenia (« = 29). In addition, the sex of each
proband is given in the pedigree diagrams shown in figure
1 of that article. After researchers combined certain variables that appeared a priori to be closely related, there
were eight variables for analysis in the current study: (1)
gender; (2) premorbid difficulties (defined as the presence
of both poor premorbid adjustment and premorbid
schizoid features); (3) age at onset (defined as age at first
hospitalization); (4) insidious onset; (5) chronic course;
(6) pervasive positive symptoms (defined by the presence
of all of the symptoms: suspiciousness/ideas of reference,
delusions, auditory hallucinations, and other hallucinations); (7) pervasive negative symptoms (defined by the
presence of all of the symptoms: social withdrawal, autistic behavior, poverty of thought/speech, and flat affect);
and (8) loose associations. All variables were categorical
(present/absent) except age at onset.
Methods
Sample. The sample is described in detail in the original
article (Kety et al. 1994). Briefly, the records of the
Danish Department of Justice were searched for every
recorded adoption, other than those to biological relatives,
that took place outside Copenhagen between 1942 and
1947. Adoptees who had developed schizophrenia were
identified via the Danish National Psychiatric Register,
which provides discharge diagnoses from all hospital
admissions; their biological parents, full siblings, and
half-siblings were identified via adoption and population
registers. In one family, there were two putative biological
fathers, both of whom were included in the study.
Psychiatric illness in the relatives was also identified via
the National Psychiatric Register. Control adoptees and
relatives were also identified, but data on these were not
analyzed in the current study.
Initial clinical abstracts based on hospital records
were augmented by structured research interviews conducted by researchers blind to illness and family status.
Consensus diagnoses were then made on the basis of all
relevant clinical information. The core diagnoses were
chronic schizophrenia—based on the descriptions of Kraepelin, Bleuler, and DSM-II—and latent schizophrenia,
which was described as "analogous but not identical with
the DSM-III diagnoses of schizotypal and paranoid personality disorders" (Kety et al. 1994, p. 444).
Statistics. These items were entered as independent variables into two forward stepwise (conditional) logistic
regression analyses in the Statistical Package for the
Social Sciences, Windows Version 10. The criterion for
entry of a variable in the analyses was p = 0.05. In the
first analysis, the dependent variable was the
presence/absence of chronic schizophrenia in each biological relative (n = 171). In the second analysis, the dependent variable was the presence/absence of chronic or
latent schizophrenia in each biological relative.
For variables showing a significant effect on risk of
schizophrenia in relatives, further analyses were performed to determine whether risk changed significantly
when alternative definitions of combined variables were
employed.
Results
The results of the logistic regression analysis for chronic
schizophrenia are shown in table 1. Chronic schizophrenia
in relatives was significantly predicted by the presence of
pervasive negative symptoms and the absence of pervasive
positive symptoms in probands. There was no significant
interaction between these two variables (Wald = 0.04, df=
Clinical Variables. Table 2 of the original article (Kety
et al. 1994) gives details of 14 illness history and clinical
Table 1. Logistic regression analysis of chronic schizophrenia in biological relatives on clinical
variables in adoptee probands
Clinical variables showing
significant associations
Pervasive negative symptoms
Pervasive positive symptoms
Wald(<ff=1)
p value
Correlation
Odds ratio (95% Cl)
7.93
4.75
0.005
0.030
0.30
-0.21
9.44(1.98-45.01)
0.09 (0.01-0.78)
Note.—Cl = confidence interval.
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Clinical Variables and Genetic Loading
Schizophrenia Bulletin, Vol. 28, No. 3, 2002
1, p = 0.84). There was a higher OR when these variables
were combined into a variable defined as the presence of
pervasive negative symptoms and the absence of pervasive
positive symptoms (Wald = 9.85, df=l,p = 0.002, OR =
13.37, 95% CI = 2.65 to 67.51); however, it should be
noted that this result was largely due to the fact that the
one proband who had this combined variable present (in
family 069) had three siblings with chronic schizophrenia.
The schizophrenia spectrum of chronic or latent schizophrenia in relatives was not significantly predicted by any
variable in probands.
The association between negative and positive symptoms in probands and risk of chronic schizophrenia in relatives was not strengthened by using narrower definitions
of symptoms or quantitative symptom scores. For a narrower definition of negative symptoms (poverty of
thought/speech and flat affect), Wald = 1.64, df = 1, p =
0.20, OR = 2.60 (95% CI = 0.60-11.18); for a narrower
definition of positive symptoms (delusions and auditory
hallucinations), Wald = 0.02, df=l,p = 0.88, OR = 1.19
(95% CI = 0.12-11.76). For negative symptom score
(number of negative symptoms present; range = 0-4),
Wald = 1.34, df= 1, p = 0.25, OR = 1.42 (95% CI =
0.78-2.60); for positive symptom score (number of positive symptoms present; range = 0-4), Wald = 2.45, df=\,
p = 0.12, OR = 0.57 (95% CI = 0.28-1.15).
Discussion
The main findings of this study are that the presence of
pervasive negative symptoms and the absence of pervasive
positive symptoms in adoptee probands significantly predicts the presence of chronic schizophrenia in their biological relatives. This is consistent with these two variables
being markers of relatively high genetic loading for schizophrenia.
Several previous studies have found that more prominent negative symptoms are associated with greater familial risk of schizophrenia and related psychoses. In a study
that involved making symptom ratings from published
case summaries of MZ twins with clinically defined schizophrenia, Dworkin and Lenzenweger (1984) found that
concordance for schizophrenia was greater when probands
had high negative symptom scores than when they had
low negative symptom scores. These authors used a broad
definition of negative symptoms that included social withdrawal in addition to poverty of speech and restricted
affect. However, McGuffin et al. (1991) found a similar
trend using Crow's (1980) narrow definition of negative
symptoms (i.e., not including social withdrawal) when
they rated the case summaries from one of the twin series
(Gottesman and Shields 1972) rated by Dworkin and
Lenzenweger (1984).
395
In a family history study of probands with Research
Diagnostic Criteria (RDC) schizophrenia or schizoaffective disorder, McGuffin et al. (1991) found a significantly
higher morbid risk of schizophrenia or other nonaffective
psychosis in parents of probands with narrowly defined
negative symptoms compared with parents of probands
with no negative symptoms, and similar trends for morbid
risks in siblings and offspring of probands. In a family history study, this time of all psychoses, Van Os et al. (1997)
found that higher familial risk was associated with higher
scores on a negative dimension derived from factor analysis that was characterized by blunted affect but also by
early and insidious onset. In a family history study of
probands with DSM-IH-R schizophrenia, Malaspina et al.
(2000) found an association between a family history of
schizophrenia-related psychosis and severity of negative
symptoms in probands, particularly symptoms related to
social withdrawal.
Other studies have found no clear relationship between
negative symptoms and familial morbid risk. In a family
history study of probands with RDC schizophrenia
(Cardno et al. 1997) based on a subset of the data analyzed
by McGuffin et al. (1991), no significant relationship was
found between negative symptom factor scores (poverty of
speech and restricted affect) and morbid risk of schizophrenia or other nonaffective psychosis in first degree relatives.
In the epidemiologically based Roscommon family study
of probands with DSM-IH-R schizophrenia, Kendler et al.
(1994ft) found that total score on the broad Scale for the
Assessment of Negative Symptoms (Andreasen 1984)
weakly predicted morbid risk of schizophrenia in relatives
(Cox model risk ratio 1.09) but that the trend weakened
when the risk of schizophrenia spectrum disorders was
included and when other definitions of negative symptoms
(based on factor scores) and other analytical approaches
(presence/absence of a family history) were used. However, it is notable that the approach that produced the
strongest effect has consistency with the approach that produced the strongest effect in the current study—namely,
using a broad rather than narrow definition of negative
symptoms and investigating familial risk of schizophrenia
rather than wider definitions including spectrum disorders.
There is also interest in persistent negative symptoms
or the deficit syndrome. We were unable to specifically
analyze persistent negative symptoms in the current study.
However, most previous studies have found either no relationship with familial risk of illness or a nonsignificant
trend toward higher familial risk when probands have persistent negative symptoms (Fenton and McGlashan 1994;
Verdoux et al. 1996; Kirkpatrick et al. 2000; Malaspino et
al. 2000).
In contrast to the above results, one family study
(Baron et al. 1992) found an association between promi-
Schizophrenia Bulletin, Vol. 28, No. 3, 2002
A.G. Cardno et al.
nent negative symptoms (broadly defined) in probands
who fulfilled criteria for both RDC and DSM-III schizophrenia, and lower morbid risk of schizophrenia in their
first degree relatives. The reasons for this discrepancy are
unclear, but possibly relevant factors include definitions of
schizophrenia in probands that do not emphasize negative
symptoms, and cross-sectional (rather than lifetime) evaluation of symptoms. The result could also potentially have
been due simply to sampling variation.
Most previous studies have found no clear relationship between level of positive symptoms and familial risk
of schizophrenia (Dworkin and Lenzenweger 1984; Baron
et al. 1992; Kendler et al. 1994&; Cardno et al. 1997; Van
Os et al. 1997). However, in a further analysis of MZ twin
data, Dworkin et al. (1988) found that concordance for
schizophrenia was predicted by probands having fewer
paranoid symptoms in addition to more negative symptoms, which is consistent with the results of the current
study.
Two family history studies (Cardno et al. 1997; Van
Os et al. 1997) have found that the strongest predictor of
familial risk of psychoses in relatives of probands with
RDC schizophrenia is higher levels of disorganized symptoms (positive formal thought disorder, inappropriate
affect, bizarre behavior). This dimension of psychopathology could not be investigated in the current study because
"loose associations" was the only symptom characteristic
of this dimension that was described in probands.
No significant association was found for age at onset
in the current study. Early age at onset has been associated
with higher familial liability in some studies of schizophrenia (Kendler et al. 1987; Dworkin et al. 1988; Kendler
and MacLean 1990; Pulver and Liang 1991; Suvisaari et
al. 1998) but not others (Kendler et al. 1987, 1996; Neale
et al. 1989). It is possible that the positive results are type I
errors; however, the consistency of the direction of results
suggests that there may be a small effect that is difficult to
replicate consistently.
The lack of significant findings for sex in the current
study is consistent with most previous studies (Cannon et
al. 1998; Sham et al. 19946; Kendler and Walsh 1995;
Suvisaari et al. 1998) but inconsistent with studies that
have reported an association between female sex and
higher familial loading for schizophrenia (Goldstein et al.
1989, 1990; Sham et al. 1994a). The positive studies could
have detected a subtle effect not found in previous studies,
although Goldstein et al. (1989) reported a risk ratio of
2.4, so the relationship between sex and familial risk of
schizophrenia remains unclear.
Poor premorbid social adjustment has been less investigated than the above variables but was associated with
higher concordance for schizophrenia in the twin analysis
of Dworkin et al. (1988). The reasons for the discrepancy
396
with the results of the current study are unclear, but potential differences in definitions of this variable and difficulties with making retrospective assessments may be relevant.
Limitations. The diagnoses of chronic and latent schizophrenia were based on criteria established by Kety and
colleagues, which were based on classical descriptions
rather than on published operational criteria. This issue is
discussed in the original article (Kety et al. 1994), where
it is argued that it may not be a limitation because,
although the narrower operational definitions enhance
reliability, they do not appear to be more genetically valid
than the authors' global diagnostic criteria, on the evidence of the Danish adoption studies (Kendler et al.
1994a; Kety et al. 1994). Also, in twin studies, the heritability of schizophrenia defined clinically in Scandinavia
and operationally in the United Kingdom is almost identical (Cannon et al. 1998; Cardno et al. 1999). An important
issue for the current study, however, is that negative
symptoms have probably been given more prominence in
the diagnosis of chronic schizophrenia than they are in
narrower operational definitions of schizophrenia, so negative symptoms are probably relatively prevalent in this
proband sample compared with samples defined by narrower operational criteria. However, this may have provided greater sensitivity for detecting a relationship
between prominent negative symptoms and familial risk
of schizophrenia than if narrower diagnostic criteria with
less emphasis on negative symptoms had been employed.
The symptoms shown by probands were listed but not
explicitly defined in the original article (Kety et al. 1994);
however, the authors state that they based their assessments on the descriptions of Kraepelin, Bleuler, and
DSM—II. As with most genetic studies, some symptoms
were rated retrospectively on the basis of hospital records.
The effects of this are not entirely predictable, but it is
most likely to have resulted in an underestimate of the true
frequency of symptoms in probands because routine clinical assessments may not inquire in detail about all symptoms relevant to a particular research study. This in turn is
likely to somewhat reduce the power to detect associations
between particular symptoms in probands and familial risk
of illness.
The ages of probands and relatives are not known, but
the assessment process included "careful follow-up" (Kety
et al. 1994, p. 445). It would have been interesting to analyze risks of chronic schizophrenia separately in parents,
full siblings, and half-siblings. However, the small number
of relatives in each category with chronic schizophrenia
meant that we could obtain meaningful results only for
parents: for prominent negative symptoms, Wald = 1.49, df
= 1, p = 0.22, OR = 5.32; and for prominent positive
Clinical Variables and Genetic Loading
Schizophrenia Bulletin, Vol. 28, No. 3, 2002
symptoms, Wald = 0.72, df=l,p = 0.40, OR = 0.32. In the
main analysis we made no weighting for half-siblings
because Kety (1983) has argued strongly against doing so.
Although this adoption sample is particularly informative for investigating the relationships between clinical
variation and genetic loading for schizophrenia, some caution is required when extrapolating the results to general
populations. Adoptees and their relatives are atypical in
various respects (Gottesman 1991). For example, adoptees
frequently have a family history of psychiatric illness, so
the proband sample in this study may have had higher than
average genetic loading for schizophrenia than people
with schizophrenia in the general population. Again, this
may have given us more power to detect associations
between clinical variables and familial risk of schizophrenia.
Conclusions. The results of this study are consistent with
the presence of pervasive negative symptoms and the
absence of pervasive positive symptoms (which is not the
same as the absence of positive symptoms) being markers
of relatively high genetic loading for schizophrenia. These
symptom groups may therefore be useful for refining the
schizophrenia phenotype in molecular genetic studies. For
example, a weighting function may be incorporated into
linkage analyses based on presumed level of genetic liability of an individual (Greenwood and Bull 1999), and
there may also be applications in association studies.
Based on the liability-threshold model (Falconer 1965),
any given susceptibility locus is more likely to be present
in individuals with high genetic liability to schizophrenia
than in individuals with schizophrenia in general.
Therefore, if, for example, an association is found
between a particular genetic polymorphism and schizophrenia, the effect size of this association should be
greater in the subsample of probands with high genetic
liability to schizophrenia than in the whole sample, if the
association is true.
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British Journal of Psychiatry, 168:620-626, 1996.
The Authors
Alastair G. Cardno, M.R.C.Psych., Ph.D., is Senior Lecturer in Neuropsychiatric Genetics, Departments of Psychological Medicine and Medical Genetics, University of
Wales College of Medicine, Cardiff, U.K. Katherine
Thomas is an undergraduate B.Sc. student in Applied Psychology, Department of Psychology, Cardiff University,
Cardiff, U.K. Peter McGuffin, F.R.C.Psych., Ph.D., is
Director and Professor of Psychiatric Genetics, Social
Genetic and Developmental Psychiatry Research Centre,
Institute of Psychiatry, Kings College London, London,
U.K.
Acknowledgments
We thank the late Seymour Kety and his colleagues for
kindly publishing the raw clinical and family data on
which this study was based.
399
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