Departments of Psychological Medicine and Medical Genetics, University of Wales College of Medicine, Cardiff, London
Institute of Psychiatry, London
Correspondence: Professor Peter McGuffin, Director and Professor of Psychiatric Genetics, Social Genetic and Developmental Psychiatry (SGDP) Research Centre, Institute of Psychiatry, Kings College London, De Crespigny Park, London SE5 8AF, UK. Tel: 020 7848 0871; Fax: 020 7848 0866; e-mail: p.mcguffin{at}iop.kcl.ac.uk
Declaration of interest None. Funding from the National Institute of Mental Health and the Stanley Foundation.
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ABSTRACT |
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Aims To estimate the heritability of the nuclear syndrome.
Method A total of 224 twin pairs (106 monozygotic, 118 same-gender dizygotic) were ascertained from the Maudsley Twin Register in London via probands with any psychosis. Lifetime-ever first-rank symptoms were rated using the OPCRIT checklist. Probandwise concordance rates were calculated for the nuclear syndrome and a heritability estimate was derived from biometric model fitting.
Results Probandwise concordance rates were 13/49 (26.5%) for monozygotic and 0/45 to 2/46 (0.0-4.3%) for dizygotic pairs. The heritability estimate for the best-fitting model was 71% (95% CI 57-82).
Conclusions These results indicate that the nuclear syndrome shows substantial heritability, although this is slightly lower than that for schizophrenia as defined by the DSM and ICD systems.
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INTRODUCTION |
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The aim of the current study was to determine probandwise concordance rates and to make a heritability estimate for a syndrome characterised by the presence of one or more first-rank symptoms in a systematically ascertained sample of twins with any psychosis. The sample came from the Maudsley Hospital Twin Register and therefore included that of Gottesman & Shields (1972) as a subsample.
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METHOD |
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Zygosity determination was carried out blind to research diagnosis and was based on all the available information, including analysis of genetic markers in 42% of pairs. Agreement between zygosity determination by genetic markers and by resemblance information was 95%.
The sample comprised 224 probandwise twin pairs (120 male and 104 female), from which 28 probands (12.5%) were doubly ascertained after checking for independence of ascertainment. A total of 197 (87.9%) pairs were White. The mean age of co-twins at last follow-up was 46.5 years (s.d.=15.4). There was no substantial ascertainment bias for zygosity (106 MZ and 118 same-gender DZ pairs), but the sample may have contained more severe cases than if we had ascertained via a population-based sample (Cardno et al, 1999b).
Clinical assessment
This was based on all available clinical information, which included a
research interview (Gottesman & Shields'
(1972) cued-questions interview
and/or the Schedule for Affective Disorders and Schizophrenia Lifetime
version (SADS-L; Spitzer & Endicott,
1978)) in 72.8% of probands and 59.4% of co-twins. Interviewed
twins gave informed consent to be studied. Clinical ratings were made by
separate assessors for each member of twin pairs concordant for psychosis.
For each subject, first-rank symptoms were rated on the OPCRIT checklist (McGuffin et al, 1991), blind to the symptoms of the other twin, under the symptom categories of thought echo, third-person auditory hallucinations, running commentary voices, delusions of passivity, primary delusional perception, thought insertion, thought withdrawal and thought broadcast. Interrater reliability for rating the presence/ absence of first-rank symptoms was assessed on 30 cases. The mean kappa score between raters was 0.66.
Of the total, 94 probands were rated as having one or more first-rank symptoms: 57 (60.6%) were male and 37 (39.4%) were female. Probands had the following distribution of RDC main-lifetime diagnoses: schizophrenia, 67 (71.3%); schizoaffective disorder, 16 (17.0%); bipolar I disorder, 5 (5.3%); depressive psychosis, 3 (3.2%); and unspecified functional psychosis, 3 (3.2%).
In the whole sample of 224 probands, the frequency of probands having first-rank symptoms in each RDC main-lifetime diagnostic category was as follows: schizophrenia, 67/106 (63.2%); schizoaffective disorder, 16/33 (48.5%); bipolar I disorder, 5/27 (18.5%); bipolar II disorder, 0/4 (0.0%); depressive psychosis, 3/20 (15.0%); unspecified functional psychosis, 3/32 (9.4%); and other, 0/2 (0.0%).
Statistical analysis
Probandwise concordance rates for MZ and DZ pairs were calculated for a
nuclear syndrome characterised by the presence of one or more first-rank
symptoms. The population lifetime morbid risk for the nuclear syndrome was
estimated as described previously (Cardno
et al, 1999b), based on data from the
Camber-well Case Register and the twin series of Gottesman & Shields
(1972), and was 0.73% (95% CI
0.57-0.99). In case of any inaccuracy in the morbid risk estimate, the
analysis was performed for the actual estimate (0.73%) and also for the upper
extreme of the 95% confidence interval (0.99%) (because heritability estimates
tend to decrease as morbid risk estimates increase).
The Mx program (Neale,
1999) was used to calculate correlations in liability for the
nuclear syndrome. These are tetrachoric correlations, based on a
liability-threshold model (Falconer,
1965), that make use of concordance rates and estimates of morbid
risk. The Mx program was used also for biometric model fitting. Five models
were fitted, differing in the parameters that were assumed to contribute
variance in liability to the nuclear syndrome: individual specific
environmental variance only (E model); common and specific environmental
variance (CE model); additive genetic and specific environmental variance (AE
model); additive genetic, common and specific environmental variance (ACE
model); and additive genetic, genetic dominance and specific environmental
variance (ADE model). Nested models were compared using the 2
difference test. Where there was no significant difference the best-fitting
model was determined on grounds of parsimony, those models with fewer
parameters being preferred.
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RESULTS |
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The results of biometric model fitting for the nuclear syndrome, assuming a
DZ concordance rate of 2/46, are shown in
Table 1. The models of
individual specific environmental factors explaining all of the variance in
liability (E) and of common plus specific environmental variance (CE) could be
rejected by the 2 difference test compared with the models of
additive genetic, common environmental and specific environmental variance
(ACE) and additive genetic, genetic dominance and specific environmental
variance (ADE). However, the model of additive genetic and specific
environmental variance (AE) could not be rejected compared with the ACE and
ADE models, and on grounds of parsimony was the best-fitting model. The ACE
and ADE models could not be rejected formally; however, under the ACE model
the additive genetic variance (a2) remained the same (0.72
or 71%) and common environmental variance (c2) was
estimated as zero. Also, under the ADE model a2 was 0.43
and variance due to genetic dominance (d2) was 0.29, so
the total genetic variance remained similar at 0.72 or 72%.
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Similar results were obtained when the morbid risk estimate for the nuclear
syndrome was increased to 0.99% (the upper extreme of the 95% CI for the
morbid risk). The AE model was best fitting (2=0.51, d.f.=1,
P=0.48), with a2=0.69 (95% CI 0.54-0.81) and
e2=0.31 (95% CI 0.19-0.46). The results also remained
similar, assuming a DZ concordance of 0/45 (and a morbid risk of 0.73%). The
AE model again was best fitting, with a2=0.69 (95% CI
0.54-0.81) and e2=0.31 (95% CI 0.19-0.46); however, in
this case the model fitted less well (
2=5.55, d.f.=1,
P=0.02), probably because of the zero concordance rate for DZ
pairs.
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DISCUSSION |
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Comparison with other definitions of schizophrenia
The heritability estimate of 71% (95% CI 57-82) is substantial but somewhat
lower than heritability estimates based on the same sample for schizophrenia
defined according to RDC (82%, 95% CI 71-90), DSM-III-R
(American Psychiatric Association,
1987) (84%, 95% CI 19-92) and ICD-10 (83%, 95% CI 7-91) criteria
(Cardno et al,
1999b). However, the confidence intervals for all these
heritability estimates overlap. Indeed, it can be argued that the true
confidence intervals for our estimate of heritability should be even larger
because we explored a range of population frequencies without allowing for
error, and our interrater agreement, although good with a mean kappa of 0.66,
was not perfect.
Familial aggregation
It should be noted that the current study takes a different approach from
those that have investigated the familial aggregation of first-rank symptoms
in pairs of siblings (Cardno et al,
1998,
1999a; Loftus et
al, 1998,
2000) or twins (details
available from the author upon request) that are concordant for schizophrenia
or other psychoses. These studies generally have found only very modest
familial aggregation of first-rank symptoms within pairs of relatives who both
have psychosis. In addition, the presence of first-rank symptoms in
individuals with schizophrenia or other psychoses has not been found to
predict the risk of psychoses in their relatives
(Cardno et al, 1997),
including co-twins from the current sample (details available from the author
upon request). Therefore, first-rank symptoms do not appear to be useful
indicators of the level of genetic liability to psychoses in affected
individuals. However, as the current study shows, a syndrome defined by the
presence or absence of first-rank symptoms (where absence of first-rank
symptoms includes individuals unaffected by psychosis) may have substantial
heritability. It appears, from a genetic point of view, that first-rank
symptoms (and other positive psychotic symptoms) are fairly non-specific
epiphenomena of general psychotic processes. If so, other combinations of
psychotic symptoms, or individual symptoms, might well also show evidence of
heritability.
Implications for molecular genetic studies
The question remains whether the nuclear syndrome is likely to provide a
useful phenotypic definition for molecular genetic studies of schizophrenia.
Given that there are other operational definitions of schizophrenia that show
trends towards higher heritabilities, and that first-rank symptoms do not
appear to be markers of particularly high genetic liability to schizophrenia,
the answer probably is no.
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Clinical Implications and Limitations |
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LIMITATIONS
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ACKNOWLEDGMENTS |
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Received for publication May 8, 2001. Revision received September 10, 2001. Accepted for publication September 27, 2001.
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