National Centre for Register-Based Research, Aarhus University, Denmark
Correspondence: Majella Byrne, National Centre for Register-Based Research, Aarhus University, Taasingegade I, Aarhus 8000 C, Denmark. E-mail: mb{at}ncrr.dk
* Presented in part at the European First Episode Schizophrenia Network
Meeting, Whistler BC, Canada, 27 April 2001.
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ABSTRACT |
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Aims To estimate the risks for schizophrenia associated with a range of psychiatric diagnoses in family members and to investigate the relationship between these risks and age at first contact for schizophrenia.
Method A nested casecontrol study design was employed. Psychiatric admission data and socio-economic data were available for 7704 cases admitted between 1981 and 1998 in Denmark, 192 590 gender- and age-matched controls, and for the parents and siblings of all subjects.
Results Controlling for socio-economic factors, risk for schizophrenia was associated with a family history of all psychiatric disorders except substance misuse and independently with a family history of suicide. The risk for schizophrenia associated with a family history of psychiatric disorders decreased as age at first contact increased.
Conclusions Risk for schizophrenia is associated with a range of psychiatric disorders in family members and these risks are not constant across the risk period.
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INTRODUCTION |
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METHOD |
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The socio-economic data were obtained from the Integrated Database for Longitudinal Labour Market Research or IDA database (Danmarks Statistiks, 1991), which includes linked information on employees and establishments. Data for this register comes from a number of administrative registers, e.g. the Danish tax authorities, the employment register, the CPR register and the education register, and can be followed over time. The information on people relates to the status in the last week of November in each year and there is continuous annual information available from 1980 to 1998. The register covers the total population and includes information on employment, education, marital status and income. All jobs are included and for each, information is available regarding the percentage of time during the year in work, salary, social benefits received during the year and type of job. For our purposes a random 5% sample of this register in addition to the patients and their families was used as the sample base from which the controls and their families were taken.
The Danish Psychiatric Central Register has monitored all psychiatric in-patient facilities in Denmark since 1969 (Munk-Jorgensen & Mortensen, 1997). There are no private psychiatric facilities in Denmark and all treatment is free of charge. All diagnoses were according to the WHO International Classification of Diseases, eighth revision (ICD-8; World Health Organization, 1967) until the end of December 1993 and according to the ICD-10 (World Health Organization, 1992) from January 1994. Parental and sibling psychiatric information related to the status before the date of first contact of the case so that only family members who had had a psychiatric contact before or on this date contributed information to the calculation of the risk associated with family history.
Study design
A time-matched, nested casecontrol study design
(Clayton & Hills, 1993) was
used to select the control sample.
Study population
For each case, 25 controls were randomly selected from a subsample of all
available controls fulfilling the matching criteria, i.e. were born in the
same calendar year, were of the same gender, and had not been admitted to a
psychiatric facility in Denmark before the date that the case was first
admitted.
Cases
The study sample comprised all persons aged over 15 years admitted to a
Danish psychiatric facility for the first time between 1981 and 1998 with an
ICD-8 295 or ICD-10 F20 diagnosis of schizophrenia and known maternal
identity. A total of 7704 persons with schizophrenia were identified, 92% had
links to a father (paternity not known/declared in 8%) and 66% were male.
Controls
The control sample consisted of 192 590 individuals, representing 25
controls per case, individually matched to the case on date of first admission
and gender and identified in the IDA database. The controls had the same
gender and age distribution as the cases and 96% had links to a father.
Socio-economic and demographic variables
Socio-economic and demographic data were included in this study to control
for the possible effects of confounding. Information included in the study was
extracted from the IDA database for cases, controls and their parents and
siblings for the year before the date when the person was first admitted. We
included information on occupational status in the following categories:
self-employed; paid employment; student; not in the work force; and labour
market status missing. For parents, we included educational level according to
three categories including basic education, high school education and
vocational training, and university level. We included a more detailed
description of education for the cases, including: basic school; high school;
vocational training; high school +3 years; bachelor's degree; and Master's
degree, doctorate. Other demographic variables included were marital status,
defined as single or married (including cohabiting), being the parent of a
child and parental age at birth of subject (grouped as <20, 20-25, 26-30,
31-35, 36-40, >40 years).
Family history
It was possible to obtain information relating to family history of
psychiatric contacts for mothers, fathers and siblings by linking with the
Danish Psychiatric Central Register. Initially the history of psychiatric
disorders in family members was defined in a hierarchical manner as follows:
schizoaffective disorder; schizophrenia; schizophrenia-like psychosis; bipolar
disorder; other affective disorder; other psychiatric disorder; and in
addition to the hierarchy, a history of substance misuse and suicide. To
increase statistical power and to simplify the models involving the
interaction between family history and age at first contact, controlling for
socio-economic and demographic variables, history of psychiatric disorders in
family members was combined into groups as follows: (a) schizophrenia,
schizoaffective disorder, and schizophrenia-like psychosis (ICD-8: 295, 295.7,
297, 298.39, 301.83; and ICD-10: F20, F25, F21-F24, F28, F29); (b) bipolar
illness and other affective illness (ICD-8: 296.1, 296.3, 296, 300.4; and
ICD-10: F30, F31, F34.0, F32-F39); (c) other psychiatric disorder (any other
diagnosis). Additional categories included family history of substance misuse
disorders (ICD-8: 303, 304; and ICD-10: F10.2, F11.2, F12.2, F13.2, F14.2,
F15.2, F16.2, F17.2, F18.2, F19.2) and a history of suicide in mothers,
fathers and siblings as identified in the Cause of Death Register
(Sundhedsstyrelsen, 1992).
Statistical analysis
The data were analysed in a conditional logistic regression model using the
PhReg procedure in SAS version 6.12 for Windows NT
(SAS Institute, 1997) and
asymptotic 95% confidence intervals were calculated. Variables were assessed
the last full year before the first admission ever to a psychiatric hospital,
irrespective of whether schizophrenia was diagnosed at first admission or
later. The method of sampling controls, risk-set sampling with the replacement
of controls after selection, means that the odds ratio estimate in the
analyses can be interpreted as an incidence rate ratio (IRR) between exposed
and unexposed categories (Flanders &
Louv, 1986).
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RESULTS |
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The results of the initial univariate models examining the risks for schizophrenia associated with having a paternal, maternal or sibling history of psychiatric disorders is given in Table 2. In Table 3 we present the IRR for family history groups according to the combined categorisation. The results of the univariate models are displayed, along with the results of the model adjusting for socio-economic and demographic factors and the interaction between family history of psychiatric illness and age at first contact.
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Gender differences in risk according to parental psychiatric
history
There was no significant difference (t=-1.08, d.f. 7702,
P=0.27) between age at first contact for males (mean=25.27 years,
s.d. 5.94) and females (mean=25.12 years, s.d. 6.02) in this sample. Based on
the combined family history categorisation, we found no significant gender
differences in risk for schizophrenia within family history categories;
females and males had similar risks within maternal and parental family
history categories. There was a significantly higher risk associated with a
maternal psychiatric history of schizophrenia and affective disorder (Wald
2=4.47 and 4.33, respectively; P<0.03), but not
other psychiatric disorders (Wald
2=0.002; P<0.99)
compared with the respective paternal diagnoses.
Interaction between family psychiatric history and age at first
contact for schizophrenia
The significance of the interaction between family psychiatric history and
age at first contact was tested to examine whether the risk for schizophrenia
associated with a family psychiatric history was similar across all ages of
first contact. We found significant interactions between age at first contact
and maternal history of schizophrenia (IRR 0.96; 95% CI 0.94-0.99;
P<0.001), affective disorders (IRR 0.97; 95% CI 0.95-0.99;
P<0.02) and other psychiatric disorders (IRR 0.98; 95% CI
0.96-0.99; P<0.02), for paternal history of other psychiatric
disorders (IRR 0.98; 95% CI 0.96-0.99; P<0.02), and for all
categories of psychiatric disorders for all relatives combined: schizophrenia
(IRR 0.98; 95% CI 0.96-0.99; P<0.002), affective disorders (IRR
0.98; 95% CI 0.96-0.99; P<0.01) and other psychiatric disorders
(IRR 0.98; 95% CI 0.96-0.99; P<0.001). The IRRs associated with
the significant interaction terms were less than 1, indicating that the risk
associated with a family history increases as age at first contact
decreases.
The interactions remained significant after controlling for the interaction between parental psychiatric history (maternal schizophrenia, paternal schizophrenia, maternal affective disorder, paternal affective disorder, maternal other diagnosis, paternal other diagnosis) and calendar year of admission, and the interaction between parental psychiatric history, calendar year of admission and age at first contact. We tested for these interactions to investigate whether the relationship between history of familial psychiatric disorders and age at first contact could be explained by the possibility that better information regarding family psychiatric history was available for the younger cases compared with the older cases. These interactions were not significant, suggesting that the quality of psychiatric history data was not the source of the significant interactions between age at first contact and parental psychiatric history. We did not find significant interactions between age at first contact and sibling psychiatric history or paternal history of schizophrenia or affective disorder.
We calculated the risks associated with a family history of psychiatric disorders for different ages of first contact for the categories of family history where a significant interaction was found (as reported above). The estimated risks and the 95% confidence intervals are presented in Table 4 and were calculated according to the method described by Hosmer & Lemeshow (1989).
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It is clear that the greatest risks were observed in the younger cases with a maternal history of a schizophrenic disorder and the risk declined as the age at first contact increased. This was also the case for offspring of mothers with affective disorders and for offspring of mothers and fathers with other psychiatric disorders. We included a second-order term (the age at first contact multiplied by family history squared) in the model to test the validity of the interaction term. This was not significant, indicating the validity of the original model including the linear interaction term to explain the relationship between age at first contact and family history for psychiatric disorders.
In order to more closely examine the interaction between age at first
contact and family history we further divided age at first contact into a
number of arbitrarily chosen categories (<17, 18-20, 21-23, 24-26, 27-29,
30-33, 34-37, 38 years) and assessed the interaction in each category
(where a significant age interaction had been found in the previous model).
The results of this analysis are shown in
Table 5.
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For maternal history of affective disorders and maternal and paternal
history of other psychiatric disorder, the oldest group was defined as 34,
as the numbers did not permit us to split the ages further. For maternal
history of affective disorder the youngest category was defined as <20, as
the numbers in this category did not permit us to break the ages down further.
The findings were very similar in the two approaches, which were statistically
indistinguishable. Inevitably a degree of measurement error was introduced by
examining the interactions in categories of age at first contact
(Altman, 1991), although the
results appear similar to those derived from the model with a single
interaction term. The advantage of the single interaction term is that only
one parameter is needed to express the interaction, whereas with age
categories many more parameters are introduced into the model; also, although
the categories were chosen to represent small bands of age, they were
essentially arbitrary.
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DISCUSSION |
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It is possible that for some cases, schizophrenic disorders existed in the wider family circle, e.g. in grandparents or uncles and aunts. If this were so, then it could be that we have overestimated the effect of disorders other than schizophrenia in our sample. It is unlikely that this could account entirely for the increased risks associated with a family history of disorders other than schizophrenia; however, we were not able to test this.
Our risk estimates are similar to previous Danish estimates (Mortensen et al, 1999; Pedersen & Mortensen, 2001); however, for the first time we have been able to control for the possible confounding effects of socio-economic factors. Controlling for personal and familial socio-economic factors, the risk for schizophrenia associated with a family history of psychiatric disorders was somewhat reduced but remained high and significant.
Gender effects
We did not find any difference between the ages at first contact for males
and females. However, the lack of gender differences in age at onset has been
previously reported (Jablensky & Cole,
1997; Suvisaari et
al, 1998). This can in part be attributed to the fact that
the sample was essentially young with a relative absence of late-onset cases.
The inclusion criteria required that for each person there was a link to a
mother and links to mothers are most complete for those born since 1960. The
relative absence of late-onset cases could also be part of the reason why
there are fewer females than males in the sample (33% v. 66%);
however, it is not uncommon to find fewer females than males in a sample based
on treated incidence (Munk-Jorgensen,
1986; Jablensky & Eaton,
1995).
We found a higher risk associated with family history of maternal psychiatric illness compared with paternal illness and the lack of gender differences within these categories. It has previously been described that relatives of females with schizophrenia have a higher risk for schizophrenia than the relatives of males (Goldstein et al, 1990). Also males typically develop illness at a younger age than females, reducing the likelihood that they will produce offspring. Fertility rates are reduced in schizophrenia (McGrath et al, 1999). In this sample there was an increased risk in those without a reference to a father. It is unlikely that this increased risk is the result of an overrepresentation of psychopathology in these fathers (Mortensen et al, 1999) and perhaps indicates a social explanation. Additionally, paternity is known to be less certain than maternity, leading to non-differential misclassification of exposure in both cases and controls, the most likely effect of which would be to bias the estimates toward null values.
Age at first contact and family history
The risk associated with a family history of psychiatric disorders was not
constant across all ages of first contact. The risk associated with a positive
family history decreased as age at first contact increased. For example,
according to our model the risk associated with a maternal history of
schizophrenia decreases by 20% (95% CI 10-30%) over a 5-year period, or on
average by 4% per year. The risk for schizophrenia associated with a family
history of the disorder was highest for those younger than 17 years. The
finding of a reduced age at onset with family history of psychiatric disorders
is consistent with some earlier studies
(Kendler & MacLean, 1990;
Albus et al, 1994; Sham et al, 1994;
Alda et al, 1996). We
modelled age at first contact with the psychiatric services, not age at first
schizophrenia diagnosis. It could be argued that children from families
well-known to the psychiatric services might be more likely to be identified
earlier than those from families without psychiatric contact. However, in a
previous register-based study (Suvisaari
et al, 1998), earlier age at first contact was not
explained by a shorter interval between the occurrence of psychotic symptoms
and first admission to hospital for those who already had an affected family
member.
Implications
Our findings suggest aetiological heterogeneity within the sample with
regard to risk from family history of psychiatric disorders. The simple
distinction of family history positive versus family history negative could
not accurately describe the risks for schizophrenia associated with a family
history of psychiatric disorders for the sample. It is clear that these risks
reduced as age at first contact increased. The risk associated with a family
history of psychiatric disorders is clearly more critical in the early years
of the risk period. Perhaps it will be important to incorporate age at first
contact interactions in all studies investigating risk factors for
schizophrenia. The findings have implications for the way that risk factors
should be modelled. Modelling the average risk might not give us
a picture of the true distribution of the association between risk factors and
outcome in samples.
The genetics of schizophrenia are complex and it is possible that the liability is shared with a number of other disorders. It might be that schizophrenia represents an extreme outcome, perhaps mediated by adverse environmental processes, which can be expressed by different, and milder, phenotypes. It is possible that environmental factors, for example obstetric complications, might interact with genetic predisposition to increase the risk for schizophrenia (Cannon et al, 1993).
Reduced age at first contact in those with a family history of psychiatric disorders might be the result of genetic factors or mediated by social and cultural factors (Jablensky & Cole, 1997), but we cannot be sure. If genetically mediated, it could have implications for modelling the transmission of schizophrenia, and/or for the calculation of the risks for illness in well relatives of different ages. It perhaps has implications for genetic counselling.
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Clinical Implications and Limitations |
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LIMITATIONS
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ACKNOWLEDGMENTS |
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REFERENCES |
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