Department of Psychiatric Demography, Institute for Basic Psychiatric Research, Aarhus University Hospital, Risskov and National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark
Correspondence: Carsten Bøcker Pedersen, National Centre for Register-Based Research, Taasingegade 1, 8000 Aarhus C, Denmark. Tel: +45 89426819; e-mail: cbp{at}ncrr.au.dk
Declaration of interest The study was supported by the Theodore and Vada Stanley Foundation.
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ABSTRACT |
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Aims This study replicates previous findings in four mutually exclusive Danish study populations, including out-patient information, ICD-10 diagnoses of schizophrenia, and a broader adjustment for mental illness in family members.
Method We established a population-based cohort of 2.66 million Danish people using data from the Civil Registration System linked with the Psychiatric Case Register.
Results Overall, 10 264 persons developed schizophrenia during the 50.7 million person-years of follow-up. The risk of schizophrenia was increased by urbanicity of place of birth and by family history of schizophrenia or other mental disorders.
Conclusions Urban-rural differences of schizophrenia risk were replicated and could not be associated with the potential sources of bias we assessed. Environmental factors underlying the effect of place of birth are major determinants of schizophrenia occurrence at the population level, although the effect of family history is the strongest at the individual level.
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INTRODUCTION |
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METHOD |
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Study design
Overall, 2.66 million people were followed from their fifth birthday or 1
April 1970 (whichever came later) until onset of schizophrenia, death,
emigration or 31 December 1998 (whichever came first). Cohort members were
recorded as having schizophrenia if they had been admitted to a psychiatric
hospital or received out-patient care with a diagnosis of schizophrenia (ICD-8
code 295 or ICD-10 code F20). Onset was defined as the first day of the first
contact leading to a diagnosis of schizophrenia. Parents and siblings were
categorised hierarchically with a history of schizophrenia (ICD-8 code 295 or
ICD-10 code F20), schizophrenia-like psychoses (ICD-8 codes 297, 298.39,
301.83 or ICD-10 codes F21-F29) or other mental disorders (any ICD-8 or ICD-10
diagnosis), respectively, if they had been admitted or received out-patient
care with one of these diagnoses.
Assessment of urbanicity
Independently of this study, Statistics Denmark
(1997a) has
categorised the 276 municipalities in Denmark in three main groups: (a)
municipalities in the capital region; (b) municipalities where the largest
city has more than 10 000 inhabitants; or (c) other municipalities.
Furthermore, each main group, which holds approximately one-third of the
population, was subdivided into four subgroups according to degree of
urbanisation (Table 1). Note
that the scale for classification of degree of urbanisation in the capital
region is a mixture of geographic location and city size, whereas the scale
for classification of degree of urbanisation in the remaining municipalities
is uniform according to city size. In our previous study
(Mortensen et al,
1999), this detailed 12-level classification of urbanisation was
grouped into five categories: (1) capital; (2) capital suburb; (3) provincial
city with more than 100 000 inhabitants; (4) provincial town with more than 10
000 inhabitants; (5) rural areas (see Table
1). By place of birth, we are referring to this fivelevel
classification unless stated otherwise.
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Denmark is a small homogeneous country with a population of 5.3 million people and a total area of 43 000 km2. The population densities for the capital, capital suburbs, provincial cities, provincial towns and rural areas respectively are 5220, 845, 470, 180 and 55 people per km2 (Statistics Denmark, 1997b). Distances are small in Denmark most people live within 25 kilometres of a city with more than 30 000 inhabitants and even closer to a psychiatric hospital.
Statistical analysis
The relative risk of schizophrenia was estimated by log-linear Poisson
regression (Breslow & Day,
1987) using the GENMOD procedure in SAS version 6.12
(SAS Institute Inc, 1997). All
relative risks were adjusted for age, gender, interaction between age and
gender, calendar year of diagnosis, age of the mother and father at the time
of the person's birth, place and season of birth, and history of mental
illness in parents or siblings. Age, calendar year of diagnosis and history of
mental illness in siblings were treated as time-dependent variables
(Clayton & Hills, 1993), whereas history of mental illness in a parent was treated as a variable that
was independent of time. To obtain complete confounder control
(Breslow & Day, 1980), age
was categorised with the following cut-off points: 5, 14, 15, 16, 17, 18, 19,
20, 22, 24, 26, 28, 30, 35 or 40 years; calendar year was categorised in
3-year bands in the ICD-8 period and in 1-year bands in the ICD-10 period.
Furthermore, maternal and paternal age at the time of the child's birth were
categorised with the following cut-off points: 12, 18, 20, 22, 25, 30, 35, 40
or unknown.
To replicate the findings in our previous study (Mortensen et al, 1999), the effect of month of birth was modelled as a sine function with a period of 12 months, where both the amplitude and the time of peak risk were estimated. The variance of the time of peak risk and that of the amplitude were calculated by the delta method (Agresti, 1990). P values were based on likelihood ratio tests and 95% confidence intervals were calculated by Wald's test (Clayton & Hills, 1993). The adjustedscore test (Breslow, 1996) suggested that the regression models were not subject to overdispersion.
Attributable risk
The population attributable risk is an estimate of the fraction of the
total number of cases of schizophrenia in the population that would not have
occurred if the effect of a specific risk factor had been eliminated, that is,
if the risk could have been reduced to that of the exposure category with the
lowest risk. The estimation was carried out as described by Bruzzi et
al (1985), on the basis of
adjusted relative risks and the distribution of exposure in the cases.
Study Populations A-D
In order to compare our results with our previous study
(Mortensen et al,
1999), to evaluate the effect of the change in the diagnostic
criteria and the inclusion of out-patient information and to eliminate
potential sources of bias in the selection of the study population used in our
previous study, analyses of relative risk were performed separately for four
mutually exclusive study populations: Study Populations A and B contained
people whose mother was born in Denmark after 1 April 1935, and Study
Populations C and D contained people whose mother was either born in Denmark
before 1 April 1935 or was born outside Denmark. Incidence of schizophrenia
was investigated in Study Populations A and C from 1 April 1970 to 31 December
1993 (ICD-8, in-patients) and in Study Populations B and D from 1 January 1994
to 31 December 1998 (ICD-10, in- and out-patients) (see
Table 2).
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Study Population A is almost identical to the study population used by Mortensen et al (1999). Compared with that study, it excludes persons born in foreign countries (32 062 people, 85 cases) and those with unknown place of birth (1506 people, four cases) and includes diagnoses for persons with schizophrenia admitted to a psychiatric hospital before 1 January 1994, who were diagnosed later than this date (104 cases).
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RESULTS |
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The relative risks associated with the risk factors identified in our study are shown in Table 2 for Study Populations A, B, C, D and for the total study population. In all study populations, history of mental illness in a parent or sibling, referred to as family history of mental illness, increased risk significantly (P < 0.0001) and the higher the rank of mental illness in family members, the higher the risk of developing schizophrenia.
Comparison with previous study
For Study Population A, the addition of the late-diagnosed cases of
schizophrenia (104 cases) and the exclusion of persons born abroad (85 cases)
and with unknown place of birth (four cases) did not affect estimates of
relative risk (Mortensen et al,
1999). The effect of place of birth was only slightly reduced when
controlling for family history of schizophrenia, schizophrenia-like psychoses
or other mental disorders instead of only for family history of schizophrenia.
If we had chosen to adjust only for family history of schizophrenia, then for
Study Population A the effect of place of birth would have been 2.37 (95% CI
2.11-2.67), 1.65 (95% CI 1.41-1.94), 1.58 (95% CI 1.37-1.82) and 1.29 (95% CI
1.15-1.46) for persons born in the capital, capital suburbs, the provincial
cities or provincial towns, respectively, as compared with persons born in
rural areas.
Family history
The relative risk associated with maternal history of mental illness
differed significantly between study populations (P < 0.0001)
whereas the relative risks associated with history of mental illness in the
father or siblings did not differ significantly between study populations
(P=0.65 and P=0.05, respectively). Compared with people
whose mother had neither been admitted to a psychiatric hospital nor had been
in out-patient care, those with a mother with schizophrenia had a relative
risk of 7.10 (95% CI 6.28-8.01), those having a mother with schizophrenia-like
psychoses had a relative risk of 3.68 (95% CI 3.28-4.13) and those having a
mother with other mental disorders had a relative risk of 1.95 (95% CI
1.85-2.06).
Urbanicity
The relative risk associated with urban birth did not differ significantly
between study populations (P=0.12), and urban birth had a significant
effect (P < 0.0001) in all study populations. Compared with people
born in rural areas, those born in the capital had a relative risk of 2.13
(95% CI 2.01-2.25). Furthermore, stratification by place of birth had no
impact on age of onset, and the effect of place of birth was not modified by
gender (P=0.30), nor by year of birth (P=0.27).
The detailed (12-level) classification of urbanisation of place of birth had a significant effect (P < 0.0001), see Table 1. Compared with those born outside built-up areas, those born in the capital had a relative risk of 2.30 (95% CI 2.04-2.60). In each main group of municipalities, the higher the degree of urbanisation of place of birth, the higher the risk of developing schizophrenia.
Seasonality
The effect of season of birth differed significantly between study
populations (P=0.01). For Study Population A there was a significant
effect of season of birth (P=0.0005): the amplitude of the sine
function was estimated to be 1.11 (95% CI 1.05-1.17) and the time of peak was
estimated to be 6 March (95% CI 7 February-April 5), meaning that persons born
in early March had a risk 1.11 times that of those born in early June or early
December. For Study Populations B, C, D and the total study population there
was no significant effect of season of birth (P>0.25), and the
effect of season of birth for Study Population A differed significantly from
that of Study Populations B, C and D (P=0.02). For the total study
population, the amplitude and the time of peak was estimated to be 1.02 (95%
CI 1.00-1.05) and 25 March (95% CI 14 January to 5 June), respectively.
Excluding out-patient information (1054 cases) did not result in any
modifications of the effect of season of birth nor of the effect of family
history of mental illness or place of birth. There was no interaction between
season of birth and age at onset (P=0.85) or gender
(P=0.14), and the effect of season of birth was not modified by year
of birth (P=0.72).
Attributable risk
The attributable risks associated with the significant risk factors in the
total study population are shown in Table
4. A family history of schizophrenia accounted for 5.4% of the
cases of schizophrenia, meaning that if those with a mother with schizophrenia
had the same risk as those with no maternal history of mental illness, 5.4% of
the total number of cases would not have occurred. The 12-level classification
of degree of urbanization of place of birth accounted for 34.3% of the cases
of schizophrenia in the population, meaning that if those born in built-up
areas had the same risk as those born outside built-up areas, 34.3% of the
cases would not have occurred. In total, family history of mental illness and
the 12-level classification of place of birth accounted for a total of 48.3%
of the cases of schizophrenia in the population. The attributable risk
associated with the 12-level categorisation of urbanicity is higher than the
one associated with the five-level categorisation. This is obvious, since the
12-level categorisation compared with the five-level categorisation indicates
a greater reduction in risk for a larger proportion of the population (see
Tables
1,2,3).
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DISCUSSION |
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The causes of urban-rural differences are unknown. A number of explanations, including methodological artefacts and differential exposure to specific risk factors, have been considered, for example, obstetric complications, infections, diet, toxic exposures, household crowding, exposure to pets, breast-feeding, or an artefact due to migration (Freeman, 1994; Mortensen, 2000). So far, we have evidence that differences are not due to selective migration (Mortensen, 2000), obstetric complications (Eaton et al, 2000; Kendell et al, 2000), socio-economic differences (Mortensen et al, 2000), or prenatal exposure to the influenza virus (Selten & Slaets, 1994; Westergaard et al, 1999). Obviously, our results above also show that the difference cannot be ascribed to differences in family history of mental illness, but neither we nor other groups have any positive evidence of factors that do explain it.
Seasonality
As seen in Fig. 1, the
incidence of schizophrenia varies greatly within 5-year age bands. This was
particularly evident in the age band from 15-19 years. To reduce the risk of
introducing methodological artefacts described as residual confounding
(Breslow & Day, 1980) or
age-incidence (Lewis, 1989),
we used a more detailed adjustment for age and calendar year of diagnosis than
was used in our previous study (Mortensen
et al, 1999). However, this had no influence on the
estimates of relative risk. Furthermore, using a Cox regression model
(Andersen et al,
1997), entering age as a continuous variable gave estimates of
relative risk identical to those presented in
Table 2 for Study Population A.
This approach excludes the possibility that age-incidence could generate an
artificial season of birth effect. Therefore, we conclude that the effect of
season of birth found for Study Population A and in the study reported by
Mortensen et al
(1999) was not due to residual
confounding by age or calendar year of diagnosis.
The distribution of age, calendar year of diagnosis, year of birth, maternal and paternal age at time of person's birth, age gap to older siblings and birth order differed between Study Populations A, B, C and D. Therefore, we expected that the finding of an effect of season of birth in Study Population A and not in Study Populations B, C and D implied that the effect of season of birth was modified by one of these variables. Additional analyses were performed, but none of these potential effect modifiers revealed any consistent pattern among the study populations. We conclude that season of birth may be an effect of an unknown factor or factors more common in Study Population A than in Study Populations B, C and D, and that this sub-population cannot be identified by any one of the variables mentioned above. In contrast to a Finnish study by Suvisaari et al (2000), we have no evidence that the season of birth effect has changed over time or between birth cohorts. In conclusion, the previous findings of an effect of season of birth could not be generalised to this larger study population, and we have not been able to identify the reason for these differences between the study populations.
Mental illness in family members
During the change of diagnostic system from the ICD-8 (1970-1993) to the
ICD-10 (1994-1998), the incidence of being diagnosed with schizophrenia
increased by 28%. As family members of patients with schizophrenia in the
ICD-10 period had typically been diagnosed during the ICD-8 period, estimates
of history of mental illness based on the ICD-10 period were attenuated
slightly compared with estimates based on the ICD-8 period. Furthermore,
family history of mental illness had a slightly higher effect for people with
mothers born in Denmark later than 1935 compared with people with mothers
either born in Denmark before 1935 or born outside Denmark. The earlier the
mother's year of birth, the greater the probability that information on
psychiatric diagnoses in parents were not included in the Danish Psychiatric
Central Register, and the greater the probability of incomplete information on
all siblings. However, these differences in relative risk were only minor and
history of schizophrenia in family members was still the strongest individual
risk factor.
It is highly plausible that both the effect of schizophrenia in family members and the effect of schizophrenia-like psychoses were due to genetic factors. However, it is less clear whether the relatively highly increased risk associated with a family history of other mental disorders was also due to genetic factors or if it was due to other mechanisms, for example, socio-economic differences.
Attributable risk
A relative risk measures an individual's own risk of acquiring a disease,
whereas an attributable risk measures the impact this relative risk has on the
population occurrence of the disease, that is, the attributable risk has two
determinants, the relative risk and the frequency of exposure in the
population. Even though the relative risk associated with urban birth is low,
the very high frequency of urban births in the population results in a high
attributable risk. Conversely, the very high relative risk associated with
schizophrenia in a mother and the very low frequency of children having a
mother with schizophrenia results in a moderate attributable risk. Therefore,
to measure the impact of an exposure at the individual level, the relative
risk should be used, whereas the attributable risk measures the impact of an
exposure at the population level.
Of course, the attributable risk associated with a family history of mental illness should not be taken as an indicator of the potential theoretical impact of eliminating genetic factors, factors that probably would not often be expressed as schizophrenia. That impact may well be 100% for one or several genetic factors if all are necessary causes. In other words, genetic factors may largely determine how many individuals might develop schizophrenia, but relatively common factors, some linked to urbanicity, may strongly influence how many individuals do develop the disease.
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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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Andersen, P. K., Borgan, Ø., Gill, R. D., et al (1997) Statistical Models Based on Counting Processes. New York: Springer-Verlag.
Breslow, N. E. (1996) Generalized linear models: checking assumptions and strengthening conclusions. Statistica Applicata, 8, 23-41.
Breslow, N. E. & Day, N. E. (1980) Statistical Methods in Cancer Research. Vol. I. The Analysis of CaseControl Studies. Lyon: International Agency for Research on Cancer.
Breslow, N. E. & Day, N. E. (1987) Statistical Methods in Cancer Research. Vol. II. The Design and Analysis of Cohort Studies. Lyon: International Agency for Research on Cancer.
Bruzzi, P., Green, S. B., Byar, D. P., et al (1985) Estimating the population attributable risk for multiple risk factors using casecontrol data. American Journal of Epidemiology, 122, 904-914.[Abstract]
Clayton, D. & Hills, M. (1993) Statistical Models in Epidemiology. Oxford: Oxford University Press.
Eaton, W. W., Mortensen, P. B. & Frydenberg, M. (2000) Obstetric factors, urbanization and psychosis. Schizophrenia Research, 43, 117-123.[CrossRef][Medline]
Freeman, H. (1994) Schizophrenia and city residence. British Journal of Psychiatry, 164 (suppl. 23), 39-50.
Gottesman, I. I. (1991) Schizophrenia Genesis. The Origins of Madness. New York: W. H. Freeman.
Kendell, R. E., McInneny, K., Juszczak, E., et al
(2000) Obstetric complications and schizophrenia. Two
casecontrol studies based on structured obstetric records.
British Journal of Psychiatry,
176,
516-522.
Lewis, G., David, A., Andreasson, S., et al (1992) Schizophrenia and city life. Lancet, 340, 137-140.[Medline]
Lewis, M. (1989) Age incidence and schizophrenia: Part 1. The season of birth controversy. Schizophrenia Bulletin, 15, 59-73.[Medline]
Malig, C. (1996) The civil registration system in Denmark. Technical Papers IIVRS, 66, 1-6.
Marcelis, M., Takei, N., van Os, J. (1999) Urbanization and risk for schizophrenia: does the effect operate before or around the time of illness onset? Psychological Medicine, 29, 1197-1203.[CrossRef][Medline]
McGuffin, P. & Gottesman, I. I. (1999) Risk
factors for schizophrenia. New England Journal of
Medicine, 341,
370-371.
Mortensen, P. B. (2000) What are the causes of urbanrural differences in schizophrenia risk? International Journal of Mental Health, 29, 101-110.
Mortensen, P. B., Agerbo, E., Eriksson, T., et al (2000) Parental education and socioeconomic variables as predictors of schizophrenia in their offspring. Schizophrenia Research, 41, 73.
Mortensen, P. B., Pedersen, C. B., Westergaard, T., et
al (1999) Effects of family history and place and season
of birth on the risk of schizophrenia. New England Journal of
Medicine, 340,
603-608.
Munk-Jørgensen, P. & Mortensen, P. B. (1997) The Danish Psychiatric Central Register. Danish Medical Bulletin, 44, 82-84.[Medline]
SAS Institute (1997) The GENMOD Procedure. In SAS/STAT Software: Changes and Enhancements through Release 6.12, pp. 247-348. Cary, NC: SAS Institute Inc.
Selten, J. P. & Slaets, J. P. (1994) Evidence against maternal influenza as a risk factor for schizophrenia. British Journal of Psychiatry, 164, 674-676.[Abstract]
Statistics Denmark (1997a) Befolkningen i kommunerne 1. januar 1997 (Population in Municipalities 1 January 1997). Copenhagen: Statistics Denmark.
Statistics Denmark (1997b)
Statistisk rhog 1997 (Statistical
Yearbook 1997). Copenhagen: Statistics Denmark.
Suvisaari, J. M., Haukka, J. K., Tanskanen, A. J., et al (2000) Decreasing seasonal variation of births in schizophrenia. Psychological Medicine, 30, 315-324.[CrossRef][Medline]
Westergaard, T., Mortensen, P. B., Pedersen, C. B., et
al (1999) Exposure to prenatal and childhood infections
and the risk of schizophrenia. Suggestions from a study of sibship
characteristics and influenza prevalence. Archives of General
Psychiatry, 56,
993-998.
World Health Organization (1967) Manual of the International Classification of Disease (ICD-8). Geneva: WHO.
World Health Organization (1992) The ICD-10 Classification of Mental and Behavioural Disorders. Clinical Descriptions and Diagnostic Guidelines. Geneva: WHO.
Received for publication August 16, 2000. Revision received February 5, 2001. Accepted for publication February 8, 2001.
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