Lund University, Malmö, Sweden
Aarhus University, Denmark
Lund University, Lund, Sweden
Aarhus University, Denmark
Correspondence: Elizabeth Cantor-Graae, Department of Community Medicine, Lund University, University Hospital Malmö, Malmö, Sweden S-20502. Tel: +46 40 336504; fax: +46 40 337096; e-mail: elizabeth.cantor-graae{at}smi.mas.lu.se
Funding listed in Acknowledgements.
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ABSTRACT |
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Aims To examine immigrant background and history of foreign residence as risk factors for schizophrenia.
Method Using data from the Danish Civil Registration System, we established a population-based cohort of 2.14 million persons resident in Denmark by their fifteenth birthday. Schizophrenia in cohort members and parental psychiatric disorder were identified by cross-linkage with the Danish Psychiatric Case Register.
Results The relative risk of developing schizophrenia was 2.45 (95% Cl 2.25-2.67) and 1.92 (95% Cl 1.74-2.12) among first- and second-generation immigrants respectively, and 1.60 (95% Cl 1.25-2.05) among Danes with a history of foreign residence.
Conclusions Migration confers an increased risk for schizophrenia that is not solely attributable to selection factors and may also be independent of foreign birth.
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INTRODUCTION |
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Improved record linkage provided the impetus for a new Danish register-based cohort study of the risk of schizophrenia associated with migration. We restricted the cohort to people residing in Denmark by their fifteenth birthday, thus minimising the impact of selective migration. History of foreign residence was examined as a putative risk factor for schizophrenia in people with a Danish background (people born in Denmark of Danish-born mothers).
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METHOD |
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The study population and their mothers and fathers were cross-linked with the Danish Psychiatric Central Register (Munk-Jørgensen & Mortensen, 1997), which contains data on all admissions to Danish psychiatric in-patient facilities since April 1969 and out-patient visits to psychiatric departments since 1995. From April 1969 to December 1993 the diagnostic system used was the ICD-8 (World Health Organization, 1967). From January 1994 this was replaced by ICD-10 (World Health Organization, 1992). Cohort members were designated 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 with a diagnosis of schizophrenia.
Statistical and data analyses
In total 2.14 million persons were followed up during residence in Denmark
from their fifteenth birthday or 1 April 1970, whichever came later, until
onset of schizophrenia, death or 31 December 1998, whichever came first. The
relative risk of schizophrenia was estimated by log-linear Poisson regression
(Breslow & Day, 1987) with
the GENMOD procedure in SAS version 8.1
(SAS Institute, 1999). All
relative risks were adjusted for age, gender, interaction between age and
gender, and calendar year of diagnosis. Age and calendar year of diagnosis
were treated as time-dependent variables
(Clayton & Hills, 1993),
whereas all other variables were treated as time-fixed variables unless stated
otherwise. To obtain complete confounder control
(Breslow & Day, 1980), age
in years was categorised with the following cut-off points: 15, 16, 17, 18,
19, 20, 22, 24, 26, 28, 30, 35 and 40, and calendar year was categorised in
3-year bands in the ICD-8 period and in 1-year bands in the ICD-10 period.
Values of P were based on likelihood ratio tests, and 95% confidence
limits were calculated by Wald's test
(Clayton & Hills, 1993). The adjusted score test (Breslow,
1996) suggested that the regression models were not subject to
overdispersion.
Country of birth was classified according to geographical region of birth: Denmark, Scandinavia (excluding Denmark), Europe (excluding Denmark and Scandinavia), Asia, the Middle East, Australia, Africa, North America, South America, Greenland, and unknown. Individuals were categorised according to the information in the Danish Civil Registration System concerning maternal country of birth, i.e. maternal reference status. Those born in Denmark were categorised as persons with Danish background (cohort members born in Denmark with mothers born in Denmark), second-generation immigrants (cohort members born in Denmark with mothers born outside Denmark) or other Danish-born (cohort members born in Denmark with no information about maternal country of birth). Individuals born outside Denmark were categorised as possible adoptions (cohort members born outside Denmark with mothers born in Denmark, i.e. either adoptions or children born to Danish women abroad), immigrants migrating with mother (cohort members born outside Denmark with information concerning maternal identity, i.e. mother has a Danish CPR number, meaning that she has been resident in Denmark) or immigrants migrating without mother (cohort members born outside Denmark with no information about maternal identity).
For those born in 1969 or later we have complete information about dates of
immigration and emigrations to and from Denmark, and were able to examine the
risk of developing schizophrenia in relationship to age at first residence in
Denmark and the accumulated number of years lived in Denmark. Age at first
residence in Denmark was categorised as: at birth, from birth to the fifth
birthday, from the fifth to the tenth birthday, and from the tenth to the
fifteenth birthday. The accumulated number of years lived in Denmark was
treated as a time- dependent variable and categorised as: 0 to <5 years,
5 to <10 years,
10 to <15 years,
15 to <20 years,
20
to <25 years, or
25 years.
Among persons with a Danish background we examined history of foreign residence (defined as ever residing outside Denmark prior to age 15 years) and the age at which foreign residence occurred, i.e. from post-birth to the fifth birthday, from the fifth to the tenth birthday, and from the tenth to the fifteenth birthday. A person resident abroad during the ages 4-12 years would belong to all three categories. Parental history of psychiatric disorder was examined as a potential modifier or confounder of the risk associated with history of foreign residence. Parents were considered to have a history of psychiatric disorder if they had ever been admitted to hospital or received out-patient care for a psychiatric disorder (any ICD-8 or ICD-10 diagnosis). Parental history of psychiatric disorder was also studied as a potential modifier of schizophrenia risk among second-generation immigrants.
Region of birth and maternal reference status were further examined in
relation to age at illness onset (total cohort). For those born in Denmark the
most common age at illness onset is 22-23 years
(Pedersen & Mortensen,
2001a). Age in years at illness onset was stratified
accordingly as <20, 20-21, 22-23, 24-25 or 26, examined in relation to
the following categories: Danish background, second-generation immigrants,
other Danish-born, and foreign-born.
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RESULTS |
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The relative risks obtained for specific categories of region of birth and maternal reference status (Table 2) were adjusted initially for age and its interaction with gender and for calendar year of diagnosis. A second similar adjustment of the relative risk adjusted simultaneously also for region of birth and for maternal reference status. In the foreign-born category, maternal reference status (possible adoption, with or without maternal reference) had no effect upon the risk of developing schizophrenia, nor was there any evidence that the effect of maternal reference status was modified by region of birth (P=0.23). Interestingly, there was no indication that foreign-born possible adoptees are at increased risk compared with foreign-born individuals from the same country. Also, the slightly elevated risk among those with unknown region of birth indicates that this category may represent a combination of Danish-born and foreign-born.
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Among those born in Denmark, the relative risk of developing schizophrenia differed significantly according to maternal reference status (P<0.001), with an increased relative risk found among second-generation immigrants (Table 2). The increased risk among second-generation immigrants was modified by parental history of psychiatric disorder (P=0.001). In second-generation immigrants with a history of psychiatric disorder in a parent, the relative risk of developing schizophrenia was 1.42 (95% CI 1.20-1.68) compared with Danes with a history of psychiatric disorder in a parent, and in second-generation immigrants with no history of psychiatric disorder in a parent, the relative risk was 2.09 (95% CI 1.85-2.35) compared with Danes with no history of psychiatric disorder in a parent. The effect of second-generation immigrant status was confounded only slightly when adjusting for history of psychiatric disorder in a parent.
Age at first residence in Denmark and the accumulated number of years lived in Denmark (for those born in 1969 or later) had no effect on the relative risk of developing schizophrenia, after adjustment for region of birth and maternal reference status for those born in Denmark (Table 3). Conversely, the effects of region of birth and maternal reference status among those born in Denmark remained strongly significant (P<0.001), and were not confounded by age at first residence and accumulated number of years of residence in Denmark (results not shown). Age at first residence and the accumulated years of residence in Denmark were thus proxy variables for foreign birth, as the effect of these variables disappeared when the results were also simultaneously adjusted for region of birth and maternal reference status (second adjustment, P=0.70 and P=0.51 respectively).
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There was no evidence that age at illness onset was modified by region of birth or, for those born in Denmark, by maternal reference status (P=0.36). Furthermore, the age category with the highest risk was age 22-23 years within all groups, thus indicating that illness onset occurs no earlier or later among first- or second-generation immigrants than among people with a Danish background.
Individual with Danish background (i.e. born in Denmark with mothers born in Denmark) and with a history of foreign residence prior to their fifteenth birthday had an increased relative risk of schizophrenia compared with those with Danish background but no such history (Table 4). The effect of history of foreign residence was not modified by age at foreign residence (P=0.36) or by history of parental psychiatric disorder (P=0.82), and was not confounded by history of parental psychiatric disorder.
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DISCUSSION |
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Limitations
Although the use of register-based diagnostic information may represent a
possible methodological limitation, the Danish Psychiatric Central Register
has shown good diagnostic validity
(Munk-Jørgensen, 1995).
Although the findings are based on patients admitted to hospital or in
outpatient care, and this may overlook some early episodes of schizophrenia,
most of these will eventually present for treatment and be registered.
However, although the sample is large and representative, the level of
demographic detail may be limited for certain categories; thus, foreign birth
is an imprecise designation of ethnic background. Also, it was not possible to
further subdivide the category represented by possible adoptees, and some of
these individuals may be people born to Danish mothers living abroad.
Migration or ethnicity?
Although we cannot precisely identify the ethnicity of the foreign-born
members of our cohort, the results of this study nevertheless have
implications for the debate about the excessively high rates of schizophrenia
found in people of AfricanCaribbean origin in the UK
(King et al, 1994;
Murray & Hutchinson, 1999; Sharpley et al,
2001). Efforts to explain this particular group's vulnerability in
terms of ethnicity have been questioned (e.g.
Harrison et al, 1997).
Our findings confirm the need for a broader focus on migration in general, and
suggest furthermore that mixed migrant populations are potentially
informative, despite the obvious difficulties posed by selection factors. The
impact of selection bias in mixed migrant samples is aptly illustrated by the
difference between the current findings and those from our previous study, in
which immigrants from Denmark's neighbouring countries primarily accounted for
the increased risk of schizophrenia found among immigrants
(Mortensen et al,
1997). It is important to note that in this current,
more-restricted cohort i.e. those residing in Denmark prior to their
fifteenth birthday the increased risk of schizophrenia found among
immigrants cannot be explained by people migrating during the
early stages of their illness. Although we cannot exclude the effects of
selective migration operating on the parents of these individuals, it should
be observed that the risk associated with second-generation immigrant status
was actually lower in second-generation immigrants with a parental history of
psychiatric disorder than in those without a parental history of psychiatric
disorder.
The results concerning region of birth show subtle but significant variation in risk magnitude across regions, although the pattern of results yields no obvious clues to possible explanatory mechanisms. Thus, for example, the countries of birth represented by regions at the higher end of the risk spectrum (e.g. Australia, Africa, the Middle East, Greenland) have seemingly little in common in terms of geography, climate, level of human development, or difficulties encountered upon arrival in Denmark. The findings concerning immigrants from Greenland may represent an interesting parallel to findings concerning immigrants to Europe from other former colonial regions (Harrison et al, 1997; Selten et al, 1997, 2001), namely the Caribbean islands and Surinam. Although information on ethnicity is lacking, most of those born in Greenland are of Inuit extraction.
Recent theorising suggests that adverse social circumstances and ethnic minority disadvantage (Sharpley et al, 2001) may have an aetiological role in the migrant effect in schizophrenia. Such factors might explain the increased risk of schizophrenia found among second-generation immigrants in this relatively young Danish cohort, and perhaps also some of the subtle regional variation found among first-generation immigrants. Nevertheless, the absence of an effect of age at first residence or duration of residence in Denmark may seem contradictory to the notion of minority-group disadvantage, unless one posits such adversity to be present regardless of how long one has lived in Denmark. It is also possible that the lack of greater regional differences with regard to the relative risks obtained among first-generation immigrants may represent a pattern in and of itself. That is, for people arriving in Denmark before the age of 15 years the experience of being uprooted might be similar regardless of country of origin. Alternatively, the experience of minority-group disadvantage during late puberty (after the age of 15 years) might be more important than specific ethnic identity. As the experience of minority disadvantage could vary according to social class and education, it is possible that further investigation of such factors might be informative for the pattern of regional differences obtained.
Perhaps the most surprising results in the current study are those implicating history of foreign residence as a risk factor for schizophrenia. Thus, migration per se might be a more important component in the migrant effect than ethnicity, even when ethnicity is broadly defined (i.e. foreign birth or foreign background). A previous population-based Danish register study found an increased risk of schizophrenia in people born abroad to Danish-born mothers (Mortensen et al, 1999). In contrast, the current results concern persons who are born in Denmark to Danish-born mothers and who subsequently emigrate and then return to Denmark again. Whatever risk factor may be involved in this process, it is not attributable to birth in a foreign region, to foreign background in one's maternal parentage, or to psychiatric disorder in a parent. A recent study of urban upbringing showed a cumulative risk with each move internally within Denmark and with increasing degree of urbanisation (Pedersen & Mortensen, 2001b). These parallels notwithstanding, the current risk associated with history of foreign residence is seemingly unaffected by the age at which such residence occurs, whereas the findings of Pedersen & Mortensen (2001b) indicate that the older the age of residential mobility within Denmark, the greater the risk.
As this study primarily concerns people resident in Denmark by their fifteenth birthday, we make no inferences about the risk of schizophrenia in immigrants in general, or in immigrants arriving in Denmark at a later age. However, although the results may not be applicable to all immigrants living in Denmark, it may not be possible to minimise selection bias and simultaneously be able to make inferences about the immigrant population at large. Paradoxically, the information obtained from a sample that might be more representative of immigrants in general would also be more compromised in terms of selection bias, as well as the correctness of the information regarding first-in-lifetime admission for the disorder.
Finally, although we have regarded people with first- and second-generation immigrant status as sharing a commonality of migration background, it remains entirely unknown whether a common risk mechanism is indeed involved, and whether such a mechanism is also relevant to history of foreign residence. However, it may be worthwhile to note the lack of differences found concerning age of onset, suggesting that schizophrenia is unaffected by region of birth or background. Our study suggests a need for new hypotheses and for further investigations concerning the nature of the relationship between migration and schizophrenia.
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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 23, 2002. Revision received August 30, 2002. Accepted for publication October 10, 2002.
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