The Danish Civil Registration System (CRS) was established in 1968 to register all people living in Denmark (24
). Among many other variables, it includes an individual’s CRS number, gender, date of birth, vital status, and CRS number of parents. The CRS number is used as a personal identifier in all national registers, enabling accurate linkage between registers. Our study population included all persons born in Denmark between 1 January 1945 and 31 December 1996 who were alive at their 10th
birthday or 1 January 1977, whichever came last (3.57 million people).
The study population was linked to the Danish Psychiatric Central Register (25
), which was computerized in 1969, to obtain information on date of first diagnosis of bipolar disorder, schizophrenia, or non-affective psychosis. The Danish Psychiatric Central Register contains data on all admissions to Danish psychiatric inpatient facilities and, from 1995 on, information on outpatient visits to psychiatric departments. From 1969 to 1993, the diagnostic system used was the Danish modification of the International Classification of Diseases, 8th
revision (ICD-8) (26
), and from 1994 on, the ICD, 10th
revision (ICD-10) (27
). Cohort members were classified with bipolar disorder (ICD-8: 296.19, 296.39; ICD-10: F30-F31), schizophrenia (ICD-8: 295 except 295.79; ICD-10: F20), or non-affective psychosis, including schizophrenia, schizophrenia-related personality disorders, schizoaffective disorder, delusional disorder, and schizophreniform disorder (ICD-8: 295, 297, 298.39, 301.83; ICD-10: F20-F29) if the individual had been admitted to a psychiatric hospital or been in outpatient care with that diagnosis. Date of onset was defined as first day of first contact (in- or outpatient) with each of these three categories of diagnosis. Individuals with multiple diagnoses on successive contacts could enter the cohorts for each of the three categories of diagnosis.
There were 9,920 cases of bipolar disorder, of whom 56% were females; 15% were aged 14–24, 55% were aged 25–44, and 29% aged over 45. There were 20,317 cases of schizophrenia, of whom 38% were females: 34% were aged 14–24, 57% were aged 25–44, and 9% over 45. There were 39,076 cases of non-affective psychosis, of whom 45% were females: 33% were aged 14–24, 56% were aged 25–44, and 11% were over 45.
Information about autoimmune diseases in cohort members and their mothers, fathers, and siblings was obtained from the Danish National Hospital Register, which contains information on all discharges from Danish hospitals since 1977; outpatients have been included in the register since 1995 (28
). Diagnostic information in the National Hospital Register is based on the Danish version of the ICD-8 from 1977 to 1993, and the ICD-10 from 1994 to 2006. All treatments in Danish hospitals are free of charge for all residents. Cohort members and their parents and siblings were classified as having a positive history of one or more of 30 autoimmune diseases () if they had been admitted or had been in outpatient care with the relevant diagnosis. The time of onset was defined as the first day of the first contact with the autoimmune diagnosis in question. Each person can have a history of more than one autoimmune disease. In these analyses some of the diagnostic categories have been narrowed compared to our previous work, focusing as tightly as possible on the autoimmune categories [compare in this paper to Table 1 in Eaton et al. (1
)]. The category of ‘any of 30 autoimmune diseases’
is included to help judge whether the pattern is general or specific to one or a limited number of autoimmune diseases.
Adjusted relative risks of bipolar disorder and schizophrenia according to history of 30 autoimmune diseases in parents or siblings
A total of 3,571,730 persons were followed from their 10th
birthday or 1 January 1977 (whichever came last) until onset of the disorders of interest, death, emigration from Denmark, or 31 December 2006 (whichever came first), amounting to 77 million person-years from 1977 to 2006. However, when type 1 diabetes was the exposure, the follow-up started at the 10th
birthday or 1 January 1986, as the diagnosis of type 1 diabetes was not introduced as a separate diagnosis until 1986. In the analysis of family history presented in , the cohort is limited to 2,901,158 persons born in Denmark between 1945 and 1996, with known identity of the mother and followed during 58 million person-years from 1977 to 2006. Persons born before 1968 have a link to their mother if they were residing on the same address when the CRS started in 1968 (24
The incidence rate ratio (in this paper referred to as relative risk
) was estimated by log-linear Poisson regression (29
) with the GENMOD procedure in SAS version 9.1 (SAS Institute, Inc., Cary, NC, USA). All relative risks were adjusted for calendar year, age, and interaction with sex. In models with family history of autoimmune diseases as the exposure of interest, the age of the mother and father at the time of the child’s birth was also adjusted. These factors are adjusted in the models presented because they may possibly affect the risk for schizophrenia and other psychoses and be associated with the occurrence of autoimmune diseases. Age, calendar year, and history of autoimmune diseases in parents or siblings were also treated as time-dependent variables, whereas all other variables (sex and mother’s and father’s age at the time of the child’s birth) were treated as variables independent of time. Calendar year was categorized in one-year periods. Age, as well as age of the parent at the child’s birth, was categorized to ensure adequate numbers of cases in the separate categories: in one category for the range 10–14 years, in one-year intervals from the 15th
to the 20th
birthday, in two-year intervals from the 20th
to the 30th
birthday, and in five-year intervals thereafter. Maternal age at the time of the child’s birth was categorized with the following cutoff points: 12, 25, 30, 35, and 40 years; paternal age had cutoff points of 12, 25, 30, 35, 40, 45, or unknown father. The p-values and 95% confidence intervals (CI) were based on likelihood ratio tests (30
). The parameters shown are presented in bold when the 95% CI does not include 1.0. The adjusted score test (31
) suggested that the regression models were not subject to overdispersion.
For study of the relative risk for the psychiatric disorders associated with prior autoimmune diseases in the individual, time since an autoimmune disease was included as a time-dependent variable (30
), which during follow-up was measured as the number of years since first contact with a diagnosis of the autoimmune disease. This variable was collapsed into two categories: 0–4 complete years (concurrent
) and ≥ 5 complete years (delayed
). These categories are arbitrary but yield a reasonable distribution of cases in each category. Since registration started in 1977, persons born between 1945 and 1967 could have had an autoimmune diagnosis before 1977, and for these persons our registered number of years since onset is biased toward being too small.
The study was approved by the Danish Data Protection Agency.