There is mounting evidence that seemingly diverse psychiatric disorders share genetic etiology, but the biological substrates mediating this overlap are not well characterized. Here we leverage the ...unique Integrative Psychiatric Research Consortium (iPSYCH) study, a nationally representative cohort ascertained through clinical psychiatric diagnoses indicated in Danish national health registers. We confirm previous reports of individual and cross-disorder single-nucleotide polymorphism heritability for major psychiatric disorders and perform a cross-disorder genome-wide association study. We identify four novel genome-wide significant loci encompassing variants predicted to regulate genes expressed in radial glia and interneurons in the developing neocortex during mid-gestation. This epoch is supported by partitioning cross-disorder single-nucleotide polymorphism heritability, which is enriched at regulatory chromatin active during fetal neurodevelopment. These findings suggest that dysregulation of genes that direct neurodevelopment by common genetic variants may result in general liability for many later psychiatric outcomes.
The Danish Civil Registration System Pedersen, Carsten Bøcker
Scandinavian journal of public health,
07/2011, Volume:
39, Issue:
7_suppl
Journal Article
Peer reviewed
Introduction: The Danish Civil Registration System (CRS) was established in 1968, and all persons alive and living in Denmark were registered for administrative use. Content: CRS includes individual ...information on the unique personal identification number, name, gender, date of birth, place of birth, citizenship, identity of parents and continuously updated information on vital status, place of residence and spouses. Validity and coverage: Since 1968, CRS has recorded current and historical information on all persons living in Denmark. Among persons born in Denmark in 1960 or later it contains complete information on maternal identity. For women born in Denmark in April 1935 or later it contains complete information on all their children. CRS contains complete information on immigrations and emigrations from 1969 onwards, permanent residence in a Danish municipality from 1971 onwards, and full address in Denmark from 1977 onwards. Conclusion: CRS in connection with other registers and biobanks will continue to provide the basis for significant knowledge relevant to the aetiological understanding and possible prevention of human diseases.
Individuals with mental disorders often develop comorbidity over time. Past studies of comorbidity have often restricted analyses to a subset of disorders and few studies have provided absolute risks ...of later comorbidity.
To undertake a comprehensive study of comorbidity within mental disorders, by providing temporally ordered age- and sex-specific pairwise estimates between the major groups of mental disorders, and to develop an interactive website to visualize all results and guide future research and clinical practice.
This population-based cohort study included all individuals born in Denmark between January 1, 1900, and December 31, 2015, and living in the country between January 1, 2000, and December 31, 2016. The analyses were conducted between June 2017 and May 2018.
Danish health registers were used to identify mental disorders, which were examined within the broad 10-level International Statistical Classification of Diseases and Related Health Problems, 10th Revision, subchapter groups (eg, codes F00-F09 and F10-F19). For each temporally ordered pair of disorders, overall and lagged hazard ratios and 95% CIs were calculated using Cox proportional hazards regression models. Absolute risks were estimated using competing risks survival analyses. Estimates for each sex were generated.
A total of 5 940 778 persons were included in this study (2 958 293 men and 2 982 485 women; mean SD age at beginning of follow-up, 32.1 25.4 years). They were followed up for 83.9 million person-years. All mental disorders were associated with an increased risk of all other mental disorders when adjusting for sex, age, and calendar time (hazard ratios ranging from 2.0 95% CI, 1.7-2.4 for prior intellectual disabilities and later eating disorders to 48.6 95% CI, 46.6-50.7 for prior developmental disorders and later intellectual disabilities). The hazard ratios were temporally patterned, with higher estimates during the first year after the onset of the first disorder, but with persistently elevated rates during the entire observation period. Some disorders were associated with substantial absolute risks of developing specific later disorders (eg, 30.6% 95% CI, 29.3%-32.0% of men and 38.4% 95% CI, 37.5%-39.4% of women with a diagnosis of mood disorders before age 20 years developed neurotic disorders within the following 5 years).
Comorbidity within mental disorders is pervasive, and the risk persists over time. This study provides disorder-, sex-, and age-specific relative and absolute risks of the comorbidity of mental disorders. Web-based interactive data visualization tools are provided for clinical utility.
Growing evidence of an etiologic overlap between schizophrenia, schizoaffective disorder, and bipolar disorder has become increasingly difficult to disregard. We investigated the magnitude of the ...overlap between the clinical diagnoses of bipolar affective disorder, schizoaffective disorder, and schizophrenia over a 35-year period based on the entire Danish population.
We established a register-based prospective cohort study of more than 2.5 million persons born in Denmark after 1954. Risks for the 3 psychiatric disorders were estimated by survival analysis using the Aalen-Johansen method. Cohort members were followed from 1970 to 2006. We introduced a new comorbidity index measuring the magnitude of the overlap between the 3 disorders.
Overall, 12,734 patients were admitted with schizophrenia, 4,205 with bipolar disorder, and 1,881 with schizoaffective disorder. A female bipolar patient's risk of also being admitted with a schizoaffective disorder by the age of 45 years was approximately 103 times higher than that of a woman at the same age in the general population. Thus, we defined the comorbidity index between schizoaffective disorder and bipolar disorder at age 45 years to be 103. At age 45 years, the index between schizophrenia and schizoaffective disorder was 80 and between schizophrenia and bipolar disorder was 20. Similar large comorbidity indexes were found for men.
A large comorbidity index between schizophrenia and schizoaffective disorder was found, as well as a large index between bipolar disorder and schizoaffective disorder. But, more surprisingly, it was clear that a substantial comorbidity index between bipolar disorder and schizophrenia was present. This study supports the existence of an overlap between bipolar disorder and schizophrenia and thus challenges the strict categorical approach used in both DSM-IV and ICD-10 classification systems.
Several studies based on clinical samples have found an association between Toxoplasma gondii infection and schizophrenia, and a case-control study among U.S. military personnel with specimens ...available from both before and after diagnosis found a positive association between T. gondii immunoglobulin G (IgG) antibody level and schizophrenia. These findings have never been replicated in a prospective cohort study. The purpose of this study was to determine whether mothers infected with T. gondii have an elevated risk of schizophrenia or related disorders and whether the risk depends on IgG antibody level.
In a register-based prospective cohort study of 45,609 women born in Denmark, the level of T. gondii-specific IgG antibodies was measured in connection with childbirth between 1992 and 1995. Women were followed up from the date of delivery until 2008.
A significant positive association between T. gondii IgG antibody level and schizophrenia spectrum disorders was found. Mothers with the highest IgG level had a relative risk of 1.73 (95% confidence interval CI=1.12-2.62) compared with mothers with the lowest IgG level. For schizophrenia, the relative risk was 1.68 (95% CI=0.77-3.46). When the mothers were classified according to IgG level, only those with the highest IgG levels had a significantly higher risk of schizophrenia spectrum disorders.
Women with high levels of T. gondii-specific IgG antibodies have a significantly elevated risk of developing schizophrenia spectrum disorders.
People born in densely populated areas have a higher risk of developing schizophrenia, bipolar disorder and autism.
The purpose of this study was to investigate whether urban-rural differences in ...place of birth influence a broad range of mental disorders.
Population-based cohort study of everyone born in Denmark between 1955 and 2006 (n = 2 894 640). Main outcome measures were incidence rate ratios for five levels of urbanisation and summary estimates contrasting birth in the capital with birth in rural areas.
For all psychiatric disorders, except intellectual disability (ICD-10 'mental retardation') and behavioural and emotional disorders with onset in childhood, people born in the capital had a higher incidence than people born in rural areas.
Birth in an urban environment is associated with an increased risk for mental illness in general and for a broad range of specific psychiatric disorders. Given this new evidence that urban-rural differences in incidence are not confined to the well-studied psychotic disorders, further work is needed to identify the underlying aetiopathogenic mechanisms.
Urban residence is associated with a higher risk of some psychiatric disorders, but the underlying drivers remain unknown. There is increasing evidence that the level of exposure to natural ...environments impacts mental health, but few large-scale epidemiological studies have assessed the general existence and importance of such associations. Here, we investigate the prospective association between green space and mental health in the Danish population. Green space presence was assessed at the individual level using high-resolution satellite data to calculate the normalized difference vegetation index within a 210 × 210 m square around each person’s place of residence (∼1 million people) from birth to the age of 10. We show that high levels of green space presence during childhood are associated with lower risk of a wide spectrum of psychiatric disorders later in life. Risk for subsequent mental illness for those who lived with the lowest level of green space during childhood was up to 55% higher across various disorders compared with those who lived with the highest level of green space. The association remained even after adjusting for urbanization, socioeconomic factors, parental history of mental illness, and parental age. Stronger association of cumulative green space presence during childhood compared with single-year green space presence suggests that presence throughout childhood is important. Our results show that green space during childhood is associated with better mental health, supporting efforts to better integrate natural environments into urban planning and childhood life.
The search for the genetic factors underlying complex neuropsychiatric disorders has proceeded apace in the past decade. Despite some advances in identifying genetic variants associated with ...psychiatric disorders, most variants have small individual contributions to risk. By contrast, disease risk increase appears to be less subtle for disease-predisposing environmental insults. In this study, we sought to identify associations between environmental pollution and risk of neuropsychiatric disorders. We present exploratory analyses of 2 independent, very large datasets: 151 million unique individuals, represented in a United States insurance claims dataset, and 1.4 million unique individuals documented in Danish national treatment registers. Environmental Protection Agency (EPA) county-level environmental quality indices (EQIs) in the US and individual-level exposure to air pollution in Denmark were used to assess the association between pollution exposure and the risk of neuropsychiatric disorders. These results show that air pollution is significantly associated with increased risk of psychiatric disorders. We hypothesize that pollutants affect the human brain via neuroinflammatory pathways that have also been shown to cause depression-like phenotypes in animal studies.
Understanding the epidemiologic profile of the life course of mental disorders is fundamental for research and planning for health care. Although previous studies have used population surveys, ...informative and complementary estimates can be derived from population-based registers.
To derive comprehensive and precise estimates of the incidence rate of and lifetime risk for any mental disorder and a range of specific mental disorders.
We conducted a follow-up study of all Danish residents (5.6 million persons), to whom all treatment is provided by the government health care system without charge to the patient, from January 1, 2000, through December 31, 2012 (total follow-up, 59.5 million person-years). During the study period, 320,543 persons received first lifetime treatment in a psychiatric setting for any mental disorder; 489,006 persons were censored owing to death; and 69,987 persons were censored owing to emigration. Specific categories of mental disorders investigated included organic mental disorders, substance abuse disorders, schizophrenia, mood disorders, anxiety, eating disorders, personality disorders, mental retardation, pervasive developmental disorders, and behavioral and emotional disorders.
Age and sex.
Sex- and age-specific incidence rates and cumulative incidences and sex-specific lifetime risks.
During the course of life, 37.66% of females (95% CI, 37.52%-37.80%) and 32.05% of males (31.91%-32.19%) received their first treatment in a psychiatric setting for any mental disorder. The occurrence of mental disorders varied markedly between diagnostic categories and by sex and age. The sex- and age-specific incidence rates for many mental disorders had a single peak incidence rate during the second and third decades of life. Some disorders had a second peak in the sex- and age-specific incidence rate later in life.
This nationwide study provides a first comprehensive assessment of the lifetime risks for treated mental disorders. Approximately one-third of the Danish population received treatment for mental disorders. The distinct signatures of the different mental disorders with respect to sex and age have important implications for service planning and etiologic research.
Self-harm and violent criminality have overlapping causes, but people who engage in these behaviours are typically studied as two discrete populations. In this study, we aimed to examine the risk of ...unnatural death (ie, death from external causes such as accidents, suicide, and undetermined causes) among people with a history of self-harm and violent crime, focusing specifically on those with co-occurring behaviours.
For this population-based nested case-control study, we used national interlinked Danish registers. Individuals aged 35 years or younger, who were alive and residing in the country on their 15th birthday, and who died from external causes (cases) were matched by age and gender to living people (controls). We compared risks of suicide, accidental death, and any death by external causes among those with a history of hospital-treated self-harm, violent criminality, or both behaviours with those in individuals without histories of either behaviour. We estimated incidence rate ratios (IRRs), adjusted for age and gender, to compare risks.
We identified 2246 individuals who died from external causes, whom we matched to 44 920 living controls. 1499 (66·7%) of 2246 individuals died from accidental causes and 604 (26·9%) died by suicide. The risk of unnatural death was elevated for individuals with a history of violence (IRR 5·19, 95% CI 4·45–6·06) or self-harm (12·65, 10·84–14·77), but the greatest risk increase was among those with histories of both behaviours (29·37, 23·08–37·38). Substance misuse disorders, particularly multiple drug use, was more prevalent among individuals with co-occurring self-harm and violence than among those engaging in just one of these behaviours. Psychiatric disorders seemed to account for some of the excess risk of unnatural death among people with dual-harm histories, but excess risk, particularly of accidental death, persisted in the multivariable models.
Among individuals with co-occurring self-harm and violence, the risk of accidental death, particularly accidental self-poisoning, should be considered to be as important as the risk of suicide. People with a history of both behaviours who also have a substance misuse disorder are at particularly high risk of dying from external causes. Strategies should be designed to be accessible for people facing turbulent lives with multiple problems. Individuals in this group with both behaviours are likely to be treated by health-care services for self-harm and have contact with criminal justice services, providing multiple opportunities for proactive intervention.
European Research Council.
PDF
