Different case definitions of schizophrenia have been used in register based research. However, no previous study has externally validated two different case definitions of schizophrenia against a wide range of risk factors for schizophrenia. We investigated hazard ratios (HRs) for a wide range of risk factors for ICD-10 DCR schizophrenia using a nationwide Danish sample of 2,772,144 residents born in 1955-1997. We compared one contact only (OCO) (the case definition of schizophrenia used in Danish register based studies) with two or more contacts (TMC) (a case definition of at least 2 inpatient contacts with schizophrenia). During the follow-up, the OCO definition included 15,074 and the TMC 7562 cases; i.e. half as many. The TMC case definition appeared to select for a worse illness course. A wide range of risk factors were uniformly associated with both case definitions and only slightly higher risk estimates were found for the TMC definition. Choosing at least 2 inpatient contacts with schizophrenia (TMC) instead of the currently used case definition would result in almost similar risk estimates for many well-established risk factors. However, this would also introduce selection and include considerably fewer cases and reduce power of e.g. genetic studies based on register-diagnosed cases only.
Strong evidence demonstrates a genetic susceptibility to suicidal behaviour and a relationship between suicide and mental disorders. The aim of this study was to test for association between suicide and five selected genetic variants, which had shown association with suicide in other populations.
We performed a nationwide case-control study on all suicide cases sent for autopsy in Denmark between the years 2000 and 2007. The study comprised 572 cases and 1049 controls and is one of the largest genetic studies in completed suicide to date. The analysed markers were located within the Serotonin Transporter (SLC6A4), Monoamine Oxidase-A (MAOA) and the Tryptophan Hydroxylase I and II (TPH1 and TPH2) genes.
None of the genetic markers within SLC6A4, MAOA, TPH1 and TPH2 were significantly associated with completed suicide or suicide method in the basic association tests. Exploratory interaction test showed that the minor allele of rs1800532 in TPH1 has a protective effect for males younger than 35 years and females older than 50 years, whereas for the oldest male subjects, it tended to be a risk factor. We also observed a significant interaction between age-group and the 5-HTTLPR genotype (with and without rs25531) in SLC6A4. The long allele or high expression allele tends to have a protective effect in the middle age-group.
We only analysed a limited number of genetic variants.
None of the analysed variants are strong risk factors. To reveal a better understanding of the genes involved in suicide, we suggest future studies should include both genetic and non-genetic factors.
Low participation in population-based follow-up studies addressing psychosocial risk factors may cause biased estimation of health risk but the issue has seldom been examined. We compared risk estimates for selected health outcomes among respondents and the entire source population.
In a Danish cohort study of associations between psychosocial characteristics of the work environment and mental health, the source population of public service workers comprised 10,036 employees in 502 work units of which 4,489 participated (participation rate 45%). Data on the psychosocial work environment were obtained for each work unit by calculating the average of the employee self-reports. The average values were assigned all employees and non-respondent at the work unit. Outcome data on sick leave and prescription of antidepressant medication during the follow-up period (1.4.2007-31.12.2008) was obtained by linkage to national registries.
Respondents differed at baseline from non-respondents by gender, age, employment status, sick leave and hospitalization for affective disorders. However, risk estimates for sick leave and prescription of antidepressant medication, during follow-up, based on the subset of participants, did only differ marginally from risk estimates based upon the entire population.
We found no indications that low participation at baseline distorts the estimates of associations between the work unit level of psychosocial work environment and mental health outcomes during follow-up. These results may not be valid for other exposures or outcomes.
Cites: Int J Epidemiol. 1999 Dec;28(6):1134-4010661659
Cites: Am J Epidemiol. 2011 Jan 1;173(1):94-10221071605
aTranslational Neuropsychiatry Unit, Department of Clinical Medicine bDepartment of Biomedicine and Centre for Integrative Sequencing (iSEQ), Aarhus University cThe Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH) dResearch Department P, Aarhus University Hospital, Risskov eAmplexa Genetics A/S fDepartment of Clinical Genetics, University of Southern Denmark, Odense gLaboratory of Neuropsychiatry, University of Copenhagen hDepartment of Psychiatry, HS Amager Hospital, Copenhagen University Hospital, Copenhagen, Denmark iDepartment of Psychiatry, the National Hospital, Torshavn, Faroe Islands jMax Planck Institute of Psychiatry, Munich, Germany.
We analysed single nucleotide polymorphisms in two transmembrane genes (TMEM98 and TMEM132E) in panic disorder (PD) patients and control individuals from the Faroe Islands, Denmark and Germany. The genes encode single-pass membrane proteins and are located within chromosome 17q11.2-q12, a previously reported candidate region for PD. Three single nucleotide polymorphisms (rs887231, rs887230 and rs4795942) located upstream and within TMEM132E showed a nominal significant association with PD primarily in the Danish cohort. No nominal significant associations were observed between TMEM98 and PD. Our data indicate that TMEM132E might contribute moderately towards the risk of developing PD.
Genetic variants in ankyrin 3 (ANK3) have recently been shown to be associated with bipolar disorder (BD). We genotyped three ANK3 SNPs previously found to be associated with BD (rs10994336, rs1938526, and rs9804190) in a Scandinavian BD case-control sample (N = 854/2,614). Due to evidence of genetic overlap between BD and schizophrenia (SZ), we also genotyped these three SNPs in a Scandinavian SZ case-control sample (N = 1,073/2,919). Combining our Scandinavian samples with an Icelandic sample (N = 435 BD cases, 651 SZ cases, and 11,491 healthy controls), we found rs10994336 and rs9804190 to be nominally significantly associated with BD in this combined Nordic BD sample (N = 1,289/14,105). Nominal P was 0.015/0.018 (fixed/random effect) for rs10994336 (Bonferroni corrected P = 0.044/0.053) and 0.023 for rs9804190 (Bonferroni corrected P = 0.069). None of the SNPs were significantly associated with SZ in the combined Nordic SZ case-control sample (N = 1,724/14,410). These results further support that ANK3 is a susceptibility gene specific to BD and that more than one risk locus is involved.
Panic disorder (PD) is a severe and disabling mental disorder, which is moderately heritable. In a previous study, we carried out a genome-wide association study using patients with PD and control individuals from the isolated population of the Faroe Islands and identified chromosome 19p13.2 as a candidate region. To further investigate this chromosomal region for association with PD, we analysed eight single nucleotide polymorphisms (SNPs) in three candidate genes - small-nuclear RNA activating complex, polypeptide 2 (SNAPC2), mitogen-activated protein kinase kinase 7 (MAP2K7) and leucine-rich repeat containing 8 family, member E (LRRC8E) - these genes have previously been directly or indirectly implicated in other mental disorders. A total of 511 patients with PD and 1029 healthy control individuals from the Faroe Islands, Denmark and Germany were included in the current study. SNPs covering the gene region of SNAPC2, MAP2K7 and LRRC8E were genotyped and tested for association with PD. In the Faroese cohort, rs7788 within SNAPC2 was significantly associated with PD, whereas rs3745383 within LRRC8E was nominally associated. No association was observed between the analysed SNPs and PD in the Danish cohorts. In the German women, we observed a nominal association between rs4804833 within MAP2K7 and PD. We present further evidence that chromosome 19p13.2 may harbour candidate genes that contribute towards the risk of developing PD. Moreover, the implication of the associated genes in other mental disorders may indicate shared genetic susceptibility between mental disorders. We show that associated variants may be sex specific, indicating the importance of carrying out a sex-specific association analysis of PD.
Psychotic and mixed affective episodes are prevalent in the course of bipolar disorder. Despite many studies on the implications of psychotic mania (PM), psychotic depression (PD) and mixed affective episodes (MAE), relatively little is known about the relationship between the three subtypes. The present study aimed to investigate whether the occurrence of PM, PD and MAE were associated with one another.
This is a nationwide register-based, historical prospective cohort study. Data was obtained from the Danish Psychiatric Central Research Register. Subjects were defined as all individuals assigned with an ICD-10 diagnosis of bipolar disorder between January 1st 1994 and December 31st 2010. Potential associations among psychotic and mixed affective episodes were tested by means of logistic regression.
We identified 14,529 individuals with bipolar disorder with lifetime incidences of PM, PD and MAE of 19%, 15% and 17% respectively. We detected significant associations between PM and MAE (Adjusted Odds Ratio (AOR)=1.26, p=0.003), PD and MAE (AOR=1.24, p=0.001), and PM and PD (AOR=1.28, p=0.005).
Diagnoses were assigned as part of routine clinical practice.
According to this register-based study, PD, PM and MAE are all associated with one another. This knowledge should be taken into consideration by clinicians when monitoring patients with bipolar disorder and by nosologists when defining the criteria and potential subtypes for mixed affective episodes for the upcoming DSM-5 and ICD-11.
OBJECTIVE: Individuals with schizophrenia and their relatives tend to have either higher or lower than expected prevalences of autoimmune disorders, especially rheumatoid arthritis, celiac disease, autoimmune thyroid diseases, and type 1 diabetes. The purpose of the study was to estimate the association of schizophrenia with these disorders as well as a range of other autoimmune diseases in a single large epidemiologic study. METHOD: The Danish Psychiatric Register, the National Patient Register, and a register with socioeconomic information were linked to form a data file that included all 7,704 persons in Denmark diagnosed with schizophrenia from 1981 to 1998 and their parents along with a sample of matched comparison subjects and their parents. The data linkage required that the autoimmune disease occur before the diagnosis of schizophrenia. RESULTS: A history of any autoimmune disease was associated with a 45% increase in risk for schizophrenia. Nine autoimmune disorders had higher prevalence rates among patients with schizophrenia than among comparison subjects (crude incidence rate ratios ranging from 1.9 to 12.5), and 12 autoimmune diseases had higher prevalence rates among parents of schizophrenia patients than among parents of comparison subjects (adjusted incidence rate ratios ranging from 1.3 to 3.8). Thyrotoxicosis, celiac disease, acquired hemolytic anemia, interstitial cystitis, and Sjögren's syndrome had higher prevalence rates among patients with schizophrenia than among comparison subjects and also among family members of schizophrenia patients than among family members of comparison subjects. CONCLUSIONS: Schizophrenia is associated with a larger range of autoimmune diseases than heretofore suspected. Future research on comorbidity has the potential to advance understanding of pathogenesis of both psychiatric and autoimmune disorders.
Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark; National Centre for Register-Based Research, Aarhus University, Denmark; Mental Health in Primary Care (MEPRICA), Research Unit for General Practice, Department of Public Health, Aarhus University, Aarhus, Denmark. Electronic address: email@example.com.
It is unknown whether an increased genetic liability to schizophrenia influences the risk of dying early. The aim of the study was to determine whether the genetic predisposition to schizophrenia is associated with the risk of dying early and experience a suicide attempt.
Case control study, Denmark. The main measure was the mortality rate ratios (MRR) for deaths and odds ratios (OR) for multiple suicide attempts, associated with one standard deviations increase of the polygenic risk-score for schizophrenia (PRS).
We replicated the high mortality MRR=9.01 (95% CI: 3.56-22.80), and high risk of multiple suicide attempts OR=33.16 (95% CI: 20.97-52.43) associated with schizophrenia compared to the general population. However, there was no effect of the PRS on mortality MRR=1.00 (95% CI 0.71-1.40) in the case-control setup or in cases only, MRR=1.05 (95% CI 0.73-1.51). Similar, no association between the PRS and multiple suicide attempts was found in the adjusted models, but in contrast, family history of mental disorders was associated with both outcomes.
A genetic predisposition for schizophrenia, measured by PRS, has little influence on the excess mortality or the risk of suicide attempts. In contrast there is a strong significant effect of family history of mental disorders. Our findings could reflect that the common variants detected by recent PRS only explain a small proportion of risk of schizophrenia, and that future, more powerful PRS instruments may be able to predict excess mortality within this disorder.
The phosphodiesterase 4B (PDE4B), which is involved in cognitive function in animal models, is a candidate susceptibility gene for schizophrenia (SZ) and bipolar disorder (BP). Variations in PDE4B have previously been associated with SZ, with a suggested gender-specific effect. We have genotyped and analyzed 40 and 72 tagging single nucleotide polymorphisms (tagSNPs) in SZ and BP multicenter samples, respectively, from the Scandinavian Collaboration on Psychiatric Etiology (SCOPE), involving 837 SZ cases and 1,473 controls plus 594 BP cases and 1,421 partly overlapping controls. Six and 16 tagSNPs were nominally associated (0.0005