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Abstract Background To examine the risk of depressive and anxiety disorders according to psychosocial working conditions in a large population-based sample. Methods Job Exposure Matrix was applied to assess psychosocial working conditions in a population-based nested case-control study of 14,166 psychiatric patients, diagnosed with depressive or anxiety disorders during 1995–1998 selected from The Danish Psychiatric Central Research Register, compared with 58,060 controls drawn from Statistics Denmark's Integrated Database for Labour Market Research. Results Low job control was associated with an increased risk of anxiety disorders in men (IRR 1.40, 95% CI 1.24–1.58). In women an elevated risk of depression was related to high emotional demands (IRR 1.39, 95%CI 1.22–1.58) and to working with people (IRR 1.15, 95% CI 1.01–1.30). In both sexes high demands were associated with a decreased risk of anxiety disorders. There was a weak association between job strain and anxiety disorders in men (IRR 1.13, 95%, CI 1.02–1.25) Conclusion Psychosocial work exposures related to the risk of depressive and anxiety disorders differ as between the sexes. The pattern of risks is inconsistent. The results give rise to rethinking both study designs and possible causal links between work exposures and mental health.

Abstract Suicide is a major cause of death among patients with schizophrenia. Research indicates that at least 5–13% of schizophrenic patients die by suicide, and it is likely that the higher end of range is the most accurate estimate. There is almost total agreement that the schizophrenic patient who is more likely to commit suicide is young, male, white and never married, with good premorbid function, post-psychotic depression and a history of substance abuse and suicide attempts. Hopelessness, social isolation, hospitalization, deteriorating health after a high level of premorbid functioning, recent loss or rejection, limited external support, and family stress or instability are risk factors for suicide in patients with schizophrenia. Suicidal schizophrenics usually fear further mental deterioration, and they experience either excessive treatment dependence or loss of faith in treatment. Awareness of illness has been reported as a major issue among suicidal schizophrenic patients, yet some researchers argue that insight into the illness does not increase suicide risk. Protective factors play also an important role in assessing suicide risk and should also be carefully evaluated. The neurobiological perspective offers a new approach for understanding self-destructive behavior among patients with schizophrenia and may improve the accuracy of screening schizophrenics for suicide. Although, there is general consensus on the risk factors, accurate knowledge as well as early recognition of patients at risk is still lacking in everyday clinical practice. Better knowledge may help clinicians and caretakers to implement preventive measures. This review paper is the results of a joint effort between researchers in the field of suicide in schizophrenia. Each expert provided a brief essay on one specific aspect of the problem. This is the first attempt to present a consensus report as well as the development of a set of guidelines for reducing suicide risk among schizophenia patients.

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 ofmental 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. [ABSTRACT FROM AUTHOR]

IMPORTANCE There has been recent interest in the findings that the offspring of older fathers have an increased risk of both de novo mutations and neuropsychiatric disorders. However, the offspring of younger parents are also at risk for some adverse mental health outcomes. OBJECTIVE To determine the association between maternal and paternal age and a comprehensive range of mental health disorders. DESIGN, SETTING, AND PARTICIPANTS A comprehensive, population-based record linkage study using the Danish Psychiatric Central Research Register from January 1, 1995, through December 31, 2011. A total of 2 894 688 persons born in Denmark from January 1, 1955, through December 31, 2006, were followed up during the study period. EXPOSURES Maternal and paternal age at the time of offspring's birth. MAIN OUTCOMES AND MEASURES We examined a broad range of International Classification of Diseases-defined mental disorders, including substance use; schizophrenia and related disorders; mood disorders; neurotic, stress-related, and somatoform disorders; eating disorders; specific personality disorders; and a range of developmental and childhood disorders. The incidence rate ratios for each mental disorder outcome were estimated by log linear Poisson regression with adjustments for the calendar period, age, sex, and age of the other parent. RESULTS The cohort was observed for 42.7 million person-years, during which 218 441 members of the cohort had their first psychiatric contact for any psychiatric disorder. Based on the overall risk of psychiatric disorders, the offspring of younger and older parents were at increased risk compared with those of parents aged 25 to 29 years. When the offspring were examined for particular disorders, the nature of the relationship changed. For example, the offspring of older fathers were at an increased risk of schizophrenia and related disorders, mental retardation, and autism spectrum disorders. In contrast, the offspring of young mothers (and to a lesser extent young fathers) were at an increased risk for substance use disorders, hyperkinetic disorders, and mental retardation. CONCLUSIONS AND RELEVANCE The offspring of younger mothers and older fathers are at risk for different mental health disorders. These differences can provide clues to the complex risk architecture underpinning the association between parental age and the mental health of offspring. [ABSTRACT FROM AUTHOR]

Objective: Greater paternal age is associated with increased risk of schizophrenia, and it has been hypothesized that de novo mutations in paternal germ cells are responsible for this association. An alternative hypothesis is that selection into late fatherhood accompanies a predisposition to schizophrenia. However, direct evidence of either hypothesis is lacking. If de novo mutations are responsible, greater paternal age at conception should increase the risk of schizophrenia. Conversely, if selection into late fatherhood is responsible for the association, greater age at which the father had his first child should increase the risk of schizophrenia. The authors aimed to distinguish between these two measures of paternal age. Method: A total of 2.2 million people born in Denmark between 1955 and 1992 were followed up until first diagnosis with schizophrenia. Incidence rate ratios were estimated in a Cox regression. Results: Among second- or later-born children, greater paternal age increased the risk of schizophrenia. However, when paternal age at the time of the father's first child was accounted for, the risk of schizophrenia did not depend on paternal age at the birth of later children. In contrast, the risk of schizophrenia increased significantly with increasing paternal age at the time of the father's first child. Conclusions: Factors related to greater paternal age when the father's first child was born, and not the father's age at conception of later children, are responsible for the association between paternal age and the risk of schizophrenia. These findings do not support the de novo mutation hypothesis. [ABSTRACT FROM AUTHOR]

The article discusses the study investigating the risks and predictors of readmission for a mental disorder during the postpartum period. It is said that a cohort study has merged the data from the Danish Civil Registration System and the Danish Psychiatric Central Register. It includes 28, 124 women, in which 10,218 were mothers who were followed up from January 1, 1973 to June 30, 2005. Results show that mothers with mental disorders have lower readmision rates compared with nonmothers with mental disorders.

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. [ABSTRACT FROM AUTHOR]

Background: Urban birth or upbringing increase schizophrenia risk. Though unknown, the causes of these urban-rural differences have been hypothesized to include, e.g., infections, diet, toxic exposures, social class, or an artefact due to selective migration. Methods: We investigated the hypothesis that traffic related exposures affect schizophrenia risk and that this potential effect is responsible for the urban-rural differences. The geographical distance from place of residence to nearest major road was used as a proxy variable for traffic related exposures. We used a large population-based sample of the Danish population (1.89 million people) including information on all permanent addresses linked with geographical information on all roads and house numbers in Denmark. Schizophrenia in cohort members (10,755 people) was identified by linkage with the Danish Psychiatric Central Register. Results: The geographical distance from place of residence to nearest major road had a significant effect. The highest risk was found in children living 500-1000 metres from nearest major road (RR = 1.30 (95% Confidence Interval: 1.17-1.44). However, when we accounted for the degree of urbanization, the geographical distance to nearest major road had no significant effect. Conclusion: The cause(s) or exposure(s) responsible for the urban-rural differences in schizophrenia risk were closer related to the degree of urbanization than to the geographical distance to nearest major road. Traffic related exposures might thus be less likely explanations for the urban-rural differences in schizophrenia risk. [ABSTRACT FROM AUTHOR]

Background: A growing body of evidence suggests that migration is a risk factor for the development of schizophrenia, although the putative mechanism remains obscure.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. [ABSTRACT FROM AUTHOR]

Background Familial clustering of suicidal behaviour has been well documented. We aimed to assess whether family history of completed suicide and mental illness that results in admission to hospital are risk factors for suicide, and whether these factors interact.Methods We did a nested case-control study using data from Danish longitudinal registers. We included 4262 people who had committed suicide aged 9–45 years during 1981–97 (cases), and 80238 population-based controls matched for age, sex, and date of suicide. Suicide and psychiatric history of parents and siblings and socioeconomic, demographic, and psychiatric data for every case were retrieved and merged. Data were analysed with conditional logistic regression.Findings A family history of completed suicide and psychiatric illness significantly and independently increased suicide risk (odds ratio 2·58 [95% CI 1·84–3·61] and 1·31 [1·19–1·45], respectively). These effects were not accounted for by the socioeconomic status and psychiatric history of cases. A history of family psychiatric illness significantly raised suicide risk only in people without a history of psychiatric illness (1·55 [1·38–1·75]), whereas a family history of suicide increased suicide risk irrespective of psychiatric illness (2·37 [1·11–5·09] and 2·66 [1·82–3·88]) for people with and without a psychiatric history, respectively.Interpretation Completed suicide and psychiatric illness in relatives are risk factors for suicide, and the effect of family suicide history is independent of the familial cluster of mental disorders. Family history of suicide should be established in the assessment of suicide risk. [Copyright &y& Elsevier]

Background Gender is one of the most frequently replicated predictors for suicide. Aims To identify risk factors for suicide among males and females and to investigate whether risk factors for suicide differ by gender. Method A time-matched nested case—control design was performed using Danish longitudinal register databases to obtain 811 suicide cases and 79 871 controls. Data were analysed using conditional logistic regression. Results A history of hospitalised mental illness was the most marked risk factor for suicide for both genders. Unemployment, retirement, being single and sickness absence were significant risk factors for men, whereas having a child < 2 years old was significantly protective for women. The relative risks for suicide differed significantly between genders according to psychiatric admission status and being the parent of a child < 2 years. However, adjustment for these factors did not eliminate the gender difference in suicide risk. Conclusions Risk factors for suicide differed by gender and gender differences could not be explained by differential exposure to known risk factors. [ABSTRACT FROM AUTHOR]

Background: The high mortality from suicide in patients admitted to hospital with an affective disorder is well documented, although specific causes of mortality and changes in mortality are less well studied.Aims: To describe the pattern of mortality in patients with affective disorder and to study changes in suicide risk during the study period.Method: All patients (n = 54,103) admitted for the first time to a psychiatric hospital in Denmark during the period 1973-1993 because of affective disorder were included in this study. The mortality rate was compared with that of the general population.Results: Mortality from natural and unnatural causes was elevated in all subgroups of affective disorder. The risk of suicide among patients ill for one year or less after first admission increased during the period 1973-1993.Conclusions: More attention should be paid to the risk of suicide and to physical illness in patients with affective disorders. [ABSTRACT FROM AUTHOR]

Although many studies have shown an increased mortality in schizophrenic patients, the literature provides little information about mortality from specific causes in relation to age, gender, and duration of illness. This study examined mortality and causes of death in a total national sample of 9156 first admitted schizophrenic patients. Suicide accounted for 50% of deaths in men and 35% of deaths in women. Suicide risk was particularly increased during the first year of follow-up. Death from natural causes, with the exception of cancer and cerebrovascular diseases, was increased. Suicide risk during the first year of follow-up increased by 56%, with a 50% reduction on psychiatric in-patient facilities. The study confirms that mortality in schizophrenia is still markedly elevated, and the finding of an increasing suicide risk may be an indicator of some adverse effects of deinstitutionalisation. [ABSTRACT FROM AUTHOR]

All Danish psychiatric patients admitted to hospital for the first time in the period 1969-88 with a diagnosis of schizophrenia given at least once during the period were included in the study. More than 8500 patients were examined in the Danish nationwide psychiatric register. First-admission rates decreased by approximately 50% irrespective of mode of calculation and increase in SMR. The use of in-patient care was unchanged despite a reduction in available beds of more than 40% in the study period. [ABSTRACT FROM AUTHOR]

Risk for depression is attributable to both genes and life stress such as childhood maltreatment or death of a close relative. Candidate gene studies have indicated that life stress interacts with single genetic variants to influence depression risk. Further, the genetic architecture of depression is highly polygenic, with genetic risk for depression primarily determined by small effects of multiple genetic variants which might also interact collectively with environmental factors. The aim of this study is to investigate gene-environment interaction in depression using three separate measures of genetic risk: a) candidate genetic variants, b) polygenic risk scores and c) a Genome-Wide Interaction Study (GWIS) based on 500,000 SNPs distributed across the genome. In the iPSYCH case-cohort study we identified 18,431 cases and 20,163 random subcohort members for whom GWAS analyses were available. All cases were diagnosed with depression at a Danish psychiatric hospital. We used nationwide Danish registers to obtain information on the life stressors: childhood abuse, family disruption, disability pension in a parent, severe somatic disease of the index person and severe somatic disease and death of first-degree relatives. Information on life stress was operationalized as a cumulative time-dependent variable. Our analyses include 180 specific candidate genetic variants previously reported to take part in gene-environment interaction in depression or identified as directly associated with depression in GWASs. Further, we evaluate if a polygenetic risk score interacts with life stress to predict depression. Finally, we apply an agnostic approach investigating if any of 500,000 SNPs selected from across the genome interact with early life stress on risk for depression. We applied extended Cox models with Prentice weighting of cases for analyses. Sex, birth cohort and principal components were included as covariates. At the time of abstract submission we have conducted preliminary analyses. Final analyses will be presented at the WCPG, 2017. To our best knowledge, this study will be the largest original investigation to date on gene-environment interaction in depression. We expect that the results will provide new insights to the understanding of the combined effects of nature and nurture on risk for depression. [ABSTRACT FROM AUTHOR]

Emerging evidence implicates altered DNA methylation in mental illness including autism, ADHD, bipolar disorder, major depressive disorder, anorexia and schizophrenia. However, it is unclear whether the DNA methylation changes observed to date are causative or reflect disease progression or treatment. The neonatal period is a time of rapid neurodevelopment during which alterations in DNA methylation may contribute to the risk of mental illness later in life. Hence, we explored whether differences in DNA methylation in neonatal blood were associated with twin discordance for mental illnesses including autism, ADHD, affective disorder, anorexia, schizophrenia or bipolar disorder. A total of 597 pairs of twins (220 monozygotic) discordant for mental illness born between 1981 and 2005 were identified for methylomic comparison. Blood samples obtained from neonatal Guthrie cards were used for DNA extraction and genome-wide profiling of DNA methylation with the use of Infinium HumanMethylation450 BeadChip or EPIC array from Illumina. Quality control, data pre-processing and statistical analysis was performed using the minfi package in R. Data were normalized using the ssNoob method and adjusted for batch effects using the Combat tool. Blood cell composition was estimated using FlowSorted.CordBlood.450k. Using linear regression models and including potential confounders such as sex, blood cell composition and zygosity, we observed differentially methylated positions (DMPs) associated with mental illness. We used VarElect (http://varelect.genecards.org/) to identify which genes are known to directly associate with mental illness. The GeneMania tool (http://genemania.org/) was used to visualize gene interactions in a network. We observed significant DMPs (P<10-06) for ADHD (mapping to TET2, HNRNPH2, HMGN5), autism (mapping to ATP1B4), and anorexia (mapping to ITGB4, GJA3, NXN). Interestingly, there is an enrichment of DMPs mapping to genes in the dopaminergic and serotonergic synapse KEGG pathways including KCNJ5, PRKCA, CACNA1D, CREB5, and ALOX12 (P<0.05). In addition, we identified 67 DMPs (P<10E-5) mapping to genes which have known direct association with at least one mental illness and are connected in a complex genetic network. Our data indicate that DNA methylation differences are quantifiable in neonatal blood from twins discordant for mental illness later in life and suggest that susceptibility to mental illness is conferred by dysregulated neurodevelopmental genes. [ABSTRACT FROM AUTHOR]

Individuals with 22q11.2 Deletion Syndrome (DS) have an increased risk of comorbid mental disorders including schizophrenia, attention deficit hyperactivity disorder, depression, as well as intellectual disability. While most 22q11.2 deletion carriers have the long 3 Mb form of the hemizygous deletion, there remains a large variation in the development and progression of psychiatric disorders, which suggests that alternative factors contribute to the pathogenesis. In this study, we investigated whether neonatal DNA methylation signatures in individuals with the 22q11.2 deletion associate with mental disorder later in life. Subjects with 22q11.2 deletion were selected from The Danish Cytogenetic Central Register. DNA methylation was measured genome-wide with the use of Infinium HumanMethylation450 BeadChip from neonatal dried blood spots in a cohort of 164 individuals with 22q11.2DS, including 48 diagnosed with a psychiatric disorder. Epigenome-Wide Association Study (EWAS) was performed to determine differential DNA methylation among 22q11.2 deletion carriers diagnosed with mental disorder compared to carriers with no current or past mental disorder diagnosis. Most associated sites were used for Gene Ontology pathway enrichment analysis. Moreover, we evaluated four sub-classes of most commonly observed psychiatric diagnoses (intellectual disability: F70-79, behavioral disorders: F90-98, disorders of psychological development: F80-89 and schizophrenia spectrum disorders: F20-29) in the cohort and compared their methylome profiles to the non-psychiatric controls. Regression models, adjusted for sex, type of 22q11.2 deletion, and age of the blood spot card, were used for all EWAS analyses to identify differentially methylated sites. Among several CpG sites with p-value < 10-6, we identified cg23546855 (p-value=2.15×10-7) mapping to STK32C to be associated with a later psychiatric diagnosis. Pathway analysis of the top findings resulted in the identification of several Gene Ontology pathways to be significantly enriched (p-value < 0.05 after BH correction), among them: neurogenesis, neuron development, neuron projection development, astrocyte development, axonogenesis, and axon guidance. Additionally, we identified differentially methylated CpG sites in LRP2BP (p-value=5.37×10-8) to be associated with intellectual disability, in TOP1 (p-value=1.86×10-7) with behavioral disorders, in NOSIP (p-value=5.12×10-8) with disorders of psychological development, and in SEMA4B (p-value=4.02×10-7) with schizophrenia spectrum disorders. In conclusion, our study suggests an association of DNA methylation differences at birth with development of mental disorder later in life in 22q11.2DS individuals. Differentially methylated sites were located in genes enriched in those involved in neurogenesis, nervous development, and neuron projection development, what supports previous studies that suggested mental disorders to have an early neurodevelopmental component. [ABSTRACT FROM AUTHOR]

Mitochondria play a significant role in human diseases. Genetic variants in mitochondrial DNA (mtDNA) – and in nuclear genes coding for mitochondrial function - have been associated with disease. Mitochondrial disease is clinically characterised by complex metabolic, neurological, muscular and psychiatric symptoms. SNPs in mtDNA have been proposed as potential disease modifiers. This has been reported in neurological degenerative diseases such as Alzheimer's disease and Parkinson's disease, metabolic diseases and cancers, as well as psychiatric diseases, notably schizophrenia (SZ) and bipolar disease. However, disease associations with mitochondrial DNA (mtDNA) SNPs have proven difficult to replicate. We identified eight mtDNA SNPs that had previously been associated with SZ and re-analysed the association with SZ in the Danish iPSYCH cohort, and examined the effect of mtDNA variation and variation in nuclear genogeographic affinity, or ancestry, on the association. Persons were recruited through the iPSYCH program, which is a case-cohort study. DNA was isolated from dried blood spots obtained through the Danish Neonatal Screening program. Genotyping was performed using the PsychChip array, comprising 418 SNPs in mtDNA. Supervised ancestry estimation of the nuclear genome was performed using a reference population of 2,248 persons assigned to one of nine population Groups. The estimation was done with 103,268 nuclear SNPs using ADMIXTURE 1.3.050. A reanalysis of eight schizophrenia-associated mtDNA SNPs, in 23,743 normal Danes and 2,538 schizophrenia patients, revealed marked inter-allelic differences both in haplogroup affiliation and nuclear ancestry, genogeophraphic affinity (GGA). Only two mitochondrial SNPs, m.15043 A and m.15218 G, were significantly associated with schizophrenia. However, these associations disappeared when corrected for haplogroup affiliation. The combined variation in mtDNA affiliation and nuclear genomic ancestry, bi-genomic linkage disequilibrium (2GLD) could entail population stratification. This might result in both false positive and negative associations between mtDNA SNPs and disease. The extensive 2GLD documented for the eight SNPs examined here is a major concern when interpreting historic as well as designing future mtDNA association studies. The fact that careful control, as here, of mtDNA affiliation and the 2GLD, results in none of eight previously SZ associated mtDNA SNPs being associated with SZ in the very large Danish iPSYCH cohort, suggests that previously reported associations could indeed be spurious findings due to cryptic population stratification. [ABSTRACT FROM AUTHOR]