Context: Prenatal infection and traumatizing experiences have both been linked with schizophrenia, but none of these factors seem sufficient to cause the disorder. However, recent evidence suggests that these environmental insults act in synergy to increase schizophrenia risk. Objective: To estimate the independent and joint effects of exposure to prenatal infection and peripubertal psychological trauma on the risk of schizophrenia. Design: Danish nationwide registers were linked in this prospective cohort study. We used survival analysis to report incidence rate ratios (IRRs) and corresponding 95% confidence intervals (95% CIs). Analyses were adjusted for age and calendar period and stratified by sex. Participants: A total of 979 701 persons born between 1980 and 1998 were followed up from January 1, 1995 through December 31, 2013, with 9656 having a hospital contact for schizophrenia. Results: Females exposed to prenatal infection had a significantly increased risk of schizophrenia (IRR: 1.61, 95% CI: 1.30-2.00), but not males (IRR: 0.99, 95% CI: 0.77-1.28). Peripubertal trauma was associated with increased risk in both sexes. Males, however, had a significantly higher risk of schizophrenia after exposure to both prenatal infection and peripubertal psychological trauma (IRR: 2.85, 95% CI: 2.32-3.51), with significant interaction between infection and peripubertal trauma on the multiplicative scale (P = .007). Conclusions: Our study demonstrated for the first time that prenatal infection and psychological trauma in peripubertal life can act in synergy to increase the risk of schizophrenia, with a potentially stronger susceptibility in males.

BackgroundThere are well-established epidemiologic associations between advanced paternal age and increased offspring risk for several psychiatric and developmental disorders. These associations are commonly attributed to age-related de novo mutations. However, the actual magnitude of risk conferred by age-related de novo mutations in the male germline is unknown. Quantifying this risk would clarify the clinical and public health significance of delayed paternity.MethodsUsing results from large, parent-child trio whole-exome-sequencing studies, we estimated the relationship between paternal-age-related de novo single nucleotide variants (dnSNVs) and offspring risk for five disorders: autism spectrum disorders (ASD), congenital heart disease (CHD), neurodevelopmental disorders with epilepsy (EPI), intellectual disability (ID), and schizophrenia (SCZ). Using Danish national registry data, we then investigated the degree to which the epidemiologic association between each disorder and advanced paternal age was consistent with the estimated role of de novo mutations.ResultsIncidence rate ratios comparing dnSNV-based risk to offspring of 45 versus 25-year-old fathers ranged from 1.05 (95% confidence interval 1.01–1.13) for SCZ to 1.29 (95% CI 1.13-1.68) for ID. Epidemiologic estimates of paternal age risk for CHD, ID and EPI were consistent with the dnSNV effect. However, epidemiologic effects for ASDs and SCZ significantly exceeded the risk that could be explained by dnSNVs alone (p<2e-4 for both comparisons).ConclusionIncreasing dnSNVs due to advanced paternal age confer a small amount of offspring risk for psychiatric and developmental disorders. For ASD and SCZ, epidemiologic associations with delayed paternity largely reflect factors that cannot be assumed to increase with age.

Background: Depression is one of the leading causes of premature workforce exit in many Western countries, but little is known about the extent to which treatment-resistance reduces number of work-years. We compared the risk of premature workforce exit among patients with treatment-resistant depression (TRD) relative to non-TRD patients and estimated work years lost (WYL) before scheduled retirement age. Methods: The study population, identified in the Danish National Prescription Registry, included all individuals born and living in Denmark who redeemed their first antidepressant (AD) prescription for depression at age 18–60 years between 2005 and 2012. TRD was defined as failure to respond to at least two different treatment trials. Premature workforce exit was measured using disability pension records. We used Cox regression to estimate the hazard ratio (HR) for premature workforce exit in TRD relative to non-TRD patients, adjusting for calendar year, psychiatric and somatic comorbidity, and educational level. Differences in WYL in patients with TRD and all depression patients were estimated through a competing risks model. Results: Out of the total sample of patients with depression ( N = 129,945), 7478 (5.75%) were classified as having TRD. During follow up, 17% of patients with TRD and 8% of non-TRD patients received disability pension, resulting in a greater than three-fold larger risk of premature workforce exit [adjusted HR (aHR) 3.23 95% confidence interval (CI) 3.05–3.43]. The TRD group lost on average six work-years (95% CI 5.64–6.47) more than the total sample due to early labor force exit. The association between TRD and age at premature workforce exit was inversely U-shaped; the hazard rate of premature workforce exit for patients with TRD compared with non-TRD patients was highest in the age groups 31–35, 36–40, and 41–45 years. Conclusion: Patients with TRD constitute a small group within depression patients, but contribute disproportionally to societal costs due to premature workforce exit at a young age.

Plenary S19and non-psychotic bipolar disorder. Differing patterns of risk by region of origin may indicate that the pre-and post-migration psychosocial stressors, treatment-seeking behavior, or diagnostic patterns may vary between migrant groups, but further research is required to determine the underlying mechanism driving this variation. Background: Childhood trauma is a risk factor in the etiology of schizophrenia. Mesolimbic dopamine sensitization has been hypothesized to be a mediating factor of childhood trauma on the risk of schizophrenia. Activity of catechol-O-methyltransferase (COMT) Val158Met increases mesolimbic dopamine signaling, and COMT activity may be further regulated by methylenetetrahydrofolate reductase (MTHFR) C677T. The objective of the present study was to investigate the hypothesized three-way interaction between childhood trauma, COMT and MTHFR. Methods: We conducted a nested case-control study on individuals born after 1981, linking Danish nationwide population-based registers to obtain information on genetics and exposure to childhood trauma. The study included 1699 schizophrenia cases and 1681 controls. We used an additive genetic model and conditional logistic regression to estimate interactions between allele count and exposure status. Incidence rate ratios (IRRs) were estimated with corresponding 95% confidence intervals (95% CI). Results: Childhood trauma was robustly associated with schizophrenia. No main genetic effects were observed. MTHFR C677T increased schizophrenia risk in a dose-dependent manner per MTHFR T-allele (P = .005) consequent upon trauma exposure. In the 3-way interaction model, the risk was further increased in a dose-dependent manner per high-activity COMT Val-allele. Hence, exposed COMT Val/Met and MTHFR T/T carriers had an IRR of 2.34 (1.51-3.61). Additional adjustments for polygenic risk score, ancestry and parental history of mental illness, attenuated the results with the interaction being only marginally significant. Conclusion: MTHFR C677T and COMT Val158Met interact with childhood trauma to increase risk of schizophrenia. Background: Epidemiological studies conducted over the past 50 years have observed an increased prevalence of psychosis among individuals with nonneurological autoimmune disorders relative to the general population, with the notable exception of rheumatoid arthritis. Whether this association reflects shared risk factors (e.g., infections or genetic liability) or a causal relationship (mediated by inflammation or brain-reactive antibodies) is yet to be determined. Quantifying the extent to which psychosis is associated with individual nonneurological autoimmune disorders may help to address this issue. A systematic review of studies investigating the comorbidity of psychosis and nonneurological autoimmune disorders was therefore conducted to clarify the nature of this association; meta-analyses were performed for individual autoimmune disorders where possible. Methods: PubMed, PsycINFO, and EMBASE were systematically searched, and supp...