Risk Factor For Schizophrenia Research Articles

Winter birth: A factor of poor functional outcome in a Swiss early psychosis cohort

ObjectiveWinter birth has consistently been identified as a risk factor for schizophrenia. This study aimed to determine whether individuals born during this season are also at higher risk for early psychosis and whether this is associated with distinct functional and clinical outcomes. MethodsWe conducted a prospective study on 222 patients during their early phase of psychosis in Switzerland, nested in the Treatment and Early Intervention in Psychosis (TIPP) cohort. We compared the birth trimesters of these patients with those of the general Swiss population. Additionally, we evaluated the Global Assessment of Functioning scale (GAF) and the Positive and Negative Syndrome Scale (PANSS) scores among patients born in winter (January to March) versus those born during the rest of the year during a three-year follow-up period. ResultsA significantly higher proportion of patients experiencing early psychosis were born in winter compared to the general Swiss population. Patients born in winter had significantly lower GAF scores at 6 months, 24 months, and 36 months of follow-up, compared to patients born during the rest of the year. They also manifested fewer positive symptoms, as indicated by the PANSS positive subscale. ConclusionBirth in winter appears to be associated with a lower functional outcome and potentially distinct symptomatology in the early phase of psychosis.

Causal association between mental disorders and cerebrovascular diseases: Evidence from Mendelian randomization study

Background and objectiveObservational studies have suggested that mental disorders and cerebrovascular diseases (CVDs) may be risk factors for each other, but genetic evidence of a causal relationship is still lacking. We used Mendelian randomization (MR) studies to explore the causal relationship between mental disorders and CVDs from the genetic perspective. MethodsTo investigate the causal association between major depressive disorder (MDD), anxiety, attention deficit/hyperactivity disorder (ADHD), bipolar disorder and schizophrenia five kinds of mental disorders and CVDs using two-sample two-way MR analysis based on publicly available genome-wide association study (GWAS) data. We used as instrumental variables (IVs) single-nucleotide polymorphisms (SNPs) that were strongly associated with mental disorders and CVDs. IVW method was used as the main analysis method, and MR-IVW, MR-Egger methods, MR-PRESSO test, leave-one-out analysis and funnel plot were used for sensitivity analysis. We further conducted a meta-analysis to summarize the currently available MR analyses. ResultsThe results of forward MR study showed that there was a significant causal relationship between ADHD and AS (any stroke) (p(AS) = 0.001, OR (95%CI) =1.118 (1.047–1.195)), any ischemic stroke (AIS) (p(AIS) = 0.004, OR (95%CI) =1.118(1.035–1.206)) and large artery stroke (LAS) (p(LAS) = 0.026, OR (95%CI): 1.206(1.023–1.422)). No heterogeneity, pleiotropy and outliers were found in sensitivity analysis. The reverse MR study showed that IA (intracranial aneurysm) (p(IA) = 0.033, OR (95%CI) = 1.123(1.009–1.249)) and UIA (unruptured intracranial aneurysm) (p(UIA) = 0.015, OR (95%CI) =1.040(1.008–1.074)) were risk factors for schizophrenia. Sensitivity analysis showed no pleiotropy, but there was heterogeneity. After excluding outliers, MR analysis showed that IA and UIA were still risk factors for schizophrenia. Our meta-analyses found statistical significance in causal relationships between ADHD and LAS (OR (95%CI) =1.18 (1.06–1.32), p = 0.003), IA and schizophrenia (OR (95%CI) =1.05 (1.02–1.08), p = 0.002) and UIA and schizophrenia (OR (95%CI) =1.03 (1.01–1.06), p = 0.010). ConclusionThe MR study and meta-analysis suggest that genetically predicted ADHD is a risk factor for LAS, and IA and UIA increase the risk of schizophrenia. The result has implications for the development of feasible prevention strategies in the future.

Clinical and Diagnostic Value of High-Density Lipoprotein-Based Inflammatory Indices and Lipid Ratios in Young Adults with Schizophrenia.

This study aimed to assess High-density Lipoprotein (HDL)-based Inflammatory Indices and lipid profile changes in antipsychotic-naive first-episode schizophrenia (AN-FES) patients, chronic schizophrenia (CS) patients, and explore the clinical and predictive value of these parameters for schizophrenia. The study cohort included 52 AN-FES patients, 46 CS patients, and 52 healthy controls (HCs), with an average age of 24 years. Upon admission, patients underwent complete blood count and lipid profile analyses. Various ratios were calculated, including neutrophil-to-HDL (NHR), monocyte-to-HDL (MHR), lymphocyte-to-HDL (LHR), and platelet-to-HDL (PHR), as well as lipid ratios like triglycerides/HDL, non-HDL/HDL, total cholesterol/HDL, and low-density lipoprotein/HDL. For the AN-FES group, these evaluations were repeated after two months of treatment with atypical antipsychotics. Statistical analyses included correlation analysis, Receiver Operating Characteristic (ROC) curve analysis, and univariate and multivariate regression. Compared to HCs, CS patients exhibited significantly higher MHR and NHR values, while AN-FES patients showed elevated levels of PHR, MHR, and NHR. No significant differences were observed in LHR or lipid ratios across the three groups. In the AN-FES cohort, MHR correlated positively with neutrophil counts, and NHR with monocyte counts. Additionally, white blood cell counts were positively associated with both MHR and NHR. Following treatment, NHR levels decreased, whereas TG/HDL ratios increased, with MHR and PHR remaining elevated. ROC analysis highlighted NHR as the most diagnostically valuable parameter (AUC = 0.799), with 86.5% specificity at an optimal cutoff of 3.534, outperforming MHR and PHR. Regression analyses recognized NHR (OR=2.225) as an independent risk factor for schizophrenia, even after adjusting for confounders. HDL-based inflammatory indices, particularly NHR, may serve as valuable diagnostic and prognostic markers in young adults with schizophrenia, even though significant alterations in lipid ratios were not observed in this demographic.

Environmental Risk Factors for Schizophrenia and Bipolar Disorder Over the Life Course: A Swedish Nested Case-Control Study

Environmental Risk Factors for Schizophrenia and Bipolar Disorder Over the Life Course: A Swedish Nested Case-Control Study

Schizophrenia genomics: genetic complexity and functional insights.

Determining the causes of schizophrenia has been a notoriously intractable problem, resistant to a multitude of investigative approaches over centuries. In recent decades, genomic studies have delivered hundreds of robust findings that implicate nearly 300 common genetic variants (via genome-wide association studies) and more than 20 rare variants (via whole-exome sequencing and copy number variant studies) as risk factors for schizophrenia. In parallel, functional genomic and neurobiological studies have provided exceptionally detailed information about the cellular composition of the brain and its interconnections in neurotypical individuals and, increasingly, in those with schizophrenia. Taken together, these results suggest unexpected complexity in the mechanisms that drive schizophrenia, pointing to the involvement of ensembles of genes (polygenicity) rather than single-gene causation. In this Review, we describe what we now know about the genetics of schizophrenia and consider the neurobiological implications of this information.

The genetics of cognition in schizophrenia

This conceptual review focuses on recent insights into the nature of the relationship between genetic predisposition and cognitive impairment as risk factors for schizophrenia, and the factors that influence the degree of cognitive impairment in those with the disorder. There is clear evidence that premorbid cognitive impairment is frequently present in those who develop schizophrenia, and, across the range of abilities, poorer premorbid cognition is associated with higher liability to the disorder. Evidence from genetic and population studies strongly supports the hypothesis that premorbid cognitive impairment is a marker for underlying neurodevelopmental risk factors for the disorder, rather than a prodromal manifestation. The premorbid cognitive deficit seems to be largely explained by non-familial factors rather than by familial factors that jointly influence liability to schizophrenia and cognitive ability, and these non-familial risk factors appear act to sensitize individuals to familial risk. There is also evidence that neurodevelopmental risk may be better indexed by the degree to which premorbid cognitive ability deviates from familial expectations than by cognitive ability per se. Premorbid cognitive impairment thus does not itself lie on the causal pathway to schizophrenia, rather it is a marker of a neurodevelopmental abnormality that is substantially non-familial, and which increases risk for schizophrenia. Genetic risk factors, including both common and rare alleles, that influence IQ in the general population also contribute both to liability for schizophrenia and to the degree of cognitive impairment in those with the disorder. There is also evidence for further decline in cognitive function after diagnosis in some individuals as well as an increased risk of dementia. This does not appear to reflect substantial shared heritability with neurodegenerative disorders, but the causes of postonset cognitive decline and its relationship to schizophrenia pathophysiology remain uncertain.

Pumilio-1 mediated translational control of claudin-5 at the blood-brain barrier

Claudin-5 is one of the most essential tight junction proteins at the blood-brain barrier. A single nucleotide polymorphism rs10314 is located in the 3’-untranslated region of claudin-5 and has been shown to be a risk factor for schizophrenia. Here, we show that the pumilio RNA-binding protein, pumilio-1, is responsible for rs10314-mediated claudin-5 regulation. The RNA sequence surrounding rs10314 is highly homologous to the canonical pumilio-binding sequence and claudin-5 mRNA with rs10314 produces 25% less protein due to its inability to bind to pumilio-1. Pumilio-1 formed cytosolic granules under stress conditions and claudin-5 mRNA appeared to preferentially accumulate in these granules. Added to this, we observed granular pumilio-1 in endothelial cells in human brain tissues from patients with psychiatric disorders or epilepsy with increased/accumulated claudin-5 mRNA levels, suggesting translational claudin-5 suppression may occur in a brain-region specific manner. These findings identify a key regulator of claudin-5 translational processing and how its dysregulation may be associated with neurological and neuropsychiatric disorders.Graphical

Revisión bibliográfica sobre la Asfixia Perinatal como factor de riesgo de esquizofrenia

Introduction: Perinatal asphyxia (PA) is one of the most prevalent injuries that occur around birth, especially in less socioeconomically developed countries. The developing brain is known to be particularly vulnerable to maternal stress and environmental insults before, during and after birth. In this sense, PA is considered a risk factor for numerous neurodevelopmental disorders. Objective: The objective of the present investigation was to analyze PA as a risk factor for schizophrenia. Materials and Methods: A search for scientific articles was carried out in the PubMed and Scielo databases, following the use of prespecified criteria, such as studies carried out on human subjects and animals, in English or Spanish, with availability of access to the text. complete and that they had been published no older than 10 years. Results: AP is associated with increased mortality rates due to the redistribution of cardiac output to the brain, heart and adrenal glands. Genes linked to a greater risk of schizophrenia have been identified, which modify their expression in a scenario of hypoxia induced by cesarean section in the brains of rodents. Likewise, hypoxia reduces brain weight and various processes such as myelination and neurogenesis Conclusions: Obstetric complications related to hypoxia increase the risk of developing schizophrenia five times in adult life

Homocysteine levels in first-episode patients with psychiatric disorders

A high homocysteine (Hcy) level is a risk factor for schizophrenia, depression, and bipolar disorder. However, the role of hyperhomocysteinemia as either an independent factor or an auxiliary contributor to specific psychiatric symptoms or disorders remains unclear. This study aimed to examine Hcy levels in first-episode inpatients with psychotic symptoms and various psychiatric diseases to elucidate the association between Hcy levels and psychiatric disorders. This study enrolled 191 patients (aged 18–40 years) with psychiatric disorders. Seventy-five patients were diagnosed with schizophrenia, 48 with acute and transient psychotic disorders, 36 with manic episodes with psychosis, 32 with major depressive episodes with psychosis, and 56 healthy controls. Serum Hcy levels were measured using the enzyme cycle method. A Hcy concentration level of > 15 μmol/L was defined as hyperhomocysteinemia. Hcy levels were significantly higher in first-episode patients with psychiatric disorders compared to healthy controls (5.99 ± 3.60 vs. 19.78 ± 16.61 vs. 15.50 ± 9.08 vs. 20.00 ± 11.33 vs. 16.22 ± 12.06, F = 12.778, P < 0.001). Hcy levels were significantly higher in males with schizophrenia, acute and transient psychotic disorder, and major depressive disorder but not in mania [schizophrenia, (t = -4.727, P < 0.001); acute and transient psychotic disorders, (t = -3.389, P = 0.001); major depressive episode with psychosis, (t = -3.796, P < 0.001); manic episodes with psychosis, (t = -1.684, P = 0.101)]. However, serum Hcy levels were not significantly different among the psychiatric disorder groups (F = 0.139, P = 0.968). Multivariate linear regression showed that males had an increased risk for homocysteinemia. (95% CI = 8.192–15.370, P < 0.001). These results suggest that first-episode patients with psychiatric disorders have higher Hcy levels than in the general population, and men are at greater risk for psychiatric disorders. In conclusion, elevated Hcy levels may contribute to the pathogenesis of first-episode patients with psychotic symptoms.

Toxoplasma gondii infection positively associated with schizophrenia: Evidences from UK Biobank cohort and case-controlled studies

Toxoplasma gondii (T. gondii) is an opportunistic pathogen affecting about 1/3 of world population. While often asymptomatic in immunocompetent individuals, it can lead to severe toxoplasmosis in immunocompromised patients. Recent research has unveiled a potential link between T. gondii infection and neuropsychiatric diseases. We implemented both a cohort study and a case control study to further identify this association. In the cohort study, we analyzed data from the UK Biobank database, which included 8814 individuals tested for T. gondii SAG1 antibodies and free of neuropsychiatric disorders at baseline. Among them, 22.52% (n = 1985) tested positive for SAG1 antibody. Over an average follow-up period of 12.26 years, Cox proportional hazards models and logistic regression analysis revealed a significant association between the SAG1 seropositivity at baseline and the incidence of schizophrenia (HR: 5.89; 95% CI: 1.69–20.53). In our case-control study, 239 patients diagnosed with schizophrenia and 455 healthy individuals were involved. Using the modified agglutination test (MAT) to detect T. gondii antibodies, logistic regression analysis showed a higher prevalence of T. gondii infection among schizophrenia patients (10.04%) compared to healthy controls (3.74%). T. gondii infection emerged as a significant risk factor for schizophrenia (OR: 3.33; 95% CI: 1.68–6.61). However, our investigations did not reveal a robust association between T. gondii infection and other neuropsychiatric conditions, including Alzheimer's disease, dementia, anxiety, depression, neurodegenerative disorders, and peripheral neurological disorders such as neurological and plexus disorders.

Coping styles do not interact with the association between childhood trauma history and the immune-inflammatory phenotype of schizophrenia: Findings from a cross-sectional study

Adverse childhood experiences (ACEs) are a well-known risk factor of schizophrenia. Moreover, individuals with schizophrenia are likely to use maladaptive stress coping strategies. Although it has been reported that a history of ACEs might be associated with a pro-inflammatory phenotype in patients with schizophrenia, the interacting effect of coping styles on this association has not been tested so far. In the present study, we aimed to investigate the levels of immune-inflammatory markers in patients with schizophrenia and healthy controls (HCs), taking into consideration a history of ACEs and coping strategies. Participants included 119 patients with schizophrenia and 120 HCs. Serum levels of 26 immune-inflammatory markers were determined. A history of any categories of ACEs was significantly more frequent in patients with schizophrenia. Moreover, patients with schizophrenia were significantly more likely to use emotion-focused coping and less likely to use active coping strategies compared to HCs. The levels of interleukin(IL)-6, RANTES, and tumor necrosis factor-α (TNF-α), appeared to be elevated in patients with schizophrenia after adjustment for potential confounding factors in all tested models. Participants reporting a history of any ACEs had significantly higher levels of TNF-α and IL-6. No significant main and interactive effects of active strategies as the predominant coping on immune-inflammatory markers with altered levels in patients with schizophrenia were found. Findings from the present study indicate that ACEs are associated with elevated TNF-α and IL-6 levels regardless of schizophrenia diagnosis and predominant coping styles.

Lymphoblast transcriptome analysis in 22q11.2 deletion syndrome individuals with schizophrenia-spectrum disorder

Objectives 22q11.2 deletion is the most prominent risk factor for schizophrenia (SZ). The aim of the present study was to identify unique transcriptome profile for 22q11.2 deletion syndrome (DS)-related SZ-spectrum disorder (SZ-SD). Methods We performed RNA-Seq screening in lymphoblasts collected from 20 individuals with 22q11.2DS (10 men and 10 women, four of each sex with SZ-SD and six with no psychotic disorders (Np)). Results Sex effect in RNA-Seq descriptive analysis led to separating the analyses between men and women. In women, only one differentially expressed gene (DEG), HLA-DQA2, was associated with SZ-SD. In men, 48 DEGs (adjp < 0.05) were found to be associated with SZ-SD. Ingenuity pathway analysis of top 85 DEGs (p < 4.66E − 04) indicated significant enrichment for immune-inflammatory response (IIR) and neuro-inflammatory signalling pathways. Additionally, NFATC2, IFNG, IFN-alpha, STAT1 and IL-4 were identified as upstream regulators. Co-expression network analysis revealed the contribution of endoplasmic reticulum protein processing and N-Glycan biosynthesis. These findings indicate dysregulation of IIR and post-translational protein modification processes in individuals with 22q11.2DS-related SZ-SD. Conclusions Candidate pathways and upstream regulators may serve as novel biomarkers and treatment targets for SZ. Future transcriptome studies, including larger samples and proteomic analysis, are needed to substantiate our findings.

Multiple myeloma, IL6, and risk of schizophrenia: A Mendelian randomization, transcriptome, and Bayesian colocalization study.

Numerous clinical studies speculated the association between multiple myeloma (MM) and inflammatory diseases; however, there is limited validation of these claims via establishing a causal relationship and revealing the underlying mechanism. This exploratory study employed bidirectional Mendelian randomization (MR) analysis to investigate the causal relationships between MM and inflammatory diseases, including atherosclerosis, asthma, ankylosing spondylitis, Alzheimer's disease (AD), Parkinson's disease (PD), sarcoidosis, inflammatory bowel disease, nonalcoholic fatty liver disease, type II diabetes, and schizophrenia (SZ). Transcriptomic and genome-wide Bayesian colocalization analyses were further applied to reveal the underlying mechanism. A significant and previously unrecognized positive association was identified between genetic predisposition to MM and the risk of SZ. Two independent case reports showed that treatment-resistant psychosis is due to underlying MM and is resolved by treating MM. From our MR analyses, various statistical methods confirmed this association without detecting heterogeneity or pleiotropy effects. Transcriptomic analysis revealed shared inflammation-relevant pathways in MM and SZ patients, suggesting inflammation as a potential pathophysiological mediator of MM's causal effect on SZ. Bayesian colocalization analysis identified rs9273086, which maps to the protein-coding region of HLA-DRB1, as a common risk variant for both MM and SZ. Polymorphism of the HLA-DRB1 allele has been implicated in AD and PD, further highlighting the impact of our results. Additionally, we confirmed that interleukin-6 (IL-6) is a risk factor for SZ through secondary MR, reinforcing the role of neuroinflammation in SZ etiology. Overall, our findings showed that genetic predisposition to MM, HLA-DRB1 polymorphism, and enhanced IL-6 signaling are associated with the increased risk of SZ, providing evidence for a causal role for neuroinflammation in SZ etiology.

Inflammatory based psychotic symptoms: when psychosis means encephalitis

AbstractSchizophrenia, as one of the most common disorders from the psychotic spectrum is most commonly detected in the phase of first psychosis and may pose a diagnostic challenge, as commonly comprise a heterogeneous group of schizophrenias, with distinct clinical presentations. If it detected in its prodromal phase without clearly developed psychotic symptoms, the diagnosis is even more unreliable, as the transition to full blown psychosis in the next two years happens in 15-40% of more, depending probably on a variety of cumulative environmental risk factors (including childhood trauma, the use of high-potency cannabis, urbanicity, season of birth). Moreover, the first episode psychosis may underlie for example the first manic episode, brief intermittent psychotic symptoms in persons with borderline personality disorders, acute reaction to trauma, the use of cannabis and psychostimulants and different organics causes, such as endocrinologic disorders and autoimmune encephalitis. Therefore, in everyday clinical practice, the diagnosis of first episode psychosis always requires an assessment of possible causes of psychosis, and also factors that may influence prognosis and treatment. Usual assessment include detailed anamnestic and heteroanamnestic data, physical examination, standard blood laboratory findings, drugs in urine/ blood, EEG and CT/MR scan. The absence of typical risk factors for schizophrenia, as well as the absence of premorbid symptoms and developmental course typical for schizophrenia, abrupt course of psychotic symptoms, symptoms such as disorientation, catatonia, speech disturbances, alteration of consciousness, neurologic signs, autonomic dysfunction and laboratory aberrations may be especially indicative for organic cause and possibly encephalitis and require further confirmation with the analysis of cerebrospinal liquor with antineuronal antibodies.Disclosure of InterestNone Declared

Understanding the Complex Relationship Between Gastrointestinal Symptoms and Psychosocial Factors in Schizophrenia

IntroductionInsensitivity to pain in schizophrenia is a complex phenomenon. Understanding schizophrenia’s heterogeneity is crucial for personalized treatments.ObjectivesIndividuals diagnosed with schizophrenia often experience gastrointestinal issues and exhibit elevated levels of depression and anxiety. There is an urgent need to understand how these factors interact and how childhood traumas, a significant risk factor for schizophrenia, can affect gastrointestinal symptoms in these individuals.MethodsThe study involved 51 individuals diagnosed with schizophrenia. The hierarchical cluster analysis on the principal components (HCPC) was performed to identify groups of similar observations for test scores and the overall results for 14 tests. Hierarchical clustering was performed using Ward’s minimum variance method. Differences in the results of individual tests between clusters were estimated using the V test.ResultsThe schizophrenia group was categorized into three clusters. The patients belonging to the first cluster are characterized by high GAF test scores and low scores on tests for gastrointestinal symptoms, ITQ, CTQ, GHQ-28, STAI, CALGARY, BDI II, SAMPS, SANS, and PANNS. In contrast, patients in the second cluster had scores significantly above the group average on the tests SANS, PANNS, and SAPS and low scores on the tests DBZ RZ, CTQ, STAI, BDI II, ITQ, and GAF. Finally, patients in the third cluster had high scores on the tests BDI II, ITQ, STAI, CTQ, GHQ 28, DBZ RZ, gastrointestinal symptoms, TEC PL, CALGARY, and CISS. High CTQ scores may contribute to increased GSSR scores due to childhood trauma’s potential to trigger chronic stress, affect the nervous system, and induce psychosomatic symptoms, including gastrointestinal problems. Elevated BDI II and STAI scores can also impact GSSR results by disrupting the connection between emotions and the gastrointestinal system.ConclusionsThis research underscores the intricate interplay of various psychosocial and physiological factors that influence the perception of pain related to gastrointestinal symptoms in individuals with schizophrenia.Disclosure of InterestNone Declared

Microglia-neuron interactions in schizophrenia.

Multiple lines of evidence implicate increased neuroinflammation mediated by glial cells to play a key role in neurodevelopmental disorders such as schizophrenia. Microglia, which are the primary innate immune cells of the brain, are crucial for the refinement of the synaptic circuitry during early brain development by synaptic pruning and the regulation of synaptic plasticity during adulthood. Schizophrenia risk factors as genetics or environmental influences may further be linked to increased activation of microglia, an increase of pro-inflammatory cytokine levels and activation of the inflammasome resulting in an overall elevated neuroinflammatory state in patients. Synaptic loss, one of the central pathological hallmarks of schizophrenia, is believed to be due to excess removal of synapses by activated microglia, primarily affecting glutamatergic neurons. Therefore, it is crucial to investigate microglia-neuron interactions, which has been done by multiple studies focusing on post-mortem brain tissues, brain imaging, animal models and patient iPSC-derived 2D culture systems. In this review, we summarize the major findings in patients and in vivo and in vitro models in the context of neuron-microglia interactions in schizophrenia and secondly discuss the potential of anti-inflammatory treatments for the alleviation of positive, negative, and cognitive symptoms.

A concerted neuron-astrocyte program declines in ageing and schizophrenia.

Human brains vary across people and over time; such variation is not yet understood in cellular terms. Here we describe a relationship between people's cortical neurons and cortical astrocytes. We used single-nucleus RNA sequencing to analyse the prefrontal cortex of 191 human donors aged 22-97 years, including healthy individuals and people with schizophrenia. Latent-factor analysis of these data revealed that, in people whose cortical neurons more strongly expressed genes encoding synaptic components, cortical astrocytes more strongly expressed distinct genes with synaptic functions and genes for synthesizing cholesterol, an astrocyte-supplied component of synaptic membranes. We call this relationship the synaptic neuron and astrocyte program (SNAP). In schizophrenia and ageing-two conditions that involve declines in cognitive flexibility and plasticity1,2-cells divested from SNAP: astrocytes, glutamatergic (excitatory) neurons and GABAergic (inhibitory) neurons all showed reduced SNAP expression to corresponding degrees. The distinct astrocytic and neuronal components of SNAP both involved genes in which genetic risk factors for schizophrenia were strongly concentrated. SNAP, which varies quantitatively even among healthy people of similar age, may underlie many aspects of normal human interindividual differences and may be an important point of convergence for multiple kinds of pathophysiology.

Environmental risk factors for schizophrenia and bipolar disorder from childhood to diagnosis: a Swedish nested case-control study.

Shared genetic risk between schizophrenia (SCZ) and bipolar disorder (BD) is well-established, yet the extent to which they share environmental risk factors remains unclear. We compare the associations between environmental exposures during childhood/prior to disorder onset with the risk of developing SCZ and BD. We conducted a Swedish register-based nested case-control study using 4184 SCZ cases and 18 681 BD cases diagnosed 1988-2013. Cases were matched to five controls by birth year, birth region, and sex. Conditional logistic regression was used to estimate incidence rate ratios (IRR) for SCZ and BD for each exposure (severe childhood infections, adverse childhood experiences (ACEs), substance use disorders (SUDs), urban birth/longest residence). All SUD types were associated with very high risk (IRR 4.9-25.5), and all forms of ACEs with higher risk (IRR 1.5-4.3) for both disorders. In the mutually adjusted models, ACEs demonstrated slightly higher risk for BD (SCZ IRR 1.30, 1.19-1.42; BD IRR 1.49, 1.44-1.55), while for SUD, risk was higher for SCZ (SCZ IRR 9.43, 8.15-10.92; BD IRR 5.50, 5.15-5.88). Infections were associated with increased risk of BD (IRR 1.21, 1.17-1.26) but not SCZ. Urban birth and urban longest residence were associated with higher risk of SCZ (IRR 1.19, 1.03-1.37), while only the combination of urban birth and rural longest residence showed higher risk for BD (IRR 1.24, 1.13-1.35). There were both shared and unique environmental risk factors: SUDs and ACEs were risk factors for both disorders, while infections were more strongly associated with BD and urbanicity with SCZ.

Identifying causal associations between women’s reproductive traits and risk of schizophrenia: a multivariate validated two-sample Mendelian randomization analysis

BackgroundA significant association between women’s reproductive traits and the risk of schizophrenia (SCZ) has been discovered, but the causalities remain unclear. We designed a two-sample univariate Mendelian randomization (MR) study using female-specific SNPs collected from a large-scale genome-wide association study as a genetic tool to explore the causal effect of female reproductive traits on the risk of SCZ, and conducted a multivariate MR study to re-validate the above findings.MethodsFrom extensive genome-wide association studies (GWAS) of people with European ancestry (n = 176,881 to 418,758 individuals), summary-level data on five female reproductive variables were extracted. Summary-level information on SCZ was taken from a GWAS meta-analysis involving 320,404 people with European ancestry. The inverse variance weighting estimations for both univariable MR (UVMR) and multivariable MR (MVMR) were presented as the primary results. MR-Egger, weighted median, simple mode, and weighted mode regression methods for UVMR, and MVMR-Egger, MVMR-Lasso, and MVMR-median methods for MVMR were used for sensitivity analyses.ResultsThe UVMR produced compelling proof for a connection between genetically predicted later age at first sexual intercourse (AFS) (OR, 0.632; 95% CI, 0.512–0.777; P < 0.01) and decreased SCZ risk. Pleiotropy analysis of the AFS-SCZ association confirmed the robustness of the MR results (P > 0.05). Consistent, substantial causal effects of AFS (OR, 0.592; 95%CI, 0.407–0.862; P < 0.01) on the risk of SCZ were demonstrated after adjusting for body mass index, years of schooling, and smoking initiation using MVMR.ConclusionsOur findings provide convincing evidence that early AFS is a risk factor for SCZ. SCZ risk may be decreased by raising awareness of reproductive healthcare for women.

Genetic prediction of the causal relationship between schizophrenia and tumors: a Mendelian randomized study.

Patients with schizophrenia are at a higher risk of developing cancer. However, the causal relationship between schizophrenia and different tumor types remains unclear. Using a two-sample, two-way Mendelian randomization method, we used publicly available genome-wide association analysis (GWAS) aggregate data to study the causal relationship between schizophrenia and different cancer risk factors. These tumors included lung adenocarcinoma, lung squamous cell carcinoma, small-cell lung cancer, gastric cancer, alcohol-related hepatocellular cancer, tumors involving the lungs, breast, thyroid gland, pancreas, prostate, ovaries and cervix, endometrium, colon and colorectum, and bladder. We used the inverse variance weighting (IVW) method to determine the causal relationship between schizophrenia and different tumor risk factors. In addition, we conducted a sensitivity test to evaluate the effectiveness of the causality. After adjusting for heterogeneity, evidence of a causal relationship between schizophrenia and lung cancer risk was observed (odds ratio [OR]=1.001, 95% confidence interval [CI], 1.000-1.001; P=0.0155). In the sensitivity analysis, the causal effect of schizophrenia on the risk of lung cancer was consistent in both direction and degree. However, no evidence of causality or reverse causality between schizophrenia and other tumors was found. This study elucidated a causal relationship between the genetic predictors of schizophrenia and the risk of lung cancer, thereby providing a basis for the prevention, pathogenesis, and treatment of schizophrenia in patients with lung cancer.