Risk Of Psychiatric Disorders Research Articles

Assessment of Risk for Immune and Psychiatric Disorders Using qPCR-Based Monitoring of the nan Gene in Gut Microbiota: A Non-invasive Approach

Aim: This study aimed to establish a non-invasive, rapid, and cost-effective method to assess the potential risk of immune and psychiatric disorders by quantifying nan gene levels in gut microbiota, specifically focusing on Ruminococcus gnavus and other Lachnospiraceae species associated with mucin degradation. Methodology: We first designed a primer set targeting the consensus sequence of the nanA gene, which is highly conserved within nan gene clusters. To validate this primer set, we performed Next-Generation Sequencing (NGS) on the PCR-amplified fragments. To explore the association between nan levels and immune or psychiatric disorders, we conducted qPCR to quantify nan levels in the intestines, analyzing intestinal DNA from both allergy-induced mice with or without fructan treatment, and dogs with or without aggressive behavior. Additionally, to assess whether nan levels reflect the clinical status of immune disorders, fecal samples were collected from 45 patients with ulcerative colitis (UC) and analyzed for nan levels. Results: NGS analysis of DNA fragments amplified from various intestinal samples using the nan primer set confirmed the presence of nanA sequences from R. gnavus and other members of the Lachnospiraceae family, including Blautia and Dorea species. The qPCR quantification of nan levels using this primer set revealed that allergy-induced mice treated with fructans, which are known to be associated with lower allergy scores compared to untreated mice, exhibited significantly reduced nan levels. Additionally, the nan levels of aggressive dogs were substantially higher than those of non-aggressive dogs. Notably, nan levels were also substantially elevated in patients with UC in comparison to the healthy control individuals. Conclusion: qPCR-based measurement of nan levels in gut microbiota shows potential for selectively detecting pathogenic nan-harboring strains and may reflect the clinical status of immune and psychiatric disorders. This approach could provide a non-invasive, rapid, and cost-effective method for assessing the risk of these disorders.

The Impact of Relationships Within Combat Units on Post-Deployment Suicide Risk

Multiple deployment factors may affect suicidality in combat veterans. The relationships between combat deployments and suicidality are complex and not completely understood. Studies of stress in the military and psychological effects of military actions are mostly focused on stressors relating to combat operations. However, many studies suggest that interactions within combat units affect post-deployment psychiatric conditions, suicidal ideation, and behavior. The goal of this article is to review and discuss how relationships within combat units may influence post-deployment suicide risk. Studies of the relationships within combat units are generally focused on two aspects: unit cohesion and harassment/abuse. Considerable evidence suggests that service members who report strong unit cohesion have a lower risk of post-deployment psychiatric disorders and suicidal behavior. Studies examining deployment sexual and non-sexual harassment and abuse have found that combat veterans who experience harassment and abuse during deployment are at heightened post-deployment suicide risk. Sound post-deployment social support and the efficient treatment of psychiatric disorders may mitigate the suicide risk associated with adverse relationships within combat units. Improvements in units’ cohesion and the prevention of harassment/abuse during a military deployment are necessary to reduce post-deployment psychiatric pathology, including suicidal behavior.

Re: The risk of psychiatric disorders in finasteride users with benign prostatic hyperplasia (BPH) and androgenetic alopecia (AGA): A population-based case-control study.

Re: The risk of psychiatric disorders in finasteride users with benign prostatic hyperplasia (BPH) and androgenetic alopecia (AGA): A population-based case-control study.

Psoriasis Is Associated With Increased Risk of Psychiatric Disorders and Sexual Dysfunction in a Case-Control Study of 29,912 Patients

Psoriasis Is Associated With Increased Risk of Psychiatric Disorders and Sexual Dysfunction in a Case-Control Study of 29,912 Patients

Do Children With Accidental Gunshot-related Fractures Experience Greater Risk of Mental Illness and Psychiatric Disorders? A Propensity-matched Study.

Firearm violence is the leading cause of death and is a major source of morbidity for children in the United States. While gunshot wounds (GSWs) are known to cause lasting psychological repercussions beyond physical injury, these effects are not well documented compared with the physical implications. Our study explores the association between accidental gunshot-related fractures in children and subsequent psychiatric outcomes. Relative to non-GSW-related fractures, do children sustaining an accidental GSW-related fracture experience higher risk of mental illness and psychiatric disorders? This study utilized the TriNetX US Collaborative Network as it provides comprehensive inpatient and outpatient data, longitudinal follow-up, and complete medical records across different facilities, closely reflecting real-world patient outcomes in orthopaedic practice. We retrospectively evaluated children diagnosed with an accidental GSW-related fracture and compared mental health diagnoses to children who experienced non-GSW-related fractures. Between January 1, 2003, and March 1, 2023, a total of 5071 children in the United States without preexisting anxiety, mood, psychotic, substance use, or insomnia disorders were reported to have experienced an accidental GSW-related fracture. Among these patients, 55% (2773) had a follow-up period of at least 1 year and met the inclusion criteria for the exposure cohort. In the non-GSW-related fracture cohort, a total of 61% (985,070) of children among 1,613,891 without the preexisting aforementioned conditions had a minimum follow-up period of 1 year and met the inclusion criteria. A total of 2769 children were successfully matched in each cohort using a greedy nearest neighbor propensity score-matching algorithm. Matching was based on age, gender, race, fracture location, and BMI, as these characteristics were identified through a regression analysis as potentially associated with psychiatric outcomes (p < 0.01). The mean ± SD age was 15 ± 4 years, and 16% (451) in the GSW cohort were girls. In the non-GSW cohort 17% (474) were girls. With respect to race and ethnicity, 62% (1709 in the GSW cohort; 1679 in the non-GSW cohort) were Black and 14% (384 in the GSW cohort; 386 in the non-GSW cohort) were Hispanic. Outcomes of interest were recorded for up to 3 years after the index event. The accidental GSW-related fracture cohort experienced a greater hazard of developing anxiety disorders (HR 3.8 [95% confidence interval (CI) 3.2 to 4.6]; p < 0.001), substance use disorders (HR 3.6 [95% CI 3.0 to 4.2]; p < 0.001), mood disorders (HR 2.4 [95% CI 1.9 to 3.1]; p < 0.001), non-mood psychotic disorders (HR 2.4 [95% CI 1.5 to 3.9]; p < 0.001), and insomnia (HR 1.8 [95% CI 1.4 to 2.3]; p < 0.001). Orthopaedic surgeons should implement early psychiatric screenings and integrate mental health support for children with gunshot-related fractures to address elevated risk of anxiety disorders, psychotic disorders, mood disorders, substance abuse, and insomnia. Future studies should focus on identifying effective interventions that mitigate these long-term psychological outcomes, with an emphasis on practical, targeted approaches in clinical care. Level III, prognostic study.

Maternal Eating Disorders, Body Mass Index, and Offspring Psychiatric Diagnoses

Maternal nutrition is essential in fetal development; thus, disordered eating may influence this process and contribute to the development of offspring psychiatric disorders. To investigate the association of maternal eating disorders and prepregnancy body mass index (BMI) with offspring psychiatric diagnoses. This population-based cohort study used Finnish national registers to assess all live births from January 1, 2004, through December 31, 2014, with follow-up until December 31, 2021. The data analyses were conducted from September 1, 2023, to September 30, 2024. Maternal eating disorder and prepregnancy BMI. Primary outcomes were 9 neurodevelopmental and psychiatric offspring diagnoses. Cox proportional hazards modeling adjusted for potential risk factors in the development of the outcome disorders was applied in 2 models. Secondary analyses were stratified for adverse birth outcomes (prematurity, small size for gestational age, and low Apgar score) or comorbid offspring eating disorders. Categories of BMI (calculated as weight in kilograms divided by height in meters squared) included underweight (BMI <18.5), normal weight (18.5-24.9), overweight (25.0-29.9), obesity (30.0-34.9), and severe obesity (≥35.0). The mean (SD) age of 392 098 included mothers was 30.15 (5.38) years, 42 590 mothers (10.86%) were born outside of Finland, 6273 mothers (1.60%) had a history of an eating disorder, 23 114 mothers (5.89%) had prepregnancy underweight, and 208 335 (53.13%) mothers had overweight or obesity. Among 649 956 included offspring, 332 359 (51.14%) were male, and 106 777 (16.43%) had received a neurodevelopmental or psychiatric diagnosis. Maternal eating disorders, prepregnancy underweight, and overweight or obesity were associated with most of the studied mental diagnoses in offspring, even after adjusting for potential covariates. The largest effect sizes were observed for maternal eating disorders not otherwise specified in association with offspring sleep disorders (hazard ratio [HR], 3.34 [95% CI, 2.39-4.67]) and social functioning and tic disorders (HR, 2.79 [95% CI, 2.21-3.52]), while for maternal severe prepregnancy obesity, offspring intellectual disabilities (HR, 2.04 [95% CI, 1.83-2.28]) had the largest effect size. Adverse birth outcomes further increased the risk of offspring having other feeding disturbances of childhood and infancy (eg, HR, 4.53 [95% CI, 2.97-6.89] for maternal eating disorders) and attention-deficit/hyperactivity disorder and conduct disorder (eg, HR, 2.27 [95% CI, 1.74-2.96] for maternal anorexia nervosa). In this population-based cohort study including 392 098 mothers and 649 956 offspring, offspring from mothers with an eating disorder history or prepregnancy BMI outside normal weight were at higher risk of psychiatric disorders. The results differed somewhat between the 2 exposures with regard to which offspring diagnoses had associations, and effect sizes were typically larger for maternal eating disorders vs BMI. These findings suggest a need to consider these 2 exposures clinically to help prevent offspring mental illness.

Cannabidiol partially rescues behavioral, neuroinflammatory and endocannabinoid dysfunctions stemming from maternal obesity in the adult offspring

Maternal obesity is known to increase the risk of psychiatric disorders, such as anxiety, depression, schizophrenia and autism spectrum disorder in the offspring. While preventive measures are well-documented, practical approaches for addressing the damages once they are already established are limited. We have recently demonstrated the interplay between maternal obesity and treatment with cannabidiol (CBD) on neuroinflammation and peripheral metabolic disturbances during adolescence, however, it is known that both factors tend to vary throughout life. Therefore, here we investigated the potential of CBD to mitigate these alterations in the adult offspring of obese dams. Female Wistar rats were fed a cafeteria diet for 12 weeks prior to mating, and during gestation and lactation. Offspring received CBD (50 mg/kg) for 3 weeks from the 70th day of life. Behavioral tests assessed anxiety-like manifestations and social behavior, while neuroinflammatory and endocannabinoid markers were evaluated in the hypothalamus, prefrontal cortex (PFC) and hippocampus, as well as the biochemical profile in the plasma. CBD treatment attenuated maternal obesity-induced anxiety-like and social behavioral alterations, restoring exacerbated astrocytic and microglial markers in the hypothalamus, PFC and hippocampus of the offspring, as well as endocannabinoid levels in the PFC, with notable sex differences. Additionally, CBD attenuated plasma glucose and lipopolysaccharides (LPS) concentrations in females. These findings underscore the persistent influence of maternal obesity on the offspring's health, encompassing metabolic irregularities and behavioral impairments, as well as the role of the endocannabinoid system in mediating these outcomes across the lifespan.

Risk of common psychiatric disorders, suicidal behaviours, and premature mortality following violent victimisation: A matched cohort and sibling-comparison study of 127,628 people who experienced violence in Finland and Sweden.

Associations between violent victimisation and psychiatric disorders are hypothesised to be bidirectional, but the role of violent victimisation in the aetiologies of psychiatric disorders and other adverse outcomes remains unclear. We aimed to estimate associations between violent victimisation and subsequent common psychiatric disorders, suicidal behaviours, and premature mortality while accounting for unmeasured familial confounders. Using nationwide registers, we identified a total of 127,628 individuals born in Finland (1987 to 2004) and Sweden (1973 to 2004) who had experienced violent victimisation, defined as either hospital admissions or secondary care outpatient visits for assault-related injuries. These were age- and sex-matched with up to 10 individuals in the general population (n = 1,276,215). Additionally, we matched those who had experienced violent victimisation with their unaffected siblings (n = 132,408). Outcomes included depression, anxiety, personality disorders, alcohol use disorders, drug use disorders, suicidal behaviours, and premature mortality. Participants were followed from the victimisation date until the date of the outcome, emigration, death, or December 31, 2020, whichever occurred first. Country-specific associations were estimated using stratified Cox regression models, which also accounted for unmeasured familial confounders via sibling comparisons. The country-specific associations were then pooled using meta-analytic models. Among 127,628 patients (69.0% male) who had experienced violent victimisation, the median age at first violent victimisation was 21 (interquartile range: 18 to 26) years. Incidence of all outcomes was larger in those who were exposed to violent victimisation compared to population controls, ranging from 2.3 (95% confidence interval (CI) [2.2; 2.4]) per 1,000 person-years for premature mortality (compared with 0.6, 95% CI [0.6; 0.6], in controls) to 22.5 (95% CI [22.3; 22.8]) per 1,000 person-years for anxiety (compared with 7.3, 95% CI [7.3; 7.4], in controls). In adjusted models, people who had experienced violent victimisation were between 2 to 3 times as likely as their siblings to develop any of the outcomes, ranging from adjusted hazard ratio [aHR] 1.7 (95% CI [1.7; 1.8]) for depression to 3.0 (95% CI [2.9; 3.1]) for drug use disorders. Risks remained elevated 2 years post-victimisation, ranging from aHR 1.4 (95% CI [1.3; 1.5]) for depression to 2.3 (95% CI [2.2; 2.4]) for drug use disorders. Our reliance on secondary care data likely excluded individuals with milder assault-related injuries and less severe psychiatric symptoms, thus suggesting that our estimates may be conservative. Another limitation is the possibility of residual genetic confounding, as full siblings share on average about half of their co-segregating genes. However, the associations remained robust even after adjusting for both measured and unmeasured familial confounders. In this longitudinal cross-national cohort study, we observed that those who had experienced violent victimisation were at least twice as likely as their unaffected siblings to develop common psychiatric disorders (i.e., depression, anxiety, personality disorder, and alcohol and drug use disorders), engage in suicidal behaviours, and to die prematurely. Importantly, these risk elevations remained 2 years after the first victimisation event. Improving clinical assessment, management, and aftercare psychosocial support could therefore potentially reduce rates of common psychiatric disorders, suicidality, and premature mortality in individuals experiencing violent victimisation.

Associations between Sjogren syndrome and psychiatric disorders in European populations: a 2-sample bidirectional Mendelian randomization study.

Psychiatric disorders, such as major depressive disorder (MDD), anxiety disorder (AD), bipolar disorder (BD), and schizophrenia (SCZ), are disturbances in brain activity that lead to disorders of cognition, behavior, and emotion regulation. Among Sjogren syndrome (SS) patients, psychiatric disorders are more prevalent than in the general population. Identifying associated risk factors can provide new evidence for clinical diagnosis and treatment. We selected genetic instruments based on published genome-wide association studies (GWASs) to determine predisposition. Then, we conducted a 2-sample bidirectional Mendelian randomization (MR) analysis to explore the potential causal associations between SS and four major psychiatric disorders. The primary analysis was performed using MR with the inverse-variance weighted method. Confirmation was achieved through Steiger filtering and testing to determine the causal direction. Sensitivity analyses were conducted using MR-Egger, MR-PRESSO, and "leave-one-out" method methods. Our study showed that SS was linked to BD and SCZ, indicating that individuals with SS may have a reduced risk of developing BD (IVW: OR = 0.940, P=0.014) and SCZ (IVW: OR = 0.854, P=1.47*10-4), while there was no causal relationship between SS and MDD or AD. MR-Egger regression shows no evidence of pleiotropy (BD: intercept = 0.007, p = 0.774; SCZ: intercept = 0.051, p = 0.209). The same as the MR-PRESSO analysis (BD: global test p = 1.000; SCZ: global test p = 0.160). However, the results from the leave-one-out analysis demonstrated instability. Specifically, after excluding SNP rs3117581, the effects on BD and SCZ were found to be non-significant, suggesting the potential influence of unrecognized confounding factors. The results of the reverse MR show that four major psychiatric disorders had no causal effects on SS. Our research findings demonstrate a causal relationship between SS and SCZ, as well as between SS and BD. There are no causal effects between the four major psychiatric disorders and SS. These findings suggest that SS may have the potential to reduce the risk of both psychiatric disorders. This study provides new insight for their prevention and treatment.

Altered functional connectivity within the primary visual networks and neurotransmitter activity in male smokers: A group ICA study

Smoking puts patients at high risk for cognitive and psychiatric disorders. The aim of this study was to explore the effects of nicotine use on primary visual network (PVN) and its association with neurotransmitters. A total of 59 tobacco use disorder (TUD) patients and 51 healthy controls (HC) participated in this study and underwent resting state functional magnetic resonance imaging scans. Functional connectivity (FC) within the network was explored using independent component analysis. In addition, the spatial correlations of PVN changes with neurotransmitters and their correlations with clinical characteristics of patients were evaluated using the JuSpace toolbox and SPSS. We found reduced FC within the PVN in patients with TUD compared with HC. In terms of relevant analysis, there is a spatial correlation between FC changes in the patient's PVN and a higher distribution of dopamine receptor and gamma-aminobutyric acid receptor. This study revealed changes in the FC and neurotransmitters of the PVN in patients with TUD, expanding the potential neural mechanisms underlying sensory perception and psychiatric disorders.

Psychiatric disorders among survivors of childhood acute lymphoblastic leukemia in Denmark and Sweden.

The diagnosis and treatment of childhood acute lymphoblastic leukemia (ALL) may impact mental health. We investigated the long-term risk of psychiatric disorders among survivors of ALL in a population-based cohort study. We identified patients diagnosed with ALL in Denmark and Sweden before age 20 during 1982-2008. Survivors of ALL (n=2026), their siblings (n=3027), and population comparison subjects (n=9713) were followed for hospital contacts for psychiatric disorders from 5years after ALL diagnosis (or corresponding index date) until 2017. By age 30, the absolute risk of psychiatric hospital contacts was 19.9% (95% confidence interval [CI]: 17.9-22.1) for ALL survivors, 18.5% (95% CI: 16.9-20.2) for siblings, and 18.3% (95% CI: 17.3-19.2) for population comparison subjects. Overall, survivors were at higher risk of any psychiatric disorders than siblings (hazard ratio [HR]=1.25; 95% CI: 1.04-1.50), and population comparison subjects (HR=1.20; 95% CI: 1.06-1.35). The subgroup of survivors (n=332) who received a hematopoietic stem cell transplantation (HSCT) and/or had a relapse were at highest risk of psychiatric disorders (HR=2.07; 95% CI: 1.26-3.41 compared to siblings; HR=1.67; 95% CI: 1.25-2.23 compared to population comparison subjects). The overall absolute risk of psychiatric hospital contacts among ALL survivors was close to that in siblings and population comparison subjects. The modestly increased relative risk was mainly driven by the subgroup of survivors who received HSCT and/or had a relapse. Our findings are reassuring for the large subgroup of ALL survivors without HSCT or relapse, and provide novel insight on both absolute and relative risk of hospital contacts for psychiatric disorders.

Bidirectional Mendelian randomization analysis of plasma lipidome and psychiatric disorders

BackgroundEvidence from observational studies and clinical experiments suggests a close association between plasma lipidome and psychiatric disorders. However, the causal relationship between plasma lipidome and psychiatric disorders remains insufficiently determined. Plasma lipidome are relatively easy to measure and regulate clinically, and they play a crucial role in neuronal signal transduction, making them a focus of interest as potential therapeutic targets for psychiatric disorders. MethodsIn this study, we utilized the latest Finnish population-based genome-wide association study (GWAS) data on 179 lipid species. We downloaded data on five psychiatric disorders from the IEU database, including schizophrenia, bipolar disorder, depression, autism from the PGC consortium, and anxiety disorder from the Neale lab. Using two-sample bidirectional Mendelian randomization (MR) analysis, we assessed the relationship between these 179 lipid species and the risk of the five psychiatric disorders. To validate the assumptions of Mendelian randomization, we conducted tests for horizontal pleiotropy and heterogeneity. ResultsAfter applying FDR correction to assess the relationship between 179 lipid species traits and the risk of five psychiatric disorders, our analysis provided evidence of a causal relationship specifically between genetic susceptibility in the plasma lipidome and bipolar disorder. This relationship notably involves eight phosphatidylcholines (PCs) and two sterols, with PCs displaying a dual and complex role in the disorder. Reverse Mendelian randomization (MR) analysis did not reveal a significant causal impact of psychiatric disorders on the plasma lipidome. LimitationsDespite using two-sample bidirectional Mendelian randomization analysis, the complex biological pathways and potential confounding factors may still affect the accuracy of the causal relationships. The impact of genetic variations on the lipidome and psychiatric disorders may involve multiple mechanisms, which cannot be fully elucidated in this study. ConclusionThis study identified a causal relationship between genetic susceptibility in plasma lipidome and bipolar disorder, indicating that plasma lipidome may influence the risk of psychiatric disorders and providing direction for exploring them as potential intervention targets. The findings not only deepen our understanding of the etiology of psychiatric disorders but also provide a critical theoretical foundation for future clinical interventions and prevention strategies, potentially contributing to the development of novel therapeutic approaches.

Multi-omics analysis of the molecular response to glucocorticoids - insights into shared genetic risk from psychiatric to medical disorders

BackgroundAlterations in the effects of glucocorticoids have been implicated in mediating some of the negative health effects associated with chronic stress, including increased risk for psychiatric disorders as well as cardiovascular and metabolic diseases. This study investigates how genetic variants influence gene expression and DNA methylation (DNAm) in response to glucocorticoid receptor (GR)-activation, and their association with disease risk. MethodsWe measured DNAm (n=199) and gene expression (n=297) in peripheral blood before and after GR-activation with dexamethasone, with matched genotype data available for all samples. A comprehensive molecular quantitative trait locus (QTL) analysis was conducted, mapping GR-response methylation (me)QTLs, GR-response expression (e)QTLs, and GR-response expression quantitative trait methylation (eQTM). A multi-level network analysis was employed to map the complex relationships between the transcriptome, epigenome, and genetic variation. ResultsWe identified 3,772 GR-response meCpGs corresponding to 104,828 local GR-response meQTLs that did not strongly overlap with baseline meQTLs. eQTM and eQTL analyses revealed distinct genetic influences on gene expression and DNAm. Multi-level network analysis uncovered GR-response network trio QTLs, characterized by SNP-CpG-transcript combinations where meQTLs act as both eQTLs and eQTMs. GR-response trio variants were enriched in GWAS for psychiatric, respiratory, autoimmune and cardiovascular diseases and conferred a higher relative heritability per SNP than GR-response meQTL and baseline QTL SNP. ConclusionsGenetic variants modulating the molecular effects of glucocorticoids are associated with psychiatric as well as medical diseases and not uncovered in baseline QTL analyses.

Association of air pollutants with psychiatric disorders: a two-sample Mendelian randomization

BackgroundThe link between air pollution and increased risk of psychiatric disorders has been growing in evidence. However, the causal relationship between air pollution and psychiatric disorders remains poorly understood. MethodsSingle-nucleotide polymorphisms associated with air pollutants (including NOx, NO2, PM2.5, PM2.5–10, and PM10) from the UK Biobank were used as instrumental variables. Summary-level data for psychiatric disorders (major depressive disorder, anxiety, bipolar disorder, schizophrenia, post-traumatic stress disorder, attention deficit hyperactivity disorder, autism spectrum disorder, anorexia nervosa, and obsessive-compulsive disorder) were procured from the Psychiatric Genomics Consortium and FinnGen consortium. Two-sample Mendelian randomization (MR) analysis was conducted to analyze the causal associations. ResultsThe MR analysis revealed significant associations between certain air pollutants and specific types of psychiatric disorders. The inverse-variance weighted model of preliminary analysis indicated that genetically predicted NO2 was associated with increased risks of major depressive disorder (odds ratio [OR]: 1.13, 95 % confidence intervals [CI]: 1.00–1.28, P = 0.041), bipolar disorder (OR: 1.26, 95 % CI: 1.00–1.58, P = 0.0497), schizophrenia (OR: 1.57, 95 % CI: 1.23–2.00, P < 0.001), attention deficit hyperactivity disorder (OR: 1.61, 95 % CI: 1.25–2.09, P < 0.001) and autism spectrum disorder (OR: 1.39, 95 % CI: 1.01–1.91, P = 0.044). Genetically predicted PM2.5 showed a positive association with the risk of major depressive disorder (OR: 1.21, 95 % CI: 1.06–1.39, P = 0.006), bipolar disorder (OR: 1.32, 95 % CI: 1.03–1.69, P = 0.030) and attention deficit hyperactivity disorder (OR: 1.57, 95 % CI: 1.16–2.12, P = 0.004). In addition, our results also indicated that NOx (OR: 1.64, 95 % CI: 1.21–2.21, P = 0.0012) and PM10 (OR: 1.70, 95 % CI: 1.23–2.36, P = 0.0014) could increase the risk of attention deficit hyperactivity disorder. ConclusionsThe MR analysis provides evidence for the causality of different air pollutants on specific psychiatric disorders, underscoring the importance of mitigating air pollution to reduce the risk of psychiatric disorders.

A population-based study of familial coaggregation and shared genetic etiology of psychiatric and gastrointestinal disorders

BackgroundIt has been proposed that having a psychiatric disorder could increase the risk of developing a gastrointestinal disorder, and vice versa. The role of familial coaggregation and shared genetic loading between psychiatric and gastrointestinal disorders remains unclear.MethodsThis study used the Taiwan National Health Insurance Research Database; 4,504,612 individuals born 1970–1999 with parental information, 51,664 same-sex twins, and 3,322,959 persons with full-sibling(s) were enrolled. Genotyping was available for 106,796 unrelated participants from the Taiwan Biobank. A logistic regression model was used to examine the associations of individual history, affected relatives, and polygenic risk scores (PRS) for schizophrenia (SCZ), bipolar disorder (BPD), major depressive disorder (MDD), and obsessive-compulsive disorder (OCD), with the risk of peptic ulcer disease (PUD), gastroesophageal reflux disease (GERD), irritable bowel syndrome (IBS), and inflammatory bowel disease (IBD), and vice versa.ResultsHere we show that parental psychiatric disorders are associated with gastrointestinal disorders. Full-siblings of psychiatric cases have an increased risk of gastrointestinal disorders except for SCZ/BPD and IBD; the magnitude of coaggregation is higher in same-sex twins than in full-siblings. The results of bidirectional analyses mostly remain unchanged. PRS for SCZ, MDD, and OCD are associated with IBS, PUD/GERD/IBS/IBD, and PUD/GERD/IBS, respectively. PRS for PUD, GERD, IBS, and IBD are associated with MDD, BPD/MDD, SCZ/BPD/MDD, and BPD, respectively.ConclusionsThere is familial coaggregation and shared genetic etiology between psychiatric and gastrointestinal comorbidity. Individuals with psychiatric disorder-affected relatives or with higher genetic risk for psychiatric disorders should be monitored for gastrointestinal disorders, and vice versa.

AMP-activated protein kinase in the amygdala and hippocampus contributes to enhanced fear memory in diabetic mice.

Diabetic patients have an increased risk of psychiatric disorders. Because hyperglycaemia increases L-lactate in the brain and L-lactate inhibits AMP-activated protein kinase (AMPK), this study investigated the role of L-lactate and AMPK in strengthened fear memory, a model for human psychiatric disorders, in diabetic mice. The diabetic model was mice injected with streptozotocin. Fear memory was measured using the conditioned fear test with low (0.45 mA) or high (0.50 mA) foot shock to cause low and high freezing, respectively. Protein levels of AMPK and phosphorylated AMPK (pAMPK) were measured by western blotting and immunohistochemistry. At 0.45 mA, the AMPK inhibitor dorsomorphin increased freezing, which was inhibited by the AMPK activator acadesine. In contrast, at 0.50 mA, acadesine decreased freezing, which was inhibited by dorsomorphin. In diabetic mice, pAMPK was decreased in the amygdala and hippocampus. Diabetic mice showed increased freezing at 0.45 mA, which was inhibited by acadesine. In the amygdala and hippocampus, L-lactate was increased in diabetic mice and injection of L-lactate into non-diabetic mice increased freezing at 0.45 mA. In addition, L-lactate decreased pAMPK in the hippocampus, but not the amygdala, and increase in freezing induced by L-lactate was inhibited by acadesine. Dorsomorphin-induced increase in freezing was inhibited by the AMPA receptor antagonist NBQX. In diabetic mice, L-lactate is increased in the amygdala and hippocampus, possibly through hyperglycaemia, which strengthens fear memory through inhibition of AMPK and activation of glutamatergic function.

Blood metabolites, neurocognition and psychiatric disorders: a Mendelian randomization analysis to investigate causal pathways

BackgroundNeurocognitive dysfunction is observationally associated with the risk of psychiatric disorders. Blood metabolites, which are readily accessible, may become highly promising biomarkers for brain disorders. However, the causal role of blood metabolites in neurocognitive function, and the biological pathways underlying their association with psychiatric disorders remain unclear.MethodsTo explore their putative causalities, we conducted bidirectional two-sample Mendelian randomization (MR) using genetic variants associated with 317 human blood metabolites (nmax = 215,551), g-Factor (an integrated index of multiple neurocognitive tests with nmax = 332,050), and 10 different psychiatric disorders (n = 9,725 to 807,553) from the large-scale genome-wide association studies of European ancestry. Mediation analysis was used to assess the potential causal pathway among the candidate metabolite, neurocognitive trait and corresponding psychiatric disorder.ResultsMR evidence indicated that genetically predicted acetylornithine was positively associated with g-Factor (0.035 standard deviation units increase in g-Factor per one standard deviation increase in acetylornithine level; 95% confidence interval, 0.021 to 0.049; P = 1.15 × 10−6). Genetically predicted butyrylcarnitine was negatively associated with g-Factor (0.028 standard deviation units decrease in g-Factor per one standard deviation increase in genetically proxied butyrylcarnitine; 95% confidence interval, −0.041 to −0.015; P = 1.31 × 10−5). There was no evidence of associations between genetically proxied g-Factor and metabolites. Furthermore, the mediation analysis via two-step MR revealed that the causal pathway from acetylornithine to bipolar disorder was partly mediated by g-Factor, with a mediated proportion of 37.1%. Besides, g-Factor mediated the causal pathway from butyrylcarnitine to schizophrenia, with a mediated proportion of 37.5%. Other neurocognitive traits from different sources provided consistent findings.ConclusionOur results provide genetic evidence that acetylornithine protects against bipolar disorder through neurocognitive abilities, while butyrylcarnitine has an adverse effect on schizophrenia through neurocognition. These findings may provide insight into interventions at the metabolic level for risk of neurocognitive and related disorders.

Familial coaggregation of major psychiatric disorders and neurodevelopmental disorders among first-degree relatives of individuals with generalized anxiety disorder

BackgroundAnxiety disorders, major psychiatric disorders (e.g., schizophrenia and major affective disorders), and neurodevelopmental disorders (e.g., autism and attention-deficit/hyperactivity disorder [ADHD]) may cluster together within families. However, whether the first-degree relatives (FDRs) of individuals with generalized anxiety disorder (GAD) are at an elevated risk of neurodevelopmental or major psychiatric disorders remains unknown. MethodsWe identified 2,378,190 FDRs of patients with GAD and 9,512,760 birth year–matched and sex-matched controls from Taiwan's National Health Insurance Research Database. Neurodevelopmental disorders, including autism and ADHD, and major psychiatric disorders, including schizophrenia, bipolar disorder, major depressive disorder, obsessive-compulsive disorder, and GAD, were identified. ResultsThe FDRs—parents, offspring, and siblings—of individuals with GAD were more likely to be diagnosed as having schizophrenia (relative risk: 1.22), bipolar disorder (1.36), major depressive disorder (1.29), autism (1.20), ADHD (1.52), obsessive–compulsive disorder (1.21), and GAD (1.61) than are the FDRs of individuals without GAD. ConclusionOur findings support the notion of a familial coaggregation between GAD, major psychiatric disorders, and neurodevelopmental disorders. Future studies should elucidate the definitive genetic etiology of this familial coaggregation.

Sleep inertia drives the association of evening chronotype with psychiatric disorders: epidemiological and genetic evidence.

Evening chronotypes (a.k.a. night-owls) are held to be at greater risk for psychiatric disorders. This is postulated to be due to delayed circadian timing increasing the likelihood of circadian misalignment in an early-oriented society. Circadian misalignment is known to heighten sleep inertia, the difficulty transitioning from sleep to wake characterized by low arousal and cognitive impairment, and evening chronotypes experience greater sleep inertia. Therefore, difficulty awakening may explain the relationship between evening chronotype and psychiatric disorders by acting as a biomarker of circadian misalignment. In analyzing the longitudinal incidence of psychiatric disorders in the UK Biobank (n = 496,820), we found that evening chronotype predicted increased incidence of major depressive disorder, schizophrenia, generalized anxiety disorder and bipolar disorder. Crucially, this effect was dependent on sleep inertia, which was a much stronger predictor of these disorders, such that evening types without sleep inertia were at no higher risk as compared to morning types. Longitudinal analyses of suicide and depressed mood (CES-D score) in the Older Finnish Twin Cohort (n = 23,854) replicated this pattern of results. Twin and genome-wide association analyses of difficulty awakening identified the trait to be heritable (Twin H2 = 0.40; SNP h2 = 0.08), enriched for circadian rhythms genes and have substantial shared genetic architecture with chronotype. Marginal and conditional Mendelian randomization analyses mirrored the epidemiological results, such that the causal effect of evening chronotype on psychiatric disorders was driven by shared genetic architecture with difficulty awakening. In contrast, difficult awakening was strongly causally associated with psychiatric disorders independently of chronotype. Psychiatric disorders were only weakly reverse causally linked to difficult awakening. Collectively, these results challenge the notion that evening chronotype is a risk factor for psychiatric disorders per se, suggesting instead that evening types are at greater risk for psychiatric disorders due to circadian misalignment, for which sleep inertia may be acting as a biomarker.

Inhibitory neuron links the causal relationship from air pollution to psychiatric disorders: a large multi-omics analysis

Psychiatric disorders are severe health challenges that exert a heavy public burden. Air pollution has been widely reported as related to psychiatric disorder risk, but their casual association and pathological mechanism remained unclear. Herein, we systematically investigated the large genome-wide association studies (6 cohorts with 1,357,645 samples), single-cell RNA (26 samples with 157,488 cells), and bulk-RNAseq (1595 samples) datasets to reveal the genetic causality and biological link between four air pollutants and nine psychiatric disorders. As a result, we identified ten positive genetic correlations between air pollution and psychiatric disorders. Besides, PM2.5 and NO2 presented significant causal effects on schizophrenia risk which was robust with adjustment of potential confounders. Besides, transcriptome-wide association studies identified the shared genes between PM2.5/NO2 and schizophrenia. We then discovered a schizophrenia-derived inhibitory neuron subtype with highly expressed shared genes and abnormal synaptic and metabolic pathways by scRNA analyses and confirmed their abnormal level and correlations with the shared genes in schizophrenia patients in a large RNA-seq cohort. Comprehensively, we discovered robust genetic causality between PM2.5, NO2, and schizophrenia and identified an abnormal inhibitory neuron subtype that links schizophrenia pathology and PM2.5/NO2 exposure. These discoveries highlight the schizophrenia risk under air pollutants exposure and provide novel mechanical insights into schizophrenia pathology, contributing to pollutant-related schizophrenia risk control and therapeutic strategies development.Graphical