Assessing the Causal Effects of Human Serum Metabolites on 5 Major Psychiatric Disorders.
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ABSTRACT:
SUBMITTER: Yang J
PROVIDER: S-EPMC7342080 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectiveTrauma has been proposed as a risk factor for the development of psychiatric disorders. This study aimed to determine the causal role of trauma in six common psychiatric disorders.MethodsWe obtained summary-level data for genetic variants associated with trauma and the corresponding association with psychiatric disorders from previous genome-wide association studies. Two-sample Mendelian randomization analyzes were performed to estimate the causal association between trauma and psychiatric disorders, with inverse variance weighted used as the main method.ResultsGenetically predisposed trauma was associated with an increased risk of psychiatric disorders [odds ratio (OR) =1.24, 95%, confidence interval (CI), 1.09-1.40], anxiety disorder (OR = 1.30, 95% CI, 1.10-1.52) and schizophrenia (OR = 1.48, 95% CI, 1.18-1.84). However, the associations between trauma and sleep disorder (OR = 1.17, 95% CI, 1.01-1.35), as well as depression (OR = 1.09, 95% CI, 1.02-1.16) did not reach a Bonferroni corrected significance level. Besides, no association was observed between trauma and risk of bipolar disorder (OR = 1.21, 95% CI, 0.98-1.48) and eating disorder (OR = 1.28, 95% CI, 0.88-1.86).ConclusionTrauma might be causally associated with an increased risk of some common psychiatric disorders such as anxiety disorder and schizophrenia. However, little evidence supported an association between trauma and risk of depression, bipolar disorder, sleep disorder, and eating disorder. Our findings offered novel insights into the trauma-mediated development mechanism of psychiatric disorders, and psychological intervention to patients with trauma may be an effective prevention strategy for psychological diseases.
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Project description:BackgroundWhether the positive associations of blood lipids with psychiatric disorders are causal is uncertain. We conducted this two-sample Mendelian randomization (MR) analysis to comprehensively investigate associations of blood lipids with psychiatric disorders.MethodsUnivariable and multivariable models were established for MR analyses. Inverse variance-weighted (IVW) MR was employed as the main approach; weighted median and MR-Egger were used as sensitivity analysis methods. The possibility of violating MR assumptions was evaluated utilizing several sensitivity analyses, including heterogeneity statistics, horizontal pleiotropy statistics, single SNP analysis, leave-one-out analysis and MR-PRESSO analysis. As instrumental variables, we screened 362 independent single-nucleotide polymorphisms (SNP) related to blood lipids from a recent genome-wide association study involving 76,627 individuals of European ancestry, with a genome-wide significance level of p < 5 × 10- 8. Summary-level information for the six psychiatric disorders was extracted from Psychiatric Genomics Consortium and Alzheimer Disease Genetics Consortium.ResultsWe observed eight significant associations in univariable MR analysis, four of which were corroborated by multivariable MR (MVMR) analysis modified for the other three lipid traits: high-density lipoprotein cholesterol (HDL-C) level with the risk of PTSD (OR = 0.91, 95% CI = 0.85-0.97, p = 0.002) and AD (OR = 0.79, 95% CI = 0.71-0.88, p < 0.001) and triglycerides (TG) level with the risk of MDD (OR = 1.02, 95% CI = 1.003-1.03, p = 0.01) and panic disorder (OR = 0.83, 95% CI = 0.74-0.92, p < 0.001). In addition, four associations were not significant in MVMR analysis after adjustment for three lipid traits: total cholesterol (TC) level with the risk of PTSD, low-density lipoprotein cholesterol (LDL-C) level with the risk of MDD and AD and TG level with the risk of AD.ConclusionsOur results show that blood lipids and psychiatric disorders may be related in a causal manner. This shows that abnormal blood lipid levels may act as reliable biomarker of psychiatric disorders and as suitable targets for their prevention and treatment.
| S-EPMC10585856 | biostudies-literature
Project description:BackgroundPsychiatric disorders (PD) pose a significant burden, with vast prevalence and mortality, inflicting substantial costs on individuals and society. Despite its widespread prevalence, the complex pathogenesis of PD remains elusive, leading to limited and challenging therapeutic development. An emerging risk factor for chronic diseases, prolonged sedentary behavior, contrasts with the therapeutic potential of exercise, regardless of its intensity, for various ailments, including PD. Yet, the diversity in exercise modalities and intensities may offer varied impacts on health. This study, leveraging Mendelian Randomization (MR), seeks to investigate the causal relationship between exercise and PD, aiming to elucidate the optimal exercise modality and intensity for PD mitigation while addressing potential confounders.MethodsThis study employed a Mendelian randomization analysis using the genome-wide association study (GWAS) database to investigate the causal relationship between types of physical activity and psychiatric disorders. Sensitivity analysis was conducted to demonstrate the reliability and robustness of the results.ResultsIn the past 4 weeks, engaging in a substantial amount of DIY physical activity was found to have a causal relationship with psychiatric disorders (IVW: OR = 0.228, 95% CI: 0.113-0.461, P = 0.000038). As for the types of exercises, there may be a potential causal association between aerobic training (including swimming, cycling, fitness, and bowling) and psychiatric disorders (IVW: OR = 0.322, 95% CI = 0.148-0.704, P = 0.004). However, there was no causal relationship found between mild DIY physical activity and psychiatric disorders (IVW: OR = 0.918, 95% CI = 0.417-2.021, P = 0.831). Furthermore, it seems that there is no causal relationship between vigorous exercise and psychiatric disorders (IVW: OR = 2.705, 95% CI = 0.081-3.419, P = 0.578).ConclusionOur study confirms that only a certain level of training activity can have a protective effect on psychiatric disorders, while mild physical activity or vigorous training does not have an impact on psychiatric disorders.
| S-EPMC10944951 | biostudies-literature
Project description:Postpartum psychiatric disorders are heritable, but how genetic liability varies by other significant risk factors is unknown. We aimed to (1) estimate associations of genetic risk scores (GRS) for major depression (MD), bipolar disorder (BD), and schizophrenia (SCZ) with postpartum psychiatric disorders, (2) examine differences by prior psychiatric history, and (3) compare genetic and familial risk of postpartum psychiatric disorders. We conducted a nested case-control study based on Danish population-based registers of all women in the iPSYCH2012 cohort who had given birth before December 31, 2015 (n = 8850). Cases were women with a diagnosed psychiatric disorder or a filled psychotropic prescription within one year after delivery (n = 5829 cases, 3021 controls). Association analyses were conducted between GRS calculated from Psychiatric Genomics Consortium discovery meta-analyses for MD, BD, and SCZ and case-control status of a postpartum psychiatric disorder. Parental psychiatric history was associated with postpartum psychiatric disorders among women with previous psychiatric history (OR, 1.14; 95% CI 1.02-1.28) but not without psychiatric history (OR, 1.08; 95% CI: 0.81-1.43). GRS for MD was associated with an increased risk of postpartum psychiatric disorders in both women with (OR, 1.44; 95% CI: 1.19-1.74) and without (OR, 1.88; 95% CI: 1.26-2.81) personal psychiatric history. SCZ GRS was only minimally associated with postpartum disorders and BD GRS was not. Results suggest GRS of lifetime psychiatric illness can be applied to the postpartum period, which may provide clues about distinct environmental or genetic elements of postpartum psychiatric disorders and ultimately help identify vulnerable groups.
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Project description:Background: Neurodegenerative diseases (NDDs) are the leading cause of disability worldwide while their metabolic pathogenesis is unclear. Genome-wide association studies (GWASs) offer an unprecedented opportunity to untangle the relationship between metabolites and NDDs. Methods: By leveraging two-sample Mendelian randomization (MR) approaches and relying on GWASs summary statistics, we here explore the causal association between 486 metabolites and five NDDs including Alzheimer's Disease (AD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Parkinson's disease (PD), and multiple sclerosis (MS). We validated our MR results with extensive sensitive analyses including MR-PRESSO and MR-Egger regression. We also performed linkage disequilibrium score regression (LDSC) and colocalization analyses to distinguish causal metabolite-NDD associations from genetic correlation and LD confounding of shared causal genetic variants. Finally, a metabolic pathway analysis was further conducted to identify potential metabolite pathways. Results: We detected 164 metabolites which were suggestively associated with the risk of NDDs. Particularly, 2-methoxyacetaminophen sulfate substantially affected ALS (OR = 0.971, 95%CIs: 0.961 ∼ 0.982, FDR = 1.04E-4) and FTD (OR = 0.924, 95%CIs: 0.885 ∼ 0.964, FDR = 0.048), and X-11529 (OR = 1.604, 95%CIs: 1.250 ∼ 2.059, FDR = 0.048) and X-13429 (OR = 2.284, 95%CIs: 1.457 ∼ 3.581, FDR = 0.048) significantly impacted FTD. These associations were further confirmed by the weighted median and maximum likelihood methods, with MR-PRESSO and the MR-Egger regression removing the possibility of pleiotropy. We also observed that ALS or FTD can alter the metabolite levels, including ALS and FTD on 2-methoxyacetaminophen sulfate. The LDSC and colocalization analyses showed that none of the identified associations could be driven by genetic correlation or confounding by LD with common causal loci. Multiple metabolic pathways were found to be involved in NDDs, such as "urea cycle" (P = 0.036), "arginine biosynthesis" (P = 0.004) on AD and "phenylalanine, tyrosine and tryptophan biosynthesis" (P = 0.046) on ALS. Conclusion: our study reveals robust bidirectional causal associations between servaral metabolites and neurodegenerative diseases, and provides a novel insight into metabolic mechanism for pathogenesis and therapeutic strategies of these diseases.
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Project description:Irritability is a heritable core mental trait associated with several psychiatric illnesses. However, the genomic basis of irritability is unclear. Therefore, this study aimed to 1) identify the genetic variants associated with irritability and investigate the associated biological pathways, genes, and tissues as well as single-nucleotide polymorphism (SNP)-based heritability; 2) explore the relationships between irritability and various traits, including psychiatric disorders; and 3) identify additional and shared genetic variants for irritability and psychiatric disorders. We conducted a genome-wide association study (GWAS) using 379,506 European samples (105,975 cases and 273,531 controls) from the UK Biobank. We utilized various post-GWAS analyses, including linkage disequilibrium score regression, the bivariate causal mixture model (MiXeR), and conditional and conjunctional false discovery rate approaches. This GWAS identified 15 independent loci associated with irritability; the total SNP heritability estimate was 4.19%. Genetic correlations with psychiatric disorders were most pronounced for major depressive disorder (MDD) and bipolar II disorder (BD II). MiXeR analysis revealed polygenic overlap with schizophrenia (SCZ), bipolar I disorder (BD I), and MDD. Conditional false discovery rate analyses identified additional loci associated with SCZ (number [n] of additional SNPs = 105), BD I (n = 54), MDD (n = 107), and irritability (n = 157). Conjunctional false discovery rate analyses identified 85, 41, and 198 shared loci between irritability and SCZ, BD I, and MDD, respectively. Multiple genetic loci were associated with irritability and three main psychiatric disorders. Given that irritability is a cross-disorder trait, these findings may help to elucidate the genomics of psychiatric disorders.
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Project description:It has recently been proposed that a single dimension, called the p factor, can capture a person's liability to mental disorder. Relevant to the p hypothesis, recent genetic research has found surprisingly high genetic correlations between pairs of psychiatric disorders. Here, for the first time, we compare genetic correlations from different methods and examine their support for a genetic p factor. We tested the hypothesis of a genetic p factor by applying principal component analysis to matrices of genetic correlations between major psychiatric disorders estimated by three methods-family study, genome-wide complex trait analysis, and linkage-disequilibrium score regression-and on a matrix of polygenic score correlations constructed for each individual in a UK-representative sample of 7 026 unrelated individuals. All disorders loaded positively on a first unrotated principal component, which accounted for 57, 43, 35, and 22% of the variance respectively for the four methods. Our results showed that all four methods provided strong support for a genetic p factor that represents the pinnacle of the hierarchical genetic architecture of psychopathology.
| S-EPMC6168558 | biostudies-literature
Project description:Dynamic functional connectivity (DFC) analysis can capture time-varying properties of connectivity. However, studies on large samples using DFC to investigate transdiagnostic dysconnectivity across schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MDD) are rare. In this study, we used resting-state functional magnetic resonance imaging and a sliding-window method to study DFC in a total of 610 individuals (150 with SZ, 100 with BD, 150 with MDD, and 210 healthy controls [HC]) at a single site. Using k-means clustering, DFCs were clustered into three functional connectivity states: one was a more frequent state with moderate positive and negative connectivity (State 1), and the other two were less frequent states with stronger positive and negative connectivity (State 2 and State 3). Significant 4-group differences (SZ, BD, MDD, and HC groups; q < .05, false-discovery rate [FDR]-corrected) in DFC were nearly only in State 1. Post hoc analyses (q < .05, FDR-corrected) in State 1 showed that transdiagnostic dysconnectivity patterns among SZ, BD and MDD featured consistently decreased connectivity within most networks (the visual, somatomotor, salience and frontoparietal networks), which was most obvious in both range and extent for SZ. Our findings suggest that there is more common dysconnectivity across SZ, BD and MDD than we previously expected and that such dysconnectivity is state-dependent, which provides new insights into the pathophysiological mechanism of major psychiatric disorders.
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Project description:Primary cilia function as cells' antennas to detect and transduce external stimuli and play crucial roles in cell signaling and communication. The vast majority of cilia genes that are causally linked with ciliopathies are also associated with neurological deficits, such as cognitive impairments. Yet, the roles of cilia dysfunctions in the pathogenesis of psychiatric disorders have not been studied. Our aim is to identify patterns of cilia gene dysregulation in the four major psychiatric disorders: schizophrenia (SCZ), autism spectrum disorder (ASD), bipolar disorder (BP), and major depressive disorder (MDD). For this purpose, we acquired differentially expressed genes (DEGs) from the largest and most recent publicly available databases. We found that 42%, 24%, 17%, and 15% of brain-expressed cilia genes were significantly differentially expressed in SCZ, ASD, BP, and MDD, respectively. Several genes exhibited cross-disorder overlap, suggesting that typical cilia signaling pathways' dysfunctions determine susceptibility to more than one psychiatric disorder or may partially underlie their pathophysiology. Our study revealed that genes encoding proteins of almost all sub-cilia structural and functional compartments were dysregulated in the four psychiatric disorders. Strikingly, the genes of 75% of cilia GPCRs and 50% of the transition zone proteins were differentially expressed in SCZ. The present study is the first to draw associations between cilia and major psychiatric disorders, and is the first step toward understanding the role that cilia components play in their pathophysiological processes, which may lead to novel therapeutic targets for these disorders.
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Project description:139 samples from cortex and hipocampus of the mice modeling human CNVs associatted with schizophrenia: Df(h15q13)/+, Df(h15q13)/-, Df(h22q11)/+, and Df(h1q21)/+
2019-05-01 | GSE129891 | GEO