RESUMO
BACKGROUND: From the pathway perspective, metabolites have the potential to improve knowledge about the aetiology of psychiatric diseases. Previous studies suggested a link between specific blood metabolites and mental disorders, but some Mendelian randomisation (MR) studies in particular are insufficient for various reasons. OBJECTIVE: This study focused on bias assessment due to interdependencies between metabolites and psychiatric mediation effects. METHODS: In a multistep framework containing network and multivariable MR, direct effects of 21 mutually adjusted metabolites on 8 psychiatric disorders were estimated based on summary statistics of genome-wide association studies from multiple resources. Robust inverse-variance weighted models were used in primary analyses. Several sensitivity analyses were performed to assess different patterns of pleiotropy and weak instrument bias. Estimates for the same phenotypes from different resources were pooled using fixed effect meta-analysis models. FINDINGS: After adjusting for mediation effects, genetically predicted metabolite levels of six metabolites of lipid, amino acid and cofactors pathways were directly associated with overall six mental disorders (attention-deficit/hyperactivity disorder, bipolar disorder, anorexia nervosa, depression, post-traumatic stress disorder and schizophrenia). Point estimates ranged from -0.45 (95% CI -0.67; -0.24, p=1.0×104) to 1.78 (95% CI 0.85; 2.71, p=0.006). No associations were found with anxiety and suicide attempt. CONCLUSIONS: This study provides insights into new metabolic pathways that seems to be causally related to certain mental disorders. CLINICAL IMPLICATIONS: Further studies are needed to investigate whether the identified associations are effects of the metabolites itself or the biochemical pathway regulating the metabolites.
Assuntos
Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Transtornos Mentais , Humanos , Transtornos Mentais/genética , Transtornos Mentais/epidemiologia , Transtornos Mentais/metabolismo , Análise de Mediação , Saúde MentalRESUMO
A previously published genome-wide association study (GWAS) meta-analysis across eight neuropsychiatric disorders identified antagonistic single-nucleotide polymorphisms (SNPs) at eleven genomic loci where the same allele was protective against one neuropsychiatric disorder and increased the risk for another. Until now, these antagonistic SNPs have not been further investigated regarding their link to brain structural phenotypes. Here, we explored their associations with cortical surface area and cortical thickness (in 34 brain regions and one global measure each) as well as the volumes of eight subcortical structures using summary statistics of large-scale GWAS of brain structural phenotypes. We assessed if significantly associated brain structural phenotypes were previously reported to be associated with major neuropsychiatric disorders in large-scale case-control imaging studies by the ENIGMA consortium. We further characterized the effects of the antagonistic SNPs on gene expression in brain tissue and their association with additional cognitive and behavioral phenotypes, and performed an exploratory voxel-based whole-brain analysis in the FOR2107 study (n = 754 patients with major depressive disorder and n = 847 controls). We found that eight antagonistic SNPs were significantly associated with brain structural phenotypes in regions such as anterior parts of the cingulate cortex, the insula, and the superior temporal gyrus. Case-control differences in implicated brain structural phenotypes have previously been reported for bipolar disorder, major depressive disorder, and schizophrenia. In addition, antagonistic SNPs were associated with gene expression changes in brain tissue and linked to several cognitive-behavioral traits. In our exploratory whole-brain analysis, we observed significant associations of gray matter volume in the left superior temporal pole and left superior parietal region with the variants rs301805 and rs1933802, respectively. Our results suggest that multiple antagonistic SNPs for neuropsychiatric disorders are linked to brain structural phenotypes. However, to further elucidate these findings, future case-control genomic imaging studies are required.
Assuntos
Encéfalo , Transtorno Depressivo Maior , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Humanos , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Transtorno Depressivo Maior/genética , Masculino , Feminino , Adulto , Imageamento por Ressonância Magnética , Estudos de Casos e Controles , Fenótipo , Pessoa de Meia-Idade , Predisposição Genética para Doença , Transtornos Mentais/genéticaRESUMO
Evidence from observational researches have suggested that mental diseases are able to affect thyroid diseases. However, the causal relationship between mental diseases and the risk of thyroid diseases still remains unclear. Herein, we conducted a two-sample Mendelian randomization (MR) statistical analysis method to assess the causality between mental diseases and thyroid diseases. Initially, publicly available genome-wide association studies summary data were leveraged to obtain single-nucleotide polymorphisms based on set parameters. Subsequently, a two-sample MR was utilized to analyze causal relationships between mental diseases (Alzheimer disease, bipolar disorder, major depressive disorder, Parkinson disease, schizophrenia) and thyroid diseases (hyperthyroidism/thyrotoxicosis, hypothyroidism) with removing outliers based on MR-PRESSO method. Finally, 8 regression MR methods (inverse variance weighted [IVW], IVW fixed effects, c, MR Egger, weighted median, penalized weighted median, simple mode, weighted mode) were performed to evaluate bias and effectiveness, of which IVW was considered as the primary method. Our results demonstrated that most of mental diseases have no causal relationships with thyroid diseases except bipolar disorder and hyperthyroidism/thyrotoxicosis based on IVW method [odds ratio: 0.999, 95% confidence interval: 0.998-1.000, P = .028], and bipolar disorder and hypothyroidism based on IVW method [odds ratio: 0.997, 95% confidence interval: 0.995-0.999, P = .002]. Then we subsequently conducted a consistent robustness analysis to assess heterogeneity and horizontal pleiotropy. Our method reports causal relationships exist mental diseases and the risk of thyroid diseases. Subsequent researches are still warranted to determine how mental diseases influence the development of thyroid diseases.
Assuntos
Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Transtornos Mentais , Doenças da Glândula Tireoide , Humanos , Doenças da Glândula Tireoide/genética , Doenças da Glândula Tireoide/epidemiologia , Transtornos Mentais/genética , Transtornos Mentais/epidemiologia , Polimorfismo de Nucleotídeo Único , CausalidadeRESUMO
Suicidality remains a clear and present danger in society in general, and for mental health patients in particular. Lack of widespread use of objective and/or quantitative information has hampered treatment and prevention efforts. Suicidality is a spectrum of severity from vague thoughts that life is not worth living, to ideation, plans, attempts, and completion. Blood biomarkers that track suicidality risk provide a window into the biology of suicidality, as well as could help with assessment and treatment. Previous studies by us were positive. Here we describe new studies we conducted transdiagnostically in psychiatric patients, starting with the whole genome, to expand the identification, prioritization, validation and testing of blood gene expression biomarkers for suicidality, using a multiple independent cohorts design. We found new as well as previously known biomarkers that were predictive of high suicidality states, and of future psychiatric hospitalizations related to them, using cross-sectional and longitudinal approaches. The overall top increased in expression biomarker was SLC6A4, the serotonin transporter. The top decreased biomarker was TINF2, a gene whose mutations result in very short telomeres. The top biological pathways were related to apoptosis. The top upstream regulator was prednisolone. Taken together, our data supports the possibility that biologically, suicidality is an extreme stress-driven form of active aging/death. Consistent with that, the top subtypes of suicidality identified by us just based on clinical measures had high stress and high anxiety. Top therapeutic matches overall were lithium, clozapine and ketamine, with lithium stronger in females and clozapine stronger in males. Drug repurposing bioinformatic analyses identified the potential of renin-angiotensin system modulators and of cyclooxygenase inhibitors. Additionally, we show how patient reports for doctors would look based on blood biomarkers testing, personalized by gender. We also integrated with the blood biomarker testing social determinants and psychological measures (CFI-S, suicidal ideation), showing synergy. Lastly, we compared that to machine learning approaches, to optimize predictive ability and identify key features. We propose that our findings and comprehensive approach can have transformative clinical utility.
Assuntos
Biomarcadores , Medicina de Precisão , Proteínas da Membrana Plasmática de Transporte de Serotonina , Ideação Suicida , Prevenção do Suicídio , Humanos , Masculino , Feminino , Adulto , Biomarcadores/sangue , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Pessoa de Meia-Idade , Estudos Transversais , Suicídio , Transtornos Mentais/genéticaRESUMO
BACKGROUND: The genetic association between urticaria and mental disorders and whether inflammatory cytokines mediate this process remains unclear. MATERIALS AND METHODS: A Mendelian randomization (MR) approaches to elucidate the causal relationship between urticaria and mental disorders and to validate the mediation of inflammatory cytokines. Genome-wide association study (GWAS) databases used were obtained from Psychiatric Genomics Cooperation (PGC), GWAS Catalog, and FinnGen Consortium. Our study was conducted using inverse variance weighted (IVW) and Bayesian weighted MR (BWMR) methods for joint analysis. RESULTS: The MR results showed that urticaria increased the risk of attention deficit hyperactivity disorder (ADHD) (odds ratio [OR] = $ = $ 1.088, 95% confidence interval [CI]: 1.026-1.154, p = $ = $ 0.0051); cholinergic urticaria increased the risk of bipolar disorder (BD) (OR = $ = $ 1.012, 95% CI: 1.001-1.022, p = $ = $ 0.0274); dermatographic urticaria increased the risk of ADHD (OR = $ = $ 1.057, 95% CI: 1.005-1.112, p = $ = $ 0.0323); idiopathic urticaria increased the risk of schizophrenia (SCZ) (OR = $ = $ 1.057, 95% CI: 1.005-1.112, p = $ = $ 0.0323); other unspecified urticaria increased the risk of ADHD (OR = $ = $ 1.085, 95% CI: 1.023-1.151, p = $ = $ 0.0063). We found that eight inflammatory cytokines were negatively associated with mental disorders and seven inflammatory cytokines were positively associated with mental disorders. Finally, our results suggested that inflammatory cytokines do not act as mediators between urticaria and mental disorders. CONCLUSIONS: Our study reveals a causal relationship between urticaria and the increased risk of mental disorders. We suggest that the treatment of urticaria could incorporate psychiatric interventions and mental health assessment of patients.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Citocinas , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Transtornos Mentais , Urticária , Humanos , Citocinas/genética , Urticária/genética , Transtornos Mentais/genética , Transtornos Mentais/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/genética , Predisposição Genética para Doença/genética , Transtorno Bipolar/genética , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: Retinal nerve fiber layer thickness, as a new visual indicator that may help diagnose mental disorders, is gaining attention from researchers. However, the causal relationship between retinal nerve fiber layer thickness and mental disorders is still to be effectively proved. METHODS: A bidirectional Two-sample Mendelian randomization analysis was utilized to analyse aggregated data from large-scale genome-wide association studies, we selected genetic loci for retinal nerve fiber layer thickness in independent retinal abnormalities and three prevalent psychiatric disorders (schizophrenia, depression, bipolar disorder) as instrumental variables. The Two-sample Mendelian randomization analysis was mainly performed by inverse variance weighting and weighted median method. The Cochran Q test and leave-one-out sensitivity were used to ensure the robustness of the results. The Mendelian random polymorphism residuals and outliers were used to detect single nucleotide polymorphism outliers, and MR-Egger intercept test was used to test single nucleotide polymorphism horizontal pleiotropy. RESULTS: IVW showed that retinal nerve fiber layer thickness was positively associated with schizophrenia (OR = 1.057, 95%CI: 1.000-1.117, P < 0.05), in the study of bipolar disorder, MR analysis also suggested a positive causal relationship between retinal nerve fiber layer thickness and bipolar disorder (OR = 1.025, 95%CI: 1.005-1.046, P < 0.05), which indicated possible causal relationships between retinal nerve fiber layer thickness and these two diseases. Depression (OR = 1.000143, 95%CI: 0.9992631-1.001024, P = 0.74) indicated no significant causal association. No reverse causal effects of psychiatric disorders on retinal nerve fiber layer thickness were found. CONCLUSIONS: A statistically significant causal relationship between retinal nerve fiber layer thickness and schizophrenia and bipolar disorder has been supported by genetic means, indicating RNFL has potential to aid in the diagnosis of schizophrenia and bipolar disorder.
Assuntos
Transtorno Bipolar , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Fibras Nervosas , Polimorfismo de Nucleotídeo Único , Esquizofrenia , Humanos , Esquizofrenia/genética , Transtorno Bipolar/genética , Polimorfismo de Nucleotídeo Único/genética , Fibras Nervosas/patologia , Retina/patologia , Transtornos Mentais/genética , Transtornos Mentais/epidemiologiaRESUMO
Slitrk proteins belong the leucine-rich repeat transmembrane family and share structural similarities with the Slits and tropomyosin receptor kinase families, which regulate the development of the nervous system. Slitrks are highly expressed in the developing nervous system of vertebrates, modulating neurite outgrowth and enhancing synaptogenesis; however, the expression and function of Slitrk protein members differ. Slitrk protein variations have been associated with various sensory and neuropsychiatric conditions, including myopia, deafness, obsessive-compulsive disorder, autism spectrum disorders, schizophrenia, attention-deficit/hyperactivity disorder, glioma, and Tourette syndrome; however, the underlying mechanism remains unclear. Therefore, the Slitrk family members' protein expression, roles in the signaling cascade, functions, and gene mutations need to be comprehensively studied to develop therapeutics against neurodegenerative diseases. This study presents complete and pertinent information demonstrating the relationship between Slitrk family proteins and neuropsychiatric illnesses. This review briefly discusses neurodevelopmental disorders, the leucine-rich repeat family, the Slitrk family, and the association of Slitrk with the neuropathology of representative disorders.
Assuntos
Proteínas de Membrana , Transtornos do Neurodesenvolvimento , Humanos , Transtornos do Neurodesenvolvimento/metabolismo , Transtornos do Neurodesenvolvimento/genética , Animais , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/metabolismo , Proteínas do Tecido Nervoso/genética , Transtornos Mentais/metabolismo , Transtornos Mentais/genética , Transdução de SinaisRESUMO
Integrating protein quantitative trait loci (pQTL) data and summary statistics from genome-wide association studies (GWAS) of brain image-derived phenotypes (IDPs) can benefit in identifying IDP-related proteins. Here, we developed a systematic omics-integration analytic framework by sequentially using proteome-wide association study (PWAS), Mendelian randomization (MR), and colocalization (COLOC) analyses to identify the potentially causal brain and plasma proteins for IDPs, followed by pleiotropy analysis, mediation analysis, and drug exploration analysis to investigate potential mediation pathways of pleiotropic proteins to neuropsychiatric disorders (NDs) as well as candidate drug targets. A total of 201 plasma proteins and 398 brain proteins were significantly associated with IDPs from PWAS analysis. Subsequent MR and COLOC analyses further identified 313 potentially causal IDP-related proteins, which were significantly enriched in neural-related phenotypes, among which 91 were further identified as pleiotropic proteins associated with both IDPs and NDs, including EGFR, TMEM106B, GPT, and HLA-B. Drug prioritization analysis showed that 6.33% of unique pleiotropic proteins had drug targets or interactions with medications for NDs. Nine potential mediation pathways were identified to illustrate the mediating roles of the IDPs in the causal effect of the pleiotropic proteins on NDs, including the indirect effect of TMEM106B on Alzheimer's disease (AD) risk via radial diffusivity (RD) of the posterior limb of the internal capsule (PLIC), with the mediation proportion being 11.18%, and the indirect effect of EGFR on AD through RD of PLIC, RD of splenium of corpus callosum (SCC), and fractional anisotropy (FA) of SCC, with the mediation proportion being 18.99%, 22.79%, and 19.91%, respectively. These findings provide novel insights into pathogenesis, drug targets, and neuroimaging biomarkers of NDs.
Assuntos
Biomarcadores , Encéfalo , Estudo de Associação Genômica Ampla , Transtornos Mentais , Neuroimagem , Locos de Características Quantitativas , Humanos , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Neuroimagem/métodos , Transtornos Mentais/metabolismo , Transtornos Mentais/diagnóstico por imagem , Transtornos Mentais/genética , Transtornos Mentais/tratamento farmacológico , Análise da Randomização Mendeliana , Proteoma/metabolismo , Proteômica/métodos , Pleiotropia Genética , Fenótipo , MultiômicaAssuntos
Pesquisa Biomédica , Disparidades em Assistência à Saúde , Transtornos Mentais , Saúde Mental , Pesquisadores , Humanos , África/epidemiologia , África/etnologia , Pesquisa Biomédica/estatística & dados numéricos , Pesquisa Biomédica/tendências , Transtornos Mentais/epidemiologia , Transtornos Mentais/genética , Transtornos Mentais/terapia , Saúde Mental/estatística & dados numéricos , Pesquisadores/provisão & distribuição , Disparidades em Assistência à Saúde/tendênciasRESUMO
BACKGROUND AND OBJECTIVES: Behavioral and neuropsychiatric symptoms are frequent in patients with genetic frontotemporal dementia (FTD). We aimed to describe behavioral and neuropsychiatric phenotypes in genetic FTD, quantify their temporal association, and investigate their regional association with brain atrophy. METHODS: We analyzed data of pathogenic variant carriers in the chromosome 9 open reading frame 72 (c9orf72), progranulin (GRN), or microtubule-associated protein tau (MAPT) gene from the Genetic Frontotemporal dementia Initiative cohort study that enrolls both symptomatic pathogenic variant carriers and first-degree relatives of known carriers. Principal component analysis was performed to identify behavioral and neuropsychiatric clusters that were compared with respect to frequency and severity between groups. Associations between neuropsychiatric clusters and MRI-assessed atrophy were determined using voxel-based morphometry. We applied linear mixed effects and generalized linear mixed effects models to assess the longitudinal course of symptoms. RESULTS: A total of 522 participants were included: 221 c9orf72 (138 presymptomatic), 213 GRN (157 presymptomatic), and 88 MAPT (62 presymptomatic) pathogenic variant carriers. Principal component analysis revealed 5 phenotypic clusters (67.6% of variance), labeled diverse behavioral, affective, psychotic, euphoric/hypersexual, and tactile hallucinations phenotype. In participants presenting behavioral or neuropsychiatric symptoms, affective symptoms were most frequent across groups (83.6%-88.1%), followed by diverse behavioral symptoms (68.4%-77.9%). In c9orf72 and GRN pathogenic variant carriers, psychotic symptoms (32.0% and 19.4%, respectively) were more frequent than euphoric/hypersexual symptoms (28.7% and 14.2%, respectively), which was the other way around in MAPT pathogenic variant carriers (28.6% and 23.8%). Although diverse behavioral symptoms were associated with gray and white matter frontotemporal atrophy, only a small atrophy cluster in the right thalamus was associated with psychotic symptoms. Euphoric/hypersexual symptoms were associated with atrophy in mesial temporal lobes, basal forebrain structures, and the striatum (p < 0.05). Estimated time to symptom onset, genetic group, education, and sex influenced behavioral and neuropsychiatric symptoms (p < 0.05). Particularly, in c9orf72 pathogenic variant carriers, psychotic symptoms may be starting decades before recognition of onset of illness. DISCUSSION: We identified multiple clusters of behavioral and neuropsychiatric symptoms in participants with genetic FTD that relate to distinct cerebral atrophy patterns. Their severity depends on time, affected gene, sex, and education. These clinical-genetic associations can guide diagnostic evaluations and the design of clinical trials for new disease-modifying and preventive treatments.
Assuntos
Proteína C9orf72 , Demência Frontotemporal , Progranulinas , Proteínas tau , Humanos , Demência Frontotemporal/genética , Demência Frontotemporal/diagnóstico por imagem , Demência Frontotemporal/patologia , Demência Frontotemporal/psicologia , Masculino , Feminino , Proteína C9orf72/genética , Pessoa de Meia-Idade , Progranulinas/genética , Proteínas tau/genética , Idoso , Estudos Longitudinais , Atrofia/patologia , Sintomas Comportamentais/etiologia , Sintomas Comportamentais/genética , Imageamento por Ressonância Magnética , Transtornos Mentais/genética , Estudos de Coortes , Fenótipo , Encéfalo/diagnóstico por imagem , Encéfalo/patologiaRESUMO
BACKGROUND: Neurocognitive 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. METHODS: To 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. RESULTS: MR 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. CONCLUSION: Our 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.
Assuntos
Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Transtornos Mentais , Humanos , Transtornos Mentais/genética , Transtornos Mentais/sangue , Biomarcadores/sangue , Disfunção Cognitiva/genética , Disfunção Cognitiva/sangue , Transtorno Bipolar/genética , Transtorno Bipolar/sangue , Análise de Mediação , Esquizofrenia/genética , Esquizofrenia/sangue , Testes Neuropsicológicos , Polimorfismo de Nucleotídeo ÚnicoRESUMO
The causal effects of mental health problems on the risk of infectious diseases remain vague. Investigating them via observational study is challenging as it presents possible confounding factors. Therefore, the objective of this study was to utilize Mendelian randomization (MR) techniques to evaluate the causal relationship between mental health problems and the risk of infectious diseases. Multivariable MR analyses were performed using genome-wide association data for sleep disorders (Nâ =â 216,700), depression (Nâ =â 500,199), anxiety (Nâ =â 290,361), nervous feelings (Nâ =â 450,700), unspecified mental disorder (Nâ =â 218,792), pneumonia (Nâ =â 486,484), skin and subcutaneous tissue infection (SSTI; Nâ =â 218,792), intestinal infectious diseases (IIDs; Nâ =â 218,792), urinary tract infection (Nâ =â 463,010), and central nervous system (CNS) infections (Nâ =â 218,792) among individuals of European ancestry. Independent genetic variants significantly (Pâ <â 10-8) associated with each exposure were considered instruments. The primary analysis used an inverse variance-weighted method, followed by a series of sensitivity analyses. Genetically predicted sleep disorders were associated with an increased risk of SSTI (odds ratio [OR], 1.29 [95% confidence interval (CI), 1.05-1.59]; Pâ =â .017). Genetically predicted depression was linked with an increased risk of CNS infections (OR, 1.59 [95% CI, 1.00-2.53]; Pâ =â .049) and SSTI (1.24 [95% CI, 1.03-1.49]; Pâ =â .024). Genetically predicted anxiety was associated with IIDs (OR, 1.19 [95% CI, 1.03-1.37]; Pâ =â .017) and SSTI (OR, 1.21 [95% CI, 1.02-1.43]; Pâ =â .029). There was no significant causal evidence for genetic prediction of nervous feelings and unspecified mental disorders in IIDs, CNS infections, SSTI, pneumonia, or urinary tract infection. Sensitivity analyses showed that the above causal association estimates were robust. In this MR study, we demonstrated a causal relationship between sleep disorders, depression, anxiety, and the risk of infectious diseases. However, no evidence was found to support causality between nervous feelings, unspecified mental disorders, and the risk of infectious diseases.
Assuntos
Doenças Transmissíveis , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Transtornos Mentais , Humanos , Doenças Transmissíveis/epidemiologia , Doenças Transmissíveis/genética , Transtornos Mentais/epidemiologia , Transtornos Mentais/genética , Fatores de Risco , Transtornos do Sono-Vigília/epidemiologia , Transtornos do Sono-Vigília/genética , Polimorfismo de Nucleotídeo Único , MasculinoRESUMO
BACKGROUND: Increasing evidences suggest that nonalcoholic fatty liver disease (NAFLD) is associated with neuropsychiatric disorders. Nevertheless, whether there were causal associations between them remained vague. A causal association between neuropsychiatric disorders and NAFLD was investigated in this study. METHODS: We assessed the published genome-wide association study summary statistics for NAFLD, seven mental disorder-related diseases and six central nervous system dysfunction-related diseases. The causal relationships were first assessed using two-sample and multivariable Mendelian randomization (MR). Then, sensitivity analyses were performed, followed by a reverse MR analysis to determine whether reverse causality is possible. Finally, we performed replication analyses and combined the findings from the above studies. RESULTS: Our meta-analysis results showed NAFLD significantly increased the risk of anxiety disorders (OR = 1.016, 95% CI = 1.010-1.021, P value < 0.0001). In addition, major depressive disorder was the potential risk factor for NAFLD (OR = 1.233, 95% CI = 1.063-1.430, P value = 0.006). Multivariable MR analysis showed that the causal effect of major depressive disorder on NAFLD remained significant after considering body mass index, but the association disappeared after adjusting for the effect of waist circumference. Furthermore, other neuropsychiatric disorders and NAFLD were not found to be causally related. CONCLUSIONS: These results implied causal relationships of NAFLD with anxiety disorders and Major Depressive Disorder. This study highlighted the need to recognize and understand the connection between neuropsychiatric disorders and NAFLD to prevent the development of related diseases.
Assuntos
Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Transtornos Mentais , Hepatopatia Gordurosa não Alcoólica , Humanos , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Transtornos Mentais/genética , Transtornos Mentais/epidemiologia , Fatores de Risco , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/epidemiologia , Causalidade , Transtornos de Ansiedade/epidemiologia , Transtornos de Ansiedade/genéticaRESUMO
BACKGROUND: Mitochondria is essential for cellular energy production, oxidative stress, and apoptosis. Mitochondrial DNA (mtDNA) encodes essential proteins for mitochondrial function. Although several studies have explored the association between changes in mtDNA copy number (mtDNA-CN) and risk of mental disorders, the results remain debated. This study used a bidirectional two-sample Mendelian randomization (MR) analysis to examine the genetic causality between mtDNA-CN and mental disorders. METHODS: Genome-wide association study (GWAS) data for mtDNA-CN were sourced from UK biobank, involving 383,476 European cases. GWAS data for seven mental disorders-attention deficit/hyperactivity disorder, autism spectrum disorder (ASD), schizophrenia, bipolar disorder, major depressive disorder, anxiety, and obsessive-compulsive disorder-were primarily obtained from the Psychiatric Genomics Consortium. Causal associations were assessed using inverse variance weighting, with sensitivity analyses via the weighted median and MR-Egger methods. Reverse MR considered the seven mental disorders as exposures. All analyses were replicated with additional mtDNA-CN GWAS data from 465,809 individuals in the Heart and Ageing Research in Genomic Epidemiology consortium and the UK Biobank. RESULTS: Forward MR observed a 27 % decrease in the risk of ASD per standard deviation increase in genetically determined blood mtDNA-CN (OR = 0.73, 95%CI: 0.58-0.92, p = 0.002), with no causal effects on other disorders. Additionally, reverse MR did not indicate a causal association between any of the mental disorders and mtDNA-CN. Validation analyses corroborated these findings, indicating their robustness. CONCLUSIONS: Our study supports the potential causal association between mtDNA-CN and the risk of ASD, suggesting that mtDNA-CN could serve as a promising biomarker for early screening of ASD.
Assuntos
Variações do Número de Cópias de DNA , DNA Mitocondrial , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Transtornos Mentais , Humanos , DNA Mitocondrial/genética , DNA Mitocondrial/sangue , Transtornos Mentais/genética , Transtornos Mentais/epidemiologia , Transtornos Mentais/sangue , Feminino , Predisposição Genética para Doença , MasculinoRESUMO
OBJECTIVES: ULK4 is an established candidate gene for mental disorders and antipsychotic treatment response. We investigated the association of functional genetic variation at the ULK4 locus with the human extended dopaminergic reward system using fMRI during the performance of a well-established reward paradigm. METHODS: Two hundred and thirty-four patients were included in this study. Association of genetic variation in the ULK4 gene with reward system functioning were determined using the Desire-Reason-Dilemma (DRD) paradigm which allows to assess brain activation in response to conditioned reward stimuli. RESULTS: Variant prioritisation revealed the strongest functional signatures for the ULK4 variant rs17215589, coding for amino acid exchange Ala715Thr. For rs17215589 minor allele carriers, we detected increased activation responses to conditioned reward stimuli in the ventral tegmental area, nucleus accumbens and several cortical brain regions of the extended reward system. CONCLUSIONS: Our findings provide further evidence in humans that genetic variation in ULK4 may increase the vulnerability to mental disorders, by modulating the extended reward system function. Future studies are needed to confirm the modulation of the extended reward system by ULK4 and to specify the role of this mechanism in the pathogenesis of psychiatric disorders.
Assuntos
Imageamento por Ressonância Magnética , Proteínas Serina-Treonina Quinases , Recompensa , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Encéfalo/diagnóstico por imagem , Transtornos Mentais/genética , Transtornos Mentais/fisiopatologia , Núcleo Accumbens/diagnóstico por imagem , Polimorfismo de Nucleotídeo Único , Proteínas Serina-Treonina Quinases/genética , Área Tegmentar Ventral/diagnóstico por imagemRESUMO
The Krüppel-like factor (KLF) family represents a group of transcription factors (TFs) performing different biological processes that are crucial for proper neuronal function, including neuronal development, synaptic plasticity, and neuronal survival. As reported, genetic variants within the KLF family have been associated with a wide spectrum of neurodevelopmental and psychiatric symptoms. In a patient exhibiting attention deficit hyperactivity disorder (ADHD) combined with both neurodevelopmental and psychiatric symptoms, whole-exome sequencing (WES) analysis revealed a de novo heterozygous variant within the Krüppel-like factor 13 (KLF13) gene, which belongs to the KLF family and regulates axonal growth, development, and regeneration in mice. Moreover, in silico analyses pertaining to the likely pathogenic significance of the variant and the impact of the mutation on the KLF13 protein structure suggested a potential deleterious effect. In fact, the variant was localized in correspondence to the starting residue of the N-terminal domain of KLF13, essential for protein-protein interactions, DNA binding, and transcriptional activation or repression. This study aims to highlight the potential involvement of the KLF13 gene in neurodevelopmental and psychiatric disorders. Nevertheless, we cannot rule out that excluded variants, those undetectable by WES, or the polygenic risk may have contributed to the patient's phenotype given ADHD's high polygenic risk. However, further functional studies are required to validate its potential contribution to these disorders.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Biologia Computacional , Humanos , Biologia Computacional/métodos , Transtorno do Deficit de Atenção com Hiperatividade/genética , Sequenciamento do Exoma , Masculino , Transtornos do Neurodesenvolvimento/genética , Fatores de Transcrição Kruppel-Like/genética , Transtornos Mentais/genética , Mutação , Proteínas Repressoras , Proteínas de Ciclo CelularRESUMO
The disruption of brain energy metabolism, leading to alterations in synaptic signaling, neural circuitry, and neuroplasticity, has been implicated in severe mental illnesses such as schizophrenia, bipolar disorder, and major depressive disorder. The therapeutic potential of ketogenic interventions in these disorders suggests a link between metabolic disturbances and disease pathology; however, the precise mechanisms underlying these metabolic disturbances, and the therapeutic effects of metabolic ketogenic therapy, remain poorly understood. In this study, we conducted an in silico analysis of transcriptomic data to investigate perturbations in metabolic pathways in the brain across severe mental illnesses via gene expression profiling. We also examined dysregulation of the same pathways in rodent or cell culture models of ketosis, comparing these expression profiles to those observed in the disease states. Our analysis revealed significant perturbations across all metabolic pathways, with the greatest perturbations in glycolysis, the tricarboxylic acid (TCA) cycle, and the electron transport chain (ETC) across all three disorders. Additionally, we observed some discordant gene expression patterns between disease states and ketogenic intervention studies, suggesting a potential role for ketone bodies in modulating pathogenic metabolic changes. Our findings highlight the importance of understanding metabolic dysregulation in severe mental illnesses and the potential therapeutic benefits of ketogenic interventions in restoring metabolic homeostasis. This study provides insights into the complex relationship between metabolism and neuropsychiatric disorders and lays the foundation for further experimental investigations aimed at appreciating the implications of the present transcriptomic findings as well as developing targeted therapeutic strategies.
Assuntos
Dieta Cetogênica , Transtornos Mentais , Transcriptoma , Humanos , Transtornos Mentais/metabolismo , Transtornos Mentais/genética , Transtornos Mentais/dietoterapia , Transtornos Mentais/etiologia , Animais , Metabolismo Energético , Perfilação da Expressão Gênica , Transtorno Bipolar/metabolismo , Transtorno Bipolar/dietoterapia , Transtorno Bipolar/genética , Redes e Vias Metabólicas , Corpos Cetônicos/metabolismo , Encéfalo/metabolismoRESUMO
Early-life adversity (ELA) is characterized by exposure to traumatic events during early periods of life, particularly involving emotional, sexual and/or physical adversities during childhood. Mental disorders are strongly influenced by environmental and lifestyle-related risk factors including ELA. However, the molecular link between ELA and the risk of an adult mental disorder is still not fully understood. Evidence is emerging that long-lasting changes in the epigenetic processes regulating gene expression, such as DNA methylation, play an important role in the biological mechanisms linking ELA and mental disorders. Based on a recent study, we analyzed the DNA methylation of a specific CpG site within the gene PXDN-cg10888111-in blood in the context of ELA across a set of psychiatric disorders, namely Borderline Personality Disorder (BPD), Major Depressive Disorder (MDD) and Social Anxiety Disorder (SAD), and its potential contribution to their pathogenesis. We found significant hypermethylation in mentally ill patients with high levels of ELA compared to patients with low levels of ELA, whereas cg10888111 methylation in healthy control individuals was not affected by ELA. Further investigations revealed that this effect was driven by the MDD cohort. Providing a direct comparison of cg10888111 DNA methylation in blood in the context of ELA across three mental disorders, our results indicate the role of PXDN regulation in the response to ELA in the pathogenesis of mental disorders, especially MDD. Further studies will be needed to validate these results and decipher the corresponding biological network that is involved in the transmission of ELA to an adult mental disorder in general.
Assuntos
Metilação de DNA , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Experiências Adversas da Infância , Transtorno da Personalidade Borderline/genética , Ilhas de CpG/genética , Transtorno Depressivo Maior/genética , Metilação de DNA/genética , Epigênese Genética , Transtornos Mentais/genéticaRESUMO
Earlier studies have revealed microRNAs (miRNAs) as potential biomarkers for neurological conditions, however, such evidence on psychiatric outcomes is limited. We utilized the Normative Aging Study (NAS) cohort to investigate the associations between extracellular miRNAs (ex-miRNA) and psychiatric symptoms among a group of older male adults, along with the targeted genes and biological pathways. We studied 569 participants with miRNA profile primarily measured in extracellular vesicles isolated from plasma, and psychiatric symptoms reported over 1996-2014 with repeated measures. Global and dimension scales of psychiatric symptoms were measured via the administration of Brief Symptom Inventory (BSI) per visit covering nine aspects of psychiatric health, such as anxiety, depression, hostility, psychoticism, etc. Ex-miRNAs were profiled using small RNA sequencing. Associations of expression of 395 ex-miRNAs (present in >70% samples) with current mental status were assessed using single-miRNA as well as Least Absolute Shrinkage and Selection Operator (LASSO)-based multi-miRNAs linear mixed effects models adjusting for key demographic and behavioral factors. Biological functions were explored using pathway analyses. We identified ex-miRNAs associated with each BSI scale. In particular, hsa-miR-320d was consistently identified for two global scales. Similar overlapping miRNAs across global and dimension scores included hsa-miR-379-3p, hsa-miR-1976, hsa-miR-151a-5p, hsa-miR-151b, hsa-miR-144-3p, etc. Top KEGG pathways for identified miRNAs included p53 signaling, Hippo signaling, FoxO signaling, protein processing in endoplasmic reticulum and several pathways related with cancer and neurological diseases. This study provided early evidence supporting the associations between extracellular miRNAs and psychiatric conditions. MiRNAs may serve as biomarkers of subclinical psychiatric illness in older adults.
Assuntos
Envelhecimento , MicroRNAs , Humanos , Masculino , Idoso , MicroRNAs/genética , MicroRNAs/sangue , Envelhecimento/fisiologia , Transtornos Mentais/genética , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Vesículas Extracelulares/metabolismo , Pessoa de Meia-Idade , Estudos de CoortesRESUMO
BACKGROUND: There is an association between obesity and psychological disorders such as depression, anxiety, and stress. Environmental factors and genetics play a crucial role in this regard. Several long non-coding RNAs (lncRNAs) are involved in the pathophysiology of the nervous system. Additionally, we intend to investigate how dietary glycemic index and load relate to psychological disorders in women with obesity and overweight by identifying the possible interaction with metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and taurine upregulated gene 1 (TUG1). METHODS: 267 overweight or obese women between the ages of 18 and 48 were recruited for the current study. A reliable and validated food frequency questionnaire (FFQ) consisting of 147 items assessed food consumption, glycemic load (GL), and glycemic index (GI). Depression-Anxiety-Stress Scales (DASS-21) were used to assess mental well-being. A real-time polymerase chain reaction (PCR) was used to assess transcript levels for lncRNAs MALAT1 and TUG1. RESULTS: In obese and overweight women, a positive correlation was found between anxiety and MALAT1 mRNA levels (P = 0.007, CC = 0.178). Age, energy intake, physical activity, total fat, income, marriage, thyroid, and BMI were adjusted, and GI and TUG1 were positively correlated on DASS-21 (ß = 0.006, CI = 0.001, 0.01, P = 0.031), depression (ß = 0.002, CI = 0.001, 0.004, P = 0.019), Stress (ß = 0.003, CI = 0.001, 0.005, P = 0.027). The interaction of GL and TUG1 on stress was also observed (ß = 0.03, CI = 0.001, 0.07, P = 0.048). CONCLUSIONS: The lncRNA TUG1 appears to be associated with depression and stress through interaction with GI and correlated with stress by interaction with GL. To establish this concept, further research is required.