Role of the Gut-Brain Axis in the Shared Genetic Etiology Between Gastrointestinal Tract Diseases and Psychiatric Disorders

JAMA Psychiatry, Journal Year: 2023, Volume and Issue: 80(4), P. 360 - 360

Published: Feb. 8, 2023

Importance Comorbidities and genetic correlations between gastrointestinal tract diseases psychiatric disorders have been widely reported, with the gut-brain axis (GBA) hypothesized as a potential biological basis. However, degree to which shared determinants are involved in these associations underlying GBA is unclear. Objective To investigate etiology identify genomic loci, genes, pathways. Design, Setting, Participants This genome-wide pleiotropic association study using summary statistics from publicly available data sources was performed various statistical approaches sequentially single-nucleotide variation (SNV; formerly polymorphism [SNP]), gene levels pathways disentangle 4 (inflammatory bowel disease, irritable syndrome, peptic ulcer gastroesophageal reflux disease) 6 (schizophrenia, bipolar disorder, major depressive attention-deficit/hyperactivity posttraumatic stress anorexia nervosa). Data were collected March 10, 2021, August 25, analysis January 8 through May 30, 2022. Main Outcomes Measures The primary outcomes consisted of list disorders. Results Extensive overlaps found among 22 24 trait pairs. Pleiotropic under composite null hypothesis identified 2910 significant SNVs 19 pairs, 83 loci colocalized detected. Gene-based 158 unique candidate highly enriched certain GBA-related phenotypes tissues, whereas pathway enrichment further highlighted primarily involving cell adhesion, synaptic structure function, immune differentiation. Several also causal variants gut microbiomes. Mendelian randomization illustrated vertical pleiotropy across pairwise traits. Notably, many for multiple traits, such 1q32.1 ( INAVA ), 19q13.33 FUT2 11q23.2 NCAM1 1p32.3 LRP8 ). Conclusions Relevance These findings suggest that extensively distributed genome. not only support basis but important implications intervention treatment targets simultaneously.

Language: Английский

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The role of the immune system in posttraumatic stress disorder

Translational Psychiatry, Journal Year: 2022, Volume and Issue: 12(1)

Published: Aug. 4, 2022

Abstract Posttraumatic stress disorder (PTSD) develops in a subset of individuals upon exposure to traumatic stress. In addition well-defined psychological and behavioral symptoms, some with PTSD also exhibit elevated concentrations inflammatory markers, including C-reactive protein, interleukin-6, tumor necrosis factor-α. Moreover, is often co-morbid immune-related conditions, such as cardiometabolic autoimmune disorders. Numerous factors, lifetime trauma burden, biological sex, genetic background, metabolic gut microbiota, may contribute inflammation PTSD. Importantly, can influence neural circuits neurotransmitter signaling regions the brain relevant fear, anxiety, emotion regulation. Given link between immune system, current studies are underway evaluate efficacy anti-inflammatory treatments those Understanding complex interactions system essential for future discovery diagnostic therapeutic tools.

Language: Английский

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Pervasive Downward Bias in Estimates of Liability-Scale Heritability in Genome-wide Association Study Meta-analysis: A Simple Solution

Biological Psychiatry, Journal Year: 2022, Volume and Issue: 93(1), P. 29 - 36

Published: June 8, 2022

Language: Английский

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Genetic estimates of correlation and causality between blood-based biomarkers and psychiatric disorders

Science Advances, Journal Year: 2022, Volume and Issue: 8(14)

Published: April 6, 2022

There is a long-standing interest in exploring the relationship between blood-based biomarkers and psychiatric disorders, despite their causal role being difficult to resolve observational studies. In this study, we leverage genome-wide association study data for large panel of heritable serum biochemical traits refine our understanding effect biochemical-psychiatric trait pairings. We observed widespread positive negative genetic correlation disorders traits. Causal inference was then implemented distinguish causation from correlation, with strong evidence that C-reactive protein (CRP) exerts on disorders. Notably, CRP demonstrated both protective risk-increasing effects different Multivariable models conditioned interleukin-6 signaling body mass index supported CRP-schizophrenia not driven by these factors. Collectively, suggest there are shared pathways influence illness.

Language: Английский

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GWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors

American Journal of Psychiatry, Journal Year: 2023, Volume and Issue: 180(10), P. 723 - 738

Published: Oct. 1, 2023

Suicidal behavior is heritable and a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered cross-validated significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both to conduct largest GWAS meta-analysis SA date. Multi-ancestry admixture-specific meta-analyses were conducted within groups African, East Asian, European ancestry admixtures.

Language: Английский

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A concerted neuron–astrocyte program declines in ageing and schizophrenia

Nature, Journal Year: 2024, Volume and Issue: 627(8004), P. 604 - 611

Published: March 6, 2024

Abstract Human brains vary across people and over time; such variation is not yet understood in cellular terms. Here we describe a relationship between people’s cortical neurons astrocytes. We used single-nucleus RNA sequencing to analyse the prefrontal cortex of 191 human donors aged 22–97 years, including healthy individuals with schizophrenia. Latent-factor analysis these data revealed that, whose more strongly expressed genes encoding synaptic components, astrocytes distinct functions for synthesizing cholesterol, an astrocyte-supplied component membranes. call this neuron astrocyte program (SNAP). In schizophrenia ageing—two conditions that involve declines cognitive flexibility plasticity 1,2 —cells divested from SNAP: astrocytes, glutamatergic (excitatory) GABAergic (inhibitory) all showed reduced SNAP expression corresponding degrees. The astrocytic neuronal components both involved which genetic risk factors were concentrated. SNAP, varies quantitatively even among similar age, may underlie many aspects normal interindividual differences be important point convergence multiple kinds pathophysiology.

Language: Английский

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Genome-wide association analyses identify 95 risk loci and provide insights into the neurobiology of post-traumatic stress disorder

Nature Genetics, Journal Year: 2024, Volume and Issue: 56(5), P. 792 - 808

Published: April 18, 2024

Language: Английский

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Systems biology dissection of PTSD and MDD across brain regions, cell types, and blood

Science, Journal Year: 2024, Volume and Issue: 384(6698)

Published: May 23, 2024

The molecular pathology of stress-related disorders remains elusive. Our brain multiregion, multiomic study posttraumatic stress disorder (PTSD) and major depressive (MDD) included the central nucleus amygdala, hippocampal dentate gyrus, medial prefrontal cortex (mPFC). Genes exons within mPFC carried most disease signals replicated across two independent cohorts. Pathways pointed to immune function, neuronal synaptic regulation, hormones. Multiomic factor gene network analyses provided underlying genomic structure. Single RNA sequencing in dorsolateral PFC revealed dysregulated (stress-related) non-neuronal cell types. Analyses brain-blood intersections >50,000 UK Biobank participants were conducted along with fine-mapping results PTSD MDD genome-wide association studies distinguish risk from processes. data suggest shared distinct both propose potential therapeutic targets biomarkers.

Language: Английский

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The Psychedelic Future of Post-Traumatic Stress Disorder Treatment

Current Neuropharmacology, Journal Year: 2024, Volume and Issue: 22(4), P. 636 - 735

Published: Jan. 5, 2024

Post-traumatic stress disorder (PTSD) is a mental health condition that can occur following exposure to traumatic experience. An estimated 12 million U.S. adults are presently affected by this disorder. Current treatments include psychological therapies (e.g., exposure-based interventions) and pharmacological selective serotonin reuptake inhibitors (SSRIs)). However, significant proportion of patients receiving standard-of-care for PTSD remain symptomatic, new approaches other trauma-related conditions greatly needed. Psychedelic compounds alter cognition, perception, mood currently being examined their efficacy in treating despite current status as Drug Enforcement Administration (DEA)- scheduled substances. Initial clinical trials have demonstrated the potential value psychedelicassisted therapy treat psychiatric disorders. In comprehensive review, we summarize state science care, including shortcomings. We review studies psychedelic interventions PTSD, disorders, common comorbidities. The classic psychedelics psilocybin, lysergic acid diethylamide (LSD), N,N-dimethyltryptamine (DMT) DMT-containing ayahuasca, well entactogen 3,4-methylenedioxymethamphetamine (MDMA) dissociative anesthetic ketamine, reviewed. For each drug, present history use, somatic effects, pharmacology, safety profile. rationale proposed mechanisms use traumarelated disorders discussed. This concludes with an in-depth consideration future directions applications maximize therapeutic benefit minimize risk individuals communities impacted conditions.

Language: Английский

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Post‐traumatic stress disorder: evolving conceptualization and evidence, and future research directions

World Psychiatry, Journal Year: 2025, Volume and Issue: 24(1), P. 52 - 80

Published: Jan. 15, 2025

The understanding of responses to traumatic events has been greatly influenced by the introduction diagnosis post‐traumatic stress disorder (PTSD). In this paper we review initial versions diagnostic criteria for condition and associated epidemiological findings, including sociocultural differences. We consider evidence reactions occurring in multiple contexts not previously defined as traumatic, implications that these observations have diagnosis. More recent developments such DSM‐5 dissociative subtype ICD‐11 complex PTSD are reviewed, adding there several distinct phenotypes. describe psychological foundations PTSD, involving disturbances memory well identity. A broader focus on identity may be able accommodate group communal influences experience trauma impact resource loss. then summarize current concerning biological with a particular genetic neuroimaging studies. Whereas progress prevention disappointing, is now an extensive supporting efficacy variety treatments established trauma‐focused interventions – cognitive behavior therapy (TF‐CBT) eye movement desensitization reprocessing (EMDR) non‐trauma‐focused therapies, which also include some emerging identity‐based approaches present‐centered compassion‐focused therapies. Additionally, promising neither nor pharmacological, or combine pharmacological approach, 3,4‐methylenedioxymethamphetamine (MDMA)‐assisted psychotherapy. advances priority areas adapting resource‐limited settings across cultural contexts, community‐based approaches. conclude identifying future directions work mental health.

Language: Английский

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