Complex brain disorders are highly heritable and arise from a complex polygenic risk architecture. Many disease-associated loci are found in non-coding regions that house regulatory elements. These ...elements influence the transcription of target genes-many of which demonstrate cell-type-specific expression patterns-and thereby affect phenotypically relevant molecular pathways. Thus, cell-type-specificity must be considered when prioritizing candidate risk loci, variants and target genes. This Review discusses the use of high-throughput assays in human induced pluripotent stem cell-based neurodevelopmental models to probe genetic risk in a cell-type- and patient-specific manner. The application of massively parallel reporter assays in human induced pluripotent stem cells can characterize the human regulome and test the transcriptional responses of putative regulatory elements. Parallel CRISPR-based screens can further functionally dissect this genetic regulatory architecture. The integration of these emerging technologies could decode genetic risk into medically actionable information, thereby improving genetic diagnosis and identifying novel points of therapeutic intervention.
Anorexia nervosa (AN) is a psychiatric disorder with complex etiology, with a significant portion of disease risk imparted by genetics. Traditional genome-wide association studies (GWAS) produce ...principal evidence for the association of genetic variants with disease. Transcriptomic imputation (TI) allows for the translation of those variants into regulatory mechanisms, which can then be used to assess the functional outcome of genetically regulated gene expression (GReX) in a broader setting through the use of phenome-wide association studies (pheWASs) in large and diverse clinical biobank populations with electronic health record phenotypes.
Here, we applied TI using S-PrediXcan to translate the most recent PGC-ED AN GWAS findings into AN-GReX. For significant genes, we imputed AN-GReX in the Mount Sinai Bio
™ Biobank and performed pheWASs on over 2000 outcomes to test the clinical consequences of aberrant expression of these genes. We performed a secondary analysis to assess the impact of body mass index (BMI) and sex on AN-GReX clinical associations.
Our S-PrediXcan analysis identified 53 genes associated with AN, including what is, to our knowledge, the first-genetic association of AN with the major histocompatibility complex. AN-GReX was associated with autoimmune, metabolic, and gastrointestinal diagnoses in our biobank cohort, as well as measures of cholesterol, medications, substance use, and pain. Additionally, our analyses showed moderation of AN-GReX associations with measures of cholesterol and substance use by BMI, and moderation of AN-GReX associations with celiac disease by sex.
Our BMI-stratified results provide potential avenues of functional mechanism for AN-genes to investigate further.
Genome-wide association studies reveal the complex polygenic architecture underlying psychiatric disorder risk, but there is an unmet need to validate causal variants, resolve their target genes(s), ...and explore their functional impacts on disorder-related mechanisms. Disorder-associated loci regulate transcription of target genes in a cell type- and context-specific manner, which can be measured through expression quantitative trait loci. In this review, we discuss methods and insights from context-specific modeling of genetically and environmentally regulated expression. Human induced pluripotent stem cell–derived cell type and organoid models have uncovered context-specific psychiatric disorder associations by investigating tissue-, cell type-, sex-, age-, and stressor-specific genetic regulation of expression. Techniques such as massively parallel reporter assays and pooled CRISPR (clustered regularly interspaced short palindromic repeats) screens make it possible to functionally fine-map genome-wide association study loci and validate their target genes at scale. Integration of disorder-associated contexts with these patient-specific human induced pluripotent stem cell models makes it possible to uncover gene by environment interactions that mediate disorder risk, which will ultimately improve our ability to diagnose and treat psychiatric disorders.
Eating disorders: are gut microbiota to blame? Xu, Jiayi; Carroll, Ian M.; Huckins, Laura M.
Trends in molecular medicine,
April 2024, 2024-Apr, 2024-04-00, 20240401, Volume:
30, Issue:
4
Journal Article
Peer reviewed
Open access
Gut microbiota could be involved in weight regulation and impact brain function via the gut–brain axis. Moreover, gut microbiota may impact the development of eating disorders (EDs) since they are ...characterized by weight-related concerns and symptoms and may represent a therapeutic target if future research can establish a causal link.
Gut microbiota could be involved in weight regulation and impact brain function via the gut–brain axis. Moreover, gut microbiota may impact the development of eating disorders since they are characterized by weight-related concerns and symptoms and may represent a therapeutic target if future research can establish a causal link.
Feeding and eating disorders (FEDs) are common and have been shown to be influenced by both genetic and environmental factors.Avoidant/restrictive food intake disorder, anorexia nervosa (AN), bulimia ...nervosa (BN), and binge-eating disorder (BED) are all heritable and genome-wide association studies (GWASs) reveal both psychiatric and metabolic/anthropometric genetic risk factors for AN. GWASs for other FEDs are underway.AN, BN, and BED might diverge etiologically in their genetic relation with metabolic and anthropometric traits.Functional genomic tools will enable translation of variants to genes, genes to pathways, and pathways to metabolic outcomes to convert genetic findings into medically actionable outcomes. This work is poised to yield the first interventions for FEDs that are informed by disorder-specific biology.
Feeding and eating disorders (FEDs) are heterogenous and characterized by varying patterns of dysregulated eating and weight. Genome-wide association studies (GWASs) are clarifying their underlying biology and their genetic relationship to other psychiatric and metabolic/anthropometric traits. Genetic research on anorexia nervosa (AN) has identified eight significant loci and uncovered genetic correlations implicating both psychiatric and metabolic/anthropometric risk factors. Careful explication of these metabolic contributors may be key to developing effective and enduring treatments for devastating, life-altering, and frequently lethal illnesses. We discuss clinical phenomenology, genomics, phenomics, intestinal microbiota, and functional genomics and propose a path that translates variants to genes, genes to pathways, and pathways to metabolic outcomes to advance the science and eventually treatment of FEDs.
Feeding and eating disorders (FEDs) are heterogenous and characterized by varying patterns of dysregulated eating and weight. Genome-wide association studies (GWASs) are clarifying their underlying biology and their genetic relationship to other psychiatric and metabolic/anthropometric traits. Genetic research on anorexia nervosa (AN) has identified eight significant loci and uncovered genetic correlations implicating both psychiatric and metabolic/anthropometric risk factors. Careful explication of these metabolic contributors may be key to developing effective and enduring treatments for devastating, life-altering, and frequently lethal illnesses. We discuss clinical phenomenology, genomics, phenomics, intestinal microbiota, and functional genomics and propose a path that translates variants to genes, genes to pathways, and pathways to metabolic outcomes to advance the science and eventually treatment of FEDs.
Abstract
Trauma is ubiquitous, but only a subset of those who experience trauma will develop posttraumatic stress disorder (PTSD). In this review, it is argued that to determine who is at risk of ...developing PTSD, it is critical to examine the genetic etiology of the disorder and individual trauma profiles of those who are susceptible. First, the state of current PTSD genetic research is described, with a particular focus on studies that present evidence for trauma type specificity, or for differential genetic etiology according to gender or race. Next, approaches that leverage non‐traditional phenotyping approaches are reviewed to identify PTSD‐associated variants and biology, and the relative advantages and limitations inherent in these studies are reflected on. Finally, it is discussed how trauma might influence the heritability of PTSD, through type, risk factors, genetics, and associations with PTSD symptomology.
Adjustment for confounding sources of expression variation is an important preprocessing step in large gene expression studies, but the effect of confound adjustment on co-expression network analysis ...has not been well-characterized. Here, we demonstrate that the choice of confound adjustment method can have a considerable effect on the architecture of the resulting co-expression network. We compare standard and alternative confound adjustment methods and provide recommendations for their use in the construction of gene co-expression networks from bulk tissue RNA-seq datasets.
Objective:Individuals at high risk for schizophrenia may benefit from early intervention, but few validated risk predictors are available. Genetic profiling is one approach to risk stratification ...that has been extensively validated in research cohorts. The authors sought to test the utility of this approach in clinical settings and to evaluate the broader health consequences of high genetic risk for schizophrenia.Methods:The authors used electronic health records for 106,160 patients from four health care systems to evaluate the penetrance and pleiotropy of genetic risk for schizophrenia. Polygenic risk scores (PRSs) for schizophrenia were calculated from summary statistics and tested for association with 1,359 disease categories, including schizophrenia and psychosis, in phenome-wide association studies. Effects were combined through meta-analysis across sites.Results:PRSs were robustly associated with schizophrenia (odds ratio per standard deviation increase in PRS, 1.55; 95% CI=1.4, 1.7), and patients in the highest risk decile of the PRS distribution had up to 4.6-fold higher odds of schizophrenia compared with those in the bottom decile (95% CI=2.9, 7.3). PRSs were also positively associated with other phenotypes, including anxiety, mood, substance use, neurological, and personality disorders, as well as suicidal behavior, memory loss, and urinary syndromes; they were inversely related to obesity.Conclusions:The study demonstrates that an available measure of genetic risk for schizophrenia is robustly associated with schizophrenia in health care settings and has pleiotropic effects on related psychiatric disorders as well as other medical syndromes. The results provide an initial indication of the opportunities and limitations that may arise with the future application of PRS testing in health care systems.
Purpose of Review
Following a life-threatening traumatic exposure, about 10% of those exposed are at considerable risk for developing posttraumatic stress disorder (PTSD), a severe and disabling ...syndrome characterized by uncontrollable intrusive memories, nightmares, avoidance behaviors, and hyperarousal in addition to impaired cognition and negative emotion symptoms. This review will explore recent genetic and epigenetic approaches to PTSD that explain some of the differential risk following trauma exposure.
Recent Findings
A substantial portion of the variance explaining differential risk responses to trauma exposure may be explained by differential inherited and acquired genetic and epigenetic risk. This biological risk is complemented by alterations in the functional regulation of genes via environmentally induced epigenetic changes, including prior childhood and adult trauma exposure.
Summary
This review will cover recent findings from large-scale genome-wide association studies as well as newer epigenome-wide studies. We will also discuss future “phenome-wide” studies utilizing electronic medical records as well as targeted genetic studies focusing on mechanistic ways in which specific genetic or epigenetic alterations regulate the biological risk for PTSD.
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