scholarly journals Sites of active gene regulation in the prenatal frontal cortex and their role in neuropsychiatric disorders

2021 ◽  
Author(s):  
Manuela R. Kouakou ◽  
Darren Cameron ◽  
Eilis Hannon ◽  
Emma L. Dempster ◽  
Jonathan Mill ◽  
...  
Keyword(s):  
Gene Regulation ◽  
Major Depressive Disorder ◽  
Genetic Variation ◽  
Frontal Cortex ◽  
Fetal Brain ◽  
Neuropsychiatric Disorders ◽  
Open Chromatin ◽  
Major Depressive ◽  
Genomic Regions ◽  
Neuropsychiatric Conditions

Common genetic variation appears to largely influence risk for neuropsychiatric disorders through effects on gene regulation. It is therefore possible to shed light on the biology of these conditions by testing for enrichment of associated genetic variation within regulatory genomic regions operating in specific tissues or cell types. Here, we have used ATAC-Seq to map open chromatin (an index of active regulatory genomic regions) in bulk tissue, NeuN+ and NeuN- nuclei from the prenatal human frontal cortex, and tested enrichment of SNP heritability for 5 neuropsychiatric disorders (autism spectrum disorder, ADHD, bipolar disorder, major depressive disorder and schizophrenia) within these regions. We observed significant enrichment of SNP heritability for ADHD, major depressive disorder and schizophrenia within open chromatin regions mapped in bulk fetal frontal cortex, and for all 5 tested neuropsychiatric conditions when we restricted these sites to those overlapping histone modifications indicative of enhancers (H3K4me1) or promoters (H3K4me3) in fetal brain. SNP heritability for neuropsychiatric disorders was significantly enriched in open chromatin regions identified in fetal frontal cortex NeuN- as well as NeuN+ nuclei overlapping fetal brain H3K4me1 or H3K4me3 sites. We additionally demonstrate the utility of our mapped open chromatin regions for prioritizing potentially functional SNPs at genome-wide significant risk loci for neuropsychiatric disorders. Our data provide evidence for an early neurodevelopmental component to a range of neuropsychiatric conditions and highlight an important role for regulatory genomic regions active within both NeuN+ and NeuN- cells of the prenatal brain.

scholarly journals Investigating regions of shared genetic variation in attention deficit/hyperactivity disorder and major depressive disorder: a GWAS meta-analysis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Victoria Powell ◽  
Joanna Martin ◽  
Anita Thapar ◽  
Frances Rice ◽  
Richard J. L. Anney
Keyword(s):  
Attention Deficit Hyperactivity Disorder ◽  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
Genetic Correlation ◽  
Attention Deficit ◽  
Meta Analysis ◽  
Major Depressive ◽  
Hyperactivity Disorder ◽  
High Level ◽  
Genomic Regions

AbstractAttention deficit/hyperactivity disorder (ADHD) demonstrates a high level of comorbidity with major depressive disorder (MDD). One possible contributor to this is that the two disorders show high genetic correlation. However, the specific regions of the genome that may be responsible for this overlap are unclear. To identify variants associated with both ADHD and MDD, we performed a meta-analysis of GWAS of ADHD and MDD. All genome wide significant (p < 5 × 10–8) SNPs in the meta-analysis that were also strongly associated (p < 5 × 10–4) independently with each disorder were followed up. These putatively pleiotropic SNPs were tested for additional associations across a broad range of phenotypes. Fourteen linkage disequilibrium-independent SNPs were associated with each disorder separately (p < 5 × 10–4) and in the cross-disorder meta-analysis (p < 5 × 10–8). Nine of these SNPs had not been highlighted previously in either individual GWAS. Evidence supported nine of the fourteen SNPs acting as eQTL and two as brain eQTL. Index SNPs and their genomic regions demonstrated associations with other mental health phenotypes. Through conducting meta-analysis on ADHD and MDD only, our results build upon the previously observed genetic correlation between ADHD and MDD and reveal novel genomic regions that may be implicated in this overlap.

Genetic variation inIL-1β, IL-2, IL-6, TSPOandBDNFand response to duloxetine or placebo treatment in major depressive disorder

2015 ◽  
Vol 16 (17) ◽  
pp. 1919-1929 ◽  
Author(s):  
Malgorzata Maciukiewicz ◽  
Victoria S Marshe ◽  
Arun K Tiwari ◽  
Trehani M Fonseka ◽  
Natalie Freeman ◽  
...  
Keyword(s):  
Major Depressive Disorder ◽  
Genetic Variation ◽  
Depressive Disorder ◽  
Placebo Treatment ◽  
Major Depressive

scholarly journals Characteristics of Neuropsychiatric Mobile Health Trials: Cross-Sectional Analysis of Studies Registered on ClinicalTrials.gov

10.2196/16180 ◽  
2020 ◽  
Vol 8 (8) ◽  
pp. e16180
Author(s):  
Mia Tova Minen ◽  
Julia Frederica Reichel ◽  
Pallavi Pemmireddy ◽  
Elizabeth Loder ◽  
John Torous
Keyword(s):  
Substance Use ◽  
Major Depressive Disorder ◽  
Alzheimer Disease ◽  
Depressive Disorder ◽  
Alcohol Use Disorders ◽  
Opioid Use ◽  
Major Depressive ◽  
High Burden ◽  
Opioid Use Disorders ◽  
Neuropsychiatric Conditions

Background The development of mobile health (mHealth) technologies is progressing at a faster pace than that of the science to evaluate their validity and efficacy. Under the International Committee of Journal Medical Editors (ICMJE) guidelines, clinical trials that prospectively assign people to interventions should be registered with a database before the initiation of the study. Objective The aim of this study was to better understand the smartphone mHealth trials for high-burden neuropsychiatric conditions registered on ClinicalTrials.gov through November 2018, including the number, types, and characteristics of the studies being conducted; the frequency and timing of any outcome changes; and the reporting of results. Methods We conducted a systematic search of ClinicalTrials.gov for the top 10 most disabling neuropsychiatric conditions and prespecified terms related to mHealth. According to the 2016 World Health Organization Global Burden of Disease Study, the top 10 most disabling neuropsychiatric conditions are (1) stroke, (2) migraine, (3) major depressive disorder, (4) Alzheimer disease and other dementias, (5) anxiety disorders, (6) alcohol use disorders, (7) opioid use disorders, (8) epilepsy, (9) schizophrenia, and (10) other mental and substance use disorders. There were no date, location, or status restrictions. Results Our search identified 135 studies. A total of 28.9% (39/135) of studies evaluated interventions for major depressive disorder, 14.1% (19/135) of studies evaluated interventions for alcohol use disorders, 12.6% (17/135) of studies evaluated interventions for stroke, 11.1% (15/135) of studies evaluated interventions for schizophrenia, 8.1% (11/135) of studies evaluated interventions for anxiety disorders, 8.1% (11/135) of studies evaluated interventions for other mental and substance use disorders, 7.4% (10/135) of studies evaluated interventions for opioid use disorders, 3.7% (5/135) of studies evaluated interventions for Alzheimer disease or other dementias, 3.0% (4/135) of studies evaluated interventions for epilepsy, and 3.0% (4/135) of studies evaluated interventions for migraine. The studies were first registered in 2008; more than half of the studies were registered from 2016 to 2018. A total of 18.5% (25/135) of trials had results reported in some publicly accessible location. Across all the studies, the mean estimated enrollment (reported by the study) was 1078, although the median was only 100. In addition, across all the studies, the actual reported enrollment was lower, with a mean of 249 and a median of 80. Only about a quarter of the studies (35/135, 25.9%) were funded by the National Institutes of Health. Conclusions Despite the increasing use of health-based technologies, this analysis of ClinicalTrials.gov suggests that only a few apps for high-burden neuropsychiatric conditions are being clinically evaluated in trials.

scholarly journals SNP and Haplotype Regional Heritability Mapping (SNHap-RHM): joint mapping of common and rare variation affecting complex traits

2021 ◽  
Author(s):  
Richard F Oppong ◽  
Pau Navarro ◽  
Chris S Haley ◽  
Sara Knott
Keyword(s):  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
Complex Traits ◽  
Health Study ◽  
P Value ◽  
Major Depressive ◽  
Genome Wide ◽  
A Genome ◽  
Joint Mapping ◽  
Genomic Regions

We describe a genome-wide analytical approach, SNP and Haplotype Regional Heritability Mapping (SNHap-RHM), that provides regional estimates of the heritability across locally defined regions in the genome. This approach utilises relationship matrices that are based on sharing of SNP and haplotype alleles at local haplotype blocks delimited by recombination boundaries in the genome. We implemented the approach on simulated data and show that the haplotype-based regional GRMs capture variation that is complementary to that captured by SNP-based regional GRMs, and thus justifying the fitting of the two GRMs jointly in a single analysis (SNHap-RHM). SNHap-RHM captures regions in the genome contributing to the phenotypic variation that existing genome-wide analysis methods may fail to capture. We further demonstrate that there are real benefits to be gained from this approach by applying it to real data from about 20,000 individuals from the Generation Scotland: Scottish Family Health Study. We analysed height and major depressive disorder (MDD). We identified seven genomic regions that are genome-wide significant for height, and three regions significant at a suggestive threshold (p-value <1x10^(-5) ) for MDD. These significant regions have genes mapped to within 400kb of them. The genes mapped for height have been reported to be associated with height in humans, whiles those mapped for MDD have been reported to be associated with major depressive disorder and other psychiatry phenotypes. The results show that SNHap-RHM presents an exciting new opportunity to analyse complex traits by allowing the joint mapping of novel genomic regions tagged by either SNPs or haplotypes, potentially leading to the recovery of some of the "missing" heritability.

scholarly journals Commentary on the study of Roy et al. Amygdala Based Altered mir-128-3p in Conferring Susceptibility to Depression-like Behavior via Wnt Signalling

2020 ◽  
Vol 23 (3) ◽  
pp. 178-180
Author(s):  
Gianluca Serafini ◽  
Alice Trabucco ◽  
Andrea Amerio ◽  
Andrea Aguglia ◽  
Mario Amore
Keyword(s):  
Gene Expression ◽  
Major Depressive Disorder ◽  
Affective Disorders ◽  
Basic Research ◽  
Biological Complexity ◽  
Methodological Issues ◽  
Major Depressive ◽  
Research Findings ◽  
Neuropsychiatric Conditions

Abstract The study of Roy and colleagues recently accepted for publication in International Journal of Neuropsychopharmacology is a very interesting report investigating the role of specific microRNAs (miRNAs) in vulnerability or resistance to major depressive disorder in a specific brain region (e.g., amygdala). MiRNAs may act as a mega-controller of gene expression being involved in the pathogenesis of major neuropsychiatric conditions. Interestingly, some of the altered miRNAs (e.g., hsa-miR-425-3p, miR-425, miR-674-3p, and miR-873-3p) identified in this study were found to be dysregulated even in existing studies, but several methodological issues may hamper the translation of basic research findings in clinical studies. MiRNAs are proposed as possible biomarkers of disease and treatment response to disentangle the biological complexity underlying major affective disorders. The main implications regarding the present findings are discussed.

scholarly journals Regionally specific alterations in functional connectivity of the anterior cingulate cortex in major depressive disorder

2012 ◽  
Vol 42 (10) ◽  
pp. 2071-2081 ◽  
Author(s):  
C. G. Davey ◽  
B. J. Harrison ◽  
M. Yücel ◽  
N. B. Allen
Keyword(s):  
Major Depressive Disorder ◽  
Functional Connectivity ◽  
Depressive Disorder ◽  
Frontal Cortex ◽  
Caudate Nucleus ◽  
Anterior Cingulate Cortex ◽  
Cingulate Cortex ◽  
Anterior Cingulate ◽  
Major Depressive ◽  
Close Link

BackgroundDepression has been associated with functional alterations in several areas of the cingulate cortex. In this study we have taken a systematic approach to examining how alterations in functional connectivity vary across the functionally diverse subregions of the rostral cingulate cortex.MethodEighteen patients with major depressive disorder, aged 15 to 24 years, were matched with 20 healthy control participants. Using resting-state functional connectivity magnetic resonance imaging (fcMRI), we systematically investigated the functional connectivity of four subregions of the rostral cingulate cortex. Voxelwise statistical maps of each subregion's connectivity with other brain areas were compared between the patient and control groups.ResultsThe depressed participants showed altered patterns of connectivity with ventral cingulate subregions. They showed increased connectivity between subgenual anterior cingulate cortex (ACC) and dorsomedial frontal cortex, with connectivity strength showing positive correlation with illness severity. Depressed participants also showed increased connectivity between pregenual ACC and left dorsolateral frontal cortex, and decreased connectivity between pregenual ACC and the caudate nucleus bilaterally.ConclusionsThe results reinforce the importance of subgenual ACC for depression, and show a close link between brain regions that support self-related processes and affective visceromotor function. The pregenual ACC also has an important role, with its increased connectivity with dorsolateral frontal cortex suggesting heightened cognitive regulation of affect; and reduced connectivity with the caudate nucleus potentially underlying symptoms such as anhedonia, reduced motivation and psychomotor dysfunction.

scholarly journals HPA Axis in the Pathomechanism of Depression and Schizophrenia: New Therapeutic Strategies Based on Its Participation

2021 ◽  
Vol 11 (10) ◽  
pp. 1298
Author(s):  
Joanna Mikulska ◽  
Gabriela Juszczyk ◽  
Monika Gawrońska-Grzywacz ◽  
Mariola Herbet
Keyword(s):  
Major Depressive Disorder ◽  
Major Depression ◽  
Gut Microbiota ◽  
Hpa Axis ◽  
Neuropsychiatric Disorders ◽  
Therapeutic Strategies ◽  
Major Depressive ◽  
V1b Receptor ◽  
Severity Of The Disease ◽  
Hpa Axis Activity

The hypothalamic-pituitary-adrenal (HPA) axis is involved in the pathophysiology of many neuropsychiatric disorders. Increased HPA axis activity can be observed during chronic stress, which plays a key role in the pathophysiology of depression. Overactivity of the HPA axis occurs in major depressive disorder (MDD), leading to cognitive dysfunction and reduced mood. There is also a correlation between the HPA axis activation and gut microbiota, which has a significant impact on the development of MDD. It is believed that the gut microbiota can influence the HPA axis function through the activity of cytokines, prostaglandins, or bacterial antigens of various microbial species. The activity of the HPA axis in schizophrenia varies and depends mainly on the severity of the disease. This review summarizes the involvement of the HPA axis in the pathogenesis of neuropsychiatric disorders, focusing on major depression and schizophrenia, and highlights a possible correlation between these conditions. Although many effective antidepressants are available, a large proportion of patients do not respond to initial treatment. This review also discusses new therapeutic strategies that affect the HPA axis, such as glucocorticoid receptor (GR) antagonists, vasopressin V1B receptor antagonists and non-psychoactive CB1 receptor agonists in depression and/or schizophrenia.

scholarly journals Associations between gut microbiota and Alzheimer’s disease, major depressive disorder, and schizophrenia

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Zhenhuang Zhuang ◽  
Ruotong Yang ◽  
Wenxiu Wang ◽  
Lu Qi ◽  
Tao Huang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Major Depressive Disorder ◽  
Gut Microbiota ◽  
Depressive Disorder ◽  
Lower Risk ◽  
Neuropsychiatric Disorders ◽  
Microbiota Composition ◽  
Major Depressive ◽  
Gut Microbiota Composition

Abstract Background Growing evidence has shown that alterations in the gut microbiota composition were associated with a variety of neuropsychiatric conditions. However, whether such associations reflect causality remains unknown. We aimed to reveal the causal relationships among gut microbiota, metabolites, and neuropsychiatric disorders including Alzheimer’s disease (AD), major depressive disorder (MDD), and schizophrenia (SCZ). Methods A two-sample bi-directional Mendelian randomization analysis was performed by using genetic variants from genome-wide association studies as instrumental variables for gut microbiota, metabolites, AD, MDD, and SCZ, respectively. Results We found suggestive associations of host-genetic-driven increase in Blautia (OR, 0.88; 95%CI, 0.79–0.99; P = 0.028) and elevated γ-aminobutyric acid (GABA) (0.96; 0.92–1.00; P = 0.034), a downstream product of Blautia-dependent arginine metabolism, with a lower risk of AD. Genetically increased Enterobacteriaceae family and Enterobacteriales order were potentially associated with a higher risk of SCZ (1.09; 1.00–1.18; P = 0.048), while Gammaproteobacteria class (0.90; 0.83–0.98; P = 0.011) was related to a lower risk for SCZ. Gut production of serotonin was potentially associated with an increased risk of SCZ (1.07; 1.00–1.15; P = 0.047). Furthermore, genetically increased Bacilli class was related to a higher risk of MDD (1.07; 1.02–1.12; P = 0.010). In the other direction, neuropsychiatric disorders altered gut microbiota composition. Conclusions These data for the first time provide evidence of potential causal links between gut microbiome and AD, MDD, and SCZ. GABA and serotonin may play an important role in gut microbiota-host crosstalk in AD and SCZ, respectively. Further investigations in understanding the underlying mechanisms of associations between gut microbiota and AD, MDD, and SCZ are required.

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