scholarly journals Pairwise genetic meta-analyses between schizophrenia and substance dependence phenotypes reveals novel association signals

2021 ◽  
Author(s):  
Laura A. Greco ◽  
William R. Reay ◽  
Christopher V. Dayas ◽  
Murray J. Cairns
Keyword(s):  
Substance Use ◽  
Molecular Mechanisms ◽  
Substance Dependence ◽  
System Development ◽  
Causal Effect ◽  
Meta Analysis ◽  
Nervous System Development ◽  
Cannabis Use ◽  
Individual Substance ◽  
Meta Analyses

AbstractAlmost half of individuals diagnosed with schizophrenia also present with a substance use disorder, however, little is known about potential molecular mechanisms underlying this comorbidity. We used genetic analyses to enhance our understanding of the molecular overlap between these conditions. Our analyses revealed a positive genetic correlation between schizophrenia and the following dependence phenotypes: alcohol (rg = 0.3685, SE = 0.0768, P = 1.61 × 10−06), cannabis use disorder (rg = 0.309, SE = 0.0332, P = 1.19 × 10−20) and nicotine dependence (rg = 0.1177, SE = 0.0436, P = 7.0 × 10-03), as well as lifetime cannabis use (rg = 0.234, SE = 0.0298, P = 3.73 × 10−15) and drinks per week (rg = 0.0688, SE = 0.0217, P = 1.5 × 10−03). We further constructed latent causal variable (LCV) models to test for partial genetic causality and found evidence for a potential causal relationship between alcohol dependence and schizophrenia (GCP = 0.6, SE = 0.22, P = 1.6 × 10−03). This putative causal effect with schizophrenia was not seen using a continuous phenotype of drinks consumed per week, suggesting that distinct molecular mechanisms underlying dependence are involved in the relationship between alcohol and schizophrenia. To localise the specific genetic overlap between schizophrenia and substance use disorders, we conducted a gene-based and gene-set pairwise meta-analysis between schizophrenia and each of the four individual substance dependence phenotypes in up to 790,806 individuals. These bivariate meta-analyses identified 44 associations not observed in the individual GWAS, including five shared genes that play a key role in early central nervous system development. These genes may play an important role in substance dependence in schizophrenia, and, as a result, could represent important targets for future treatment or early intervention, as comorbid substance dependence is associated with poor treatment adherence, greater chronicity and increased mortality.

scholarly journals Zebrafish Models of Autosomal Recessive Ataxias

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 836
Author(s):  
Ana Quelle-Regaldie ◽  
Daniel Sobrido-Cameán ◽  
Antón Barreiro-Iglesias ◽  
María Jesús Sobrido ◽  
Laura Sánchez
Keyword(s):  
Animal Models ◽  
Autosomal Recessive ◽  
Molecular Mechanisms ◽  
System Development ◽  
Rapid Development ◽  
Nervous System Development ◽  
Central Nervous System Development ◽  
Cellular Processes ◽  
Recessive Disorders

Autosomal recessive ataxias are much less well studied than autosomal dominant ataxias and there are no clearly defined systems to classify them. Autosomal recessive ataxias, which are characterized by neuronal and multisystemic features, have significant overlapping symptoms with other complex multisystemic recessive disorders. The generation of animal models of neurodegenerative disorders increases our knowledge of their cellular and molecular mechanisms and helps in the search for new therapies. Among animal models, the zebrafish, which shares 70% of its genome with humans, offer the advantages of being small in size and demonstrating rapid development, making them optimal for high throughput drug and genetic screening. Furthermore, embryo and larval transparency allows to visualize cellular processes and central nervous system development in vivo. In this review, we discuss the contributions of zebrafish models to the study of autosomal recessive ataxias characteristic phenotypes, behavior, and gene function, in addition to commenting on possible treatments found in these models. Most of the zebrafish models generated to date recapitulate the main features of recessive ataxias.

Effect of metabolites levels on type 2 diabetes mellitus and glycemic traits: a Mendelian randomization study

2021 ◽  
Author(s):  
Yue Sun ◽  
Ya-Ke Lu ◽  
Hao-Yu Gao ◽  
Yu-Xiang Yan
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Meta Analysis ◽  
Significance Level ◽  
Inverse Variance ◽  
Meta Analyses

Abstract Objective To assess the causal associations of plasma levels of metabolites with type 2 diabetes mellitus (T2DM) and glycemic traits. Methods Two-sample mendelian randomization (MR) was conducted to assess the causal associations. Genetic variants strongly associated with metabolites at genome-wide significance level (P < 5 × 10 −8) were selected from public GWAS, and SNPs of Outcomes were obtained from the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium for T2DM and from the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) for the fasting glucose, insulin and HbA1c. The Wald ratio and inverse-variance weighted methods were used for analyses, and MR-Egger was used for sensitivity analysis. Results The β estimates per 1 SD increasement of arachidonic acid (AA) level was 0.16 (95% CI: 0.078, 0.242; P<0.001). Genetic predisposition to higher plasma AA levels were associated with higher FG levels (β 0.10 [95%CI: 0.064, 0.134], P<0.001), higher HbA1c levels (β 0.04 [95%CI: 0.027, 0.061]) and lower FI levels (β -0.025 [95%CI: -0.047, -0.002], P=0.033). Besides, 2-hydroxybutyric acid (2-HBA) might have positive causal effect on glycemic traits. Conclusions Our findings suggest that AA and 2-HBA may have the causal associations on T2DM and glycemic traits. It is beneficial for clarifying the pathogenesis of T2DM, which would be valuable for early identification and prevention for T2DM.

scholarly journals Systems pathology analysis identifies neurodegenerative nature of age-related retinal diseases

2018 ◽  
Author(s):  
Tiina Öhman ◽  
Fitsum Tamene ◽  
Helka Göös ◽  
Sirpa Loukovaara ◽  
Markku Varjosalo
Keyword(s):  
Molecular Mechanisms ◽  
System Development ◽  
Fibrous Tissue ◽  
Nervous System Development ◽  
Public Health Issue ◽  
Retinal Diseases ◽  
Label Free ◽  
Systems Pathology ◽  
Age Related ◽  
Vitreoretinal Diseases

AbstractAging is a phenomenon associated with profound medical implications. Idiopathic epiretinal membrane (iEMR) and macular hole (MH) are the major vision-threatening vitreoretinal diseases affecting millions of aging people globally, making these conditions an important public health issue. The iERM is characterized by fibrous tissue developing on the surface of the macula, leading to biomechanical and biochemical macular damage. MH is a small breakage in the macula associated with many ocular conditions. Although several individual factors and pathways are suggested, a systems pathology level understanding of the molecular mechanisms underlying these disorders is lacking. Therefore, we performed mass spectrometry based label-free quantitative proteomics analysis of the vitreous proteomes from patients with iERM (n=26) and MH (n=21) to identify the key proteins as well as the multiple interconnected biochemical pathways contributing to the development of these diseases. We identified a total of 1014 unique proteins, of which many were linked to inflammation and complement cascade, revealing the inflammational processes in retinal diseases. Additionally, we detected a profound difference in proteomes of the iEMR and MH compared to the non-proliferative diabetic retinopathy. A large number of neuronal proteins were present at higher levels in iERM and MH vitreous, including neuronal adhesion molecules, nervous system development proteins and signalling molecules. This points toward the important role of neurodegeneration component in the pathogenesis of age-related vitreoretinal diseases. Despite of marked similarities, several unique vitreous proteins were identified in both iERM and MH conditions, providing a candidate targets for diagnostic and new therapeutic approaches. Identification of previously reported and novel proteins in human vitreous humor from patient with iERM and MH provide renewed understanding of the pathogenesis of age-related vitreoretinal diseases.

scholarly journals Adolescent Sport Participation and Symptoms of Anxiety and Depression: A Systematic Review and Meta-Analysis

2020 ◽  
Vol 42 (3) ◽  
pp. 201-218
Author(s):  
Michael J. Panza ◽  
Scott Graupensperger ◽  
Jennifer P. Agans ◽  
Isabelle Doré ◽  
Stewart A. Vella ◽  
...  
Keyword(s):  
Systematic Review ◽  
Sport Participation ◽  
Causal Effect ◽  
Meta Analysis ◽  
Effect Sizes ◽  
Anxiety And Depression ◽  
Organized Sport ◽  
Protective Environment ◽  
Meta Analyses ◽  
The Relationship

Sport may protect against symptoms of mental disorders that are increasingly prevalent among adolescents. This systematic review explores the relationship between adolescent organized sport participation and self-reported symptoms of anxiety and depression. From 9,955 records screened, 29 unique articles were selected that included 61 effect sizes and 122,056 participants. Effects were clustered into four categories based on the operationalization of sport involvement: absence or presence of involvement, frequency of involvement, volume of involvement, and duration of participation. Results from the random-effects meta-analyses indicated that symptoms of anxiety and depression were significantly lower among sport-involved adolescents than in those not involved in sport, although this effect size was small in magnitude. Meta-regression was used to identify how age and sex explained heterogeneity in effects. Although these results do not signify a causal effect, they do support theorizing that sport participation during adolescence may be a protective environment against anxiety and depressive symptoms.

Altered neural activities during response inhibition in adults with addiction: a voxel-wise meta-analysis

2021 ◽  
pp. 1-13
Author(s):  
Zeguo Qiu ◽  
Junjing Wang
Keyword(s):  
Response Inhibition ◽  
Substance Dependence ◽  
Brain Activity ◽  
Meta Analysis ◽  
Inferior Frontal Gyrus ◽  
Activity Patterns ◽  
Behavioral Addiction ◽  
Middle Temporal Gyrus ◽  
Precentral Gyrus ◽  
Meta Analyses

Abstract Background Previous literature has extensively investigated the brain activity during response inhibition in adults with addiction. Inconsistent results including both hyper- and hypo-activities in the fronto-parietal network (FPN) and the ventral attention network (VAN) have been found in adults with addictions, compared with healthy controls (HCs). Methods Voxel-wise meta-analyses of abnormal task-evoked regional activity were conducted for adults with substance dependence (SD) and behavioral addiction during response inhibition tasks to solve previous inconsistencies. Twenty-three functional magnetic resonance imaging studies including 479 substance users, 38 individuals with behavioral addiction and 494 HCs were identified. Results Compared with HCs, all addictions showed hypo-activities in regions within FPN (inferior frontal gyrus and supramarginal gyrus) and VAN (inferior frontal gyrus, middle temporal gyrus, temporal pole and insula), and hyper-activities in the cerebellum during response inhibition. SD subgroup showed almost the same activity patterns, with an additional hypoactivation of the precentral gyrus, compared with HCs. Stronger activation of the cerebellum was associated with longer addiction duration for adults with SD. We could not conduct meta-analytic investigations into the behavioral addiction subgroup due to the small number of datasets. Conclusion This meta-analysis revealed altered activation of FPN, VAN and the cerebellum in adults with addiction during response inhibition tasks using non-addiction-related stimuli. Although FPN and VAN showed lower activity, the cerebellum exhibited stronger activity. These results may help to understand the neural pathology of response inhibition in addiction.

scholarly journals Association between substance use disorder and polygenic liability to schizophrenia

2017 ◽  
Author(s):  
Sarah M. Hartz ◽  
Amy Horton ◽  
Mary Oehlert ◽  
Caitlin E. Carey ◽  
Arpana Agrawal ◽  
...  
Keyword(s):  
Substance Use ◽  
Substance Use Disorder ◽  
Meta Analysis ◽  
Risk Scores ◽  
Polygenic Risk Score ◽  
Individual Substance ◽  
Polygenic Risk ◽  
Genome Wide ◽  
Individual Dataset ◽  
Shared Genetic

AbstractBackgroundThere are high levels of comorbidity between schizophrenia and substance use disorder, but little is known about the genetic etiology of this comorbidity.MethodsHere, we test the hypothesis that shared genetic liability contributes to the high rates of comorbidity between schizophrenia and substance use disorder. To do this, polygenic risk scores for schizophrenia derived from a large meta-analysis by the Psychiatric Genomics Consortium were computed in three substance use disorder datasets: COGEND (ascertained for nicotine dependence n=918 cases, 988 controls), COGA (ascertained for alcohol dependence n=643 cases, 384 controls), and FSCD (ascertained for cocaine dependence n=210 cases, 317 controls). Phenotypes were harmonized across the three datasets and standardized analyses were performed. Genome-wide genotypes were imputed to 1000 Genomes reference panel.ResultsIn each individual dataset and in the mega-analysis, strong associations were observed between any substance use disorder diagnosis and the polygenic risk score for schizophrenia (mega-analysis pseudo R2 range 0.8%-3.7%, minimum p=4×10-23).ConclusionsThese results suggest that comorbidity between schizophrenia and substance use disorder is partially attributable to shared polygenic liability. This shared liability is most consistent with a general risk for substance use disorder rather than specific risks for individual substance use disorders and adds to increasing evidence of a blurred boundary between schizophrenia and substance use disorder.

scholarly journals Common and separable neural alterations in substance use disorders: evidence from coordinate-based meta-analyses of functional neuroimaging studies in human

2020 ◽  
Author(s):  
Benjamin Klugah-Brown ◽  
Xin Di ◽  
Jana Zweerings ◽  
Klaus Mathiak ◽  
Benjamin Becker ◽  
...  
Keyword(s):  
Substance Use ◽  
Substance Use Disorders ◽  
Cognitive Processes ◽  
Functional Neuroimaging ◽  
Meta Analysis ◽  
Treatment Strategies ◽  
Specific Treatment ◽  
Behavioral Alterations ◽  
Meta Analyses

AbstractDelineating common and separable neural alterations in substance use disorders (SUD) is imperative to understand the neurobiological basis of the addictive process and to inform substance-specific treatment strategies. Given numerous functional MRI (fMRI) studies in different SUDs, meta-analysis could provide an opportunity to determine robust shared and substance-specific alterations. The present study employed a coordinate-based meta-analysis covering fMRI studies in individuals with addictive cocaine, cannabis, alcohol, and nicotine use. The primary meta-analysis demonstrated common alterations in primary dorsal striatal, and frontal circuits engaged in reward/salience processing, habit formation, and executive control across different substances and task-paradigms. Subsequent sub-analyses revealed substance-specific alterations in frontal and limbic regions, with marked frontal and insula-thalamic alterations in alcohol and nicotine use disorders respectively. Finally, examining task-specific alterations across substances revealed pronounced frontal alterations during cognitive processes yet stronger striatal alterations during reward-related processes. Together the findings emphasize the role of dysregulations in striato-frontal circuits and dissociable contributions of these systems in the domains of reward-related and cognitive processes which may contribute to substance-specific behavioral alterations.

Cannabis use and transition to psychosis in individuals at ultra-high risk: review and meta-analysis

2015 ◽  
Vol 46 (4) ◽  
pp. 673-681 ◽  
Author(s):  
T. Kraan ◽  
E. Velthorst ◽  
L. Koenders ◽  
K. Zwaart ◽  
H. K. Ising ◽  
...  
Keyword(s):  
High Risk ◽  
Psychotic Disorders ◽  
Meta Analysis ◽  
Cannabis Use ◽  
Transition Rates ◽  
Cannabis Abuse ◽  
Ultra High Risk ◽  
Meta Analyses ◽  
Risk Review ◽  
The Relationship

BackgroundPrevious research has established the relationship between cannabis use and psychotic disorders. Whether cannabis use is related to transition to psychosis in patients at ultra-high risk (UHR) for psychosis remains unclear. The present study aimed to review the existing evidence on the association between cannabis use and transition to psychosis in UHR samples.MethodA search of PsychInfo, Embase and Medline was conducted from 1996 to August 2015. The search yielded 5559 potentially relevant articles that were selected on title and abstract. Subsequently 36 articles were screened on full text for eligibility. Two random-effects meta-analyses were performed. First, we compared transition rates to psychosis of UHR individuals with lifetime cannabis use with non-cannabis-using UHR individuals. Second, we compared transition rates of UHR individuals with a current DSM-IV cannabis abuse or dependence diagnosis with lifetime users and non-using UHR individuals.ResultsWe found seven prospective studies reporting on lifetime cannabis use in UHR subjects (n = 1171). Of these studies, five also examined current cannabis abuse or dependence. Lifetime cannabis use was not significantly associated with transition to psychosis [odds ratio (OR) 1.14, 95% confidence interval (CI) 0.856–1.524, p = 0.37]. A second meta-analysis yielded an OR of 1.75 (95% CI 1.135–2.710, p = 0.01), indicating a significant association between current cannabis abuse or dependence and transition to psychosis.ConclusionsOur results show that cannabis use was only predictive of transition to psychosis in those who met criteria for cannabis abuse or dependence, tentatively suggesting a dose–response relationship between current cannabis use and transition to psychosis.

Environment and Brain Plasticity: Towards an Endogenous Pharmacotherapy

2014 ◽  
Vol 94 (1) ◽  
pp. 189-234 ◽  
Author(s):  
Alessandro Sale ◽  
Nicoletta Berardi ◽  
Lamberto Maffei
Keyword(s):  
Environmental Enrichment ◽  
Molecular Mechanisms ◽  
Brain Plasticity ◽  
System Development ◽  
Basic Research ◽  
Nervous System Development ◽  
Adult Brain ◽  
Aging Brain ◽  
Cerebral Neurons ◽  
And Function

Brain plasticity refers to the remarkable property of cerebral neurons to change their structure and function in response to experience, a fundamental theoretical theme in the field of basic research and a major focus for neural rehabilitation following brain disease. While much of the early work on this topic was based on deprivation approaches relying on sensory experience reduction procedures, major advances have been recently obtained using the conceptually opposite paradigm of environmental enrichment, whereby an enhanced stimulation is provided at multiple cognitive, sensory, social, and motor levels. In this survey, we aim to review past and recent work concerning the influence exerted by the environment on brain plasticity processes, with special emphasis on the underlying cellular and molecular mechanisms and starting from experimental work on animal models to move to highly relevant work performed in humans. We will initiate introducing the concept of brain plasticity and describing classic paradigmatic examples to illustrate how changes at the level of neuronal properties can ultimately affect and direct key perceptual and behavioral outputs. Then, we describe the remarkable effects elicited by early stressful conditions, maternal care, and preweaning enrichment on central nervous system development, with a separate section focusing on neurodevelopmental disorders. A specific section is dedicated to the striking ability of environmental enrichment and physical exercise to empower adult brain plasticity. Finally, we analyze in the last section the ever-increasing available knowledge on the effects elicited by enriched living conditions on physiological and pathological aging brain processes.

scholarly journals Regulation of Gliogenesis by lin-32/Atoh1 in Caenorhabditis elegans

2020 ◽  
Vol 10 (9) ◽  
pp. 3271-3278 ◽  
Author(s):  
Albert Zhang ◽  
Kentaro Noma ◽  
Dong Yan
Keyword(s):  
Nervous System ◽  
Caenorhabditis Elegans ◽  
Embryonic Development ◽  
Molecular Mechanisms ◽  
System Development ◽  
Nervous System Development ◽  
Proneural Gene ◽  
C Elegans ◽  
Fundamental Process ◽  
Mutant Phenotypes

Abstract The regulation of gliogenesis is a fundamental process for nervous system development, as the appropriate glial number and identity is required for a functional nervous system. To investigate the molecular mechanisms involved in gliogenesis, we used C. elegans as a model and identified the function of the proneural gene lin-32/Atoh1 in gliogenesis. We found that lin-32 functions during embryonic development to negatively regulate the number of AMsh glia. The ectopic AMsh cells at least partially arise from cells originally fated to become CEPsh glia, suggesting that lin-32 is involved in the specification of specific glial subtypes. Moreover, we show that lin-32 acts in parallel with cnd-1/ NeuroD1 and ngn-1/ Neurog1 in negatively regulating an AMsh glia fate. Furthermore, expression of murine Atoh1 fully rescues lin-32 mutant phenotypes, suggesting lin-32/Atoh1 may have a conserved role in glial specification.

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