Systematic dissection of pleiotropic loci and critical regulons in excitatory neurons and microglia relevant to neuropsychiatric and ocular diseases

Translational Psychiatry, Journal Year: 2025, Volume and Issue: 15(1)

Published: Jan. 25, 2025

Advancements in single-cell multimodal techniques have greatly enhanced our understanding of disease-relevant loci identified through genome-wide association studies (GWASs). To investigate the biological connections between eye and brain, we integrated bulk multiomic profiles with GWAS summary statistics for eight neuropsychiatric five ocular diseases. Our analysis uncovered latent factors explaining 61.7% genetic variance across these 13 diseases, revealing diverse correlational patterns among them. We 45 pleiotropic 91 candidate genes that contribute to disease risk. By integrating profiles, implicated excitatory neurons microglia as key contributors eye-brain connections. Polygenic enrichment further 15 regulons 16 were linked comorbid conditions. Functionally, neuron-specific involved axon guidance synaptic activity, while microglia-specific associated immune response cell activation. In sum, findings underscore link psychiatric disorders

Language: Английский

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Multi-ancestral genome-wide association study of clinically defined nicotine dependence reveals strong genetic correlations with other substance use disorders and health-related traits.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 31, 2025

ABSTRACT Genetic research on nicotine dependence has utilized multiple assessments that are in weak agreement. We conducted a genome-wide association study of defined using the Diagnostic and Statistical Manual Mental Disorders (DSM-NicDep) 61,861 individuals (47,884 European ancestry, 10,231 African 3,746 East Asian ancestry) compared results to other nicotine-related phenotypes. replicated well-known at CHRNA5 locus (lead SNP: rs147144681, p =1.27E-11 ancestry; lead SNP = rs2036527, 6.49e-13 cross-ancestry analysis). DSM-NicDep showed strong positive genetic correlations with cannabis use disorder, opioid problematic alcohol use, lung cancer, material deprivation, several psychiatric disorders, negative respiratory function educational attainment. A polygenic score predicted DSM-5 tobacco disorder 6 11 individual diagnostic criteria, but none Fagerström Test for Nicotine Dependence (FTND) items, independent NESARC-III sample. In genomic structural equation models, loaded more strongly previously identified factor general addiction liability than did “problematic use” (a combination cigarettes per day by FTND). Finally, was genetically correlated GWAS as electronic health records, suggesting combining wide availability EHR data nuanced criterion-level analyses DSM may produce new insights into genetics this disorder.

Language: Английский

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Pleiotropy and genetically inferred causality linking multisite chronic pain to substance use disorders

Molecular Psychiatry, Journal Year: 2024, Volume and Issue: 29(7), P. 2021 - 2030

Published: Feb. 15, 2024

Language: Английский

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Genetic contribution to the comorbidity between attention-deficit/hyperactivity disorder and substance use disorders

Psychiatry Research, Journal Year: 2024, Volume and Issue: 333, P. 115758 - 115758

Published: Feb. 3, 2024

We characterized the genetic architecture of attention-deficit hyperactivity disorder-substance use disorder (ADHD-SUD) relationship by investigating correlation, causality, pleiotropy, and common polygenic risk. Summary statistics from genome-wide association studies (GWAS) were used to investigate ADHD (Neff=51,568), cannabis (CanUD, Neff=161,053), opioid (OUD, Neff=57,120), problematic alcohol (PAU, Neff=502,272), tobacco (PTU, Neff=97,836). ADHD, CanUD, OUD GWAS meta-analyses included cohorts with case definitions based on different diagnostic criteria. PAU combined information related disorder, dependence, items consequences assessed disorders identification test. PTU was generated a multi-trait analysis including regarding Fagerström Test for Nicotine Dependence cigarettes per day. Linkage disequilibrium score regression analyses indicated positive correlation OUD, PAU, PTU. Genomic structural equation modeling showed that these correlations two latent factors: one other PAU. had larger causal effect than reverse in two-sample Mendelian randomization analyses. Conversely, similar sizes found between CanUD. CADM2 rs62250713 pleiotropic SNP all SUDs. seven, one, twenty-eight variants PTU, respectively. Finally, PRS associated increased odds ADHD. Our findings demonstrated contribution multiple mechanisms comorbidity

Language: Английский

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Combining Transdiagnostic and Disorder-Level GWAS Enhances Precision of Psychiatric Genetic Risk Profiles in a Multi-Ancestry Sample

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: May 10, 2024

Abstract The etiology of substance use disorders (SUDs) and psychiatric reflects a combination both transdiagnostic (i.e., common) disorder-level independent) genetic risk factors. We applied genomic structural equation modeling to examine these factors across SUDs, psychotic, mood, anxiety using genome-wide association studies (GWAS) European-(EUR) African-ancestry (AFR) individuals. In EUR individuals, represented SUDs (143 lead single nucleotide polymorphisms [SNPs]), psychotic (162 SNPs), mood/anxiety (112 SNPs). identified two novel SNPs for that have probable regulatory roles on FOXP1 , NECTIN3 BTLA genes. AFR (1 SNP) (no significant SUD factor SNP, although previously in EUR- cross-ancestry GWAS, is finding Shared variance accounted overlap between their comorbidities, with second-order GWAS identifying up 12 not significantly associated either first-order Finally, common independent effects showed different associations psychiatric, sociodemographic, medical phenotypes. For example, the components schizophrenia bipolar disorder had distinct affective risk-taking behaviors, phenome-wide conditions tobacco broader factor. Thus, combining approaches can improve our understanding co-occurring increase specificity discovery, which critical demonstrate considerable symptom etiological overlap.

Language: Английский

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Genetic influences and causal pathways shared between cannabis use disorder and other substance use traits

Molecular Psychiatry, Journal Year: 2024, Volume and Issue: unknown

Published: April 5, 2024

Abstract Cannabis use disorder (CanUD) has increased with the legalization of cannabis. Around 20% individuals using cannabis develop CanUD, and number users grown increasing ease access. CanUD other substance disorders (SUDs) are associated phenotypically genetically. We leveraged new genomics data to undertake genetically-informed analyses unprecedented power, investigate genetic architecture causal relationships between lifetime risk for developing SUDs traits. Analyses included calculating local global correlations, genomic structural equation modeling (genomicSEM), Mendelian Randomization (MR). Results from correlation genomicSEM demonstrated that differ in their found significant effects influencing all analyzed traits: opioid (OUD) (Inverse variant weighted, IVW β = 0.925 ± 0.082), problematic alcohol (PAU) (IVW 0.443 0.030), drinks per week (DPW) 0.182 0.025), Fagerström Test Nicotine Dependence (FTND) 0.183 0.052), cigarettes day 0.150 0.045), current versus former smokers 0.178 smoking initiation 0.405 0.042). also evidence bidirectionality showing OUD, PAU, initiation, cessation, DPW increase CanUD. For use, bidirectional were inferred DPW; was a higher OUD 0.785 0.266). GenomicSEM confirmed load onto different factors. conclude can SUDs. This substantial public health implications; move towards may be expected kinds use. These harmful outcomes addition medical harms directly

Language: Английский

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Determining the diagnostic cut-off on the Chinese version of severity of dependence scale for cannabis

Frontiers in Psychiatry, Journal Year: 2025, Volume and Issue: 15

Published: Jan. 7, 2025

Cannabis use and misuse are surging among the Chinese community in East Southeast Asia. A quick screening instrument that can effectively identify users with dependence for early intervention is utmost need. This study examined psychometric properties of version Severity Dependence Scale cannabis (C-SDS-C) DSM-5 defined Use Disorder (CUD). retrospective chart review was conducted on Chinese-speaking individuals reporting from three different substance studies. Their demographic data, frequency within past 30 days, scorings C-SDS-C severity CUD at baseline were analyzed. The exhibited high reliability (Cronbach's alpha = 0.778). It had a strong correlation (r 0.456, p <.001) moderate days 0.335, .001). All items loaded into single factor which accounted 56.64% variance. Receiver operating characteristic analysis demonstrated cut-off score ≥ 3 provided optimal discrimination to severe using cannabis. valid reliable moderate-to-severe population.

Language: Английский

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Impulsivity behaviors and white matter mediate the relationship between genetic risk for cannabis use disorder and early cannabis use in adolescents

Addiction, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 10, 2025

Abstract Background and Aim Cannabis use disorder (CUD) is strongly influenced by genetic factors; however the mechanisms underpinning this association are not well understood. This study investigated whether a polygenic risk score (PRS) based on genome‐wide for CUD in adults predicts cannabis adolescents can be explained inter‐individual variation structural properties of brain white matter or risk‐taking behaviors. Design setting Longitudinal cross‐sectional analyses using data from IMAGEN cohort, European longitudinal integrating genetic, neuroimaging behavioral measures. We measured associations between PRS CUD, novelty sensation seeking traits fractional anisotropy (FA) tracts. Mediation modeling explored FA mediated use. Participants were assessed at 14 ( n = 1762), 19 1175) 23 1139) years old. Measurements School Survey Project Alcohol Other Drugs, substance profile scale, Fagerstrom Test Nicotine Dependence, temperament character inventory, Kirby Monetary Questionnaire, diffusor tensor imaging CUD‐PRS. Findings CUD‐PRS was associated with adolescent total exposure [ P < 0.001, beta 0.098 (95% confidence interval 0.059, 0.137)] as other measures [alcohol 0.002, 0.058 (0.020, 0.096); cigarettes smoked 0.086 (0.044, 0.128); fargestrom 0.062 (0.028, drug 0.106 (0.065, 0.147)]. also impulsivity, behaviors [impulsivity (0.060, 0.142); 0.094 (0.0523, 0.1357); 0.105 (0.064, 0.146); discounting task 0.051 (0.013, 0.089)] average −0.010 (−0.015, −0.005)]. mediation models showed that these could mediate [overall indirect effect 0.048 0.068); impulsivity 0.016, 0.019 (0.004, 0.035); 0.034 (0.017, 0.05)]. Conclusions The adult appears to behavior structure early age 14. observed consistent notion increases way leads more adolescents.

Language: Английский

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Cannabis Use Cessation and the Risk of Psychotic Disorders: A Case–Control Analysis from the First Episode Case–Control EU-GEI WP2 Study: L’arrêt de l’utilisation du cannabis et le risque de troubles psychotiques: Une analyse cas-témoins tirée de l’étude cas-témoins EU-GEI WP2 centrée sur les premiers épisodes psychotiques

The Canadian Journal of Psychiatry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 15, 2025

To establish whether the risk of psychotic disorders in cannabis users changes with time following cessation using data from European Network National Networks studying Gene-Environment Interactions Schizophrenia (EU-GEI) case-control study. The EU-GEI study collected first episode psychosis patients and population controls across sites Europe Brazil between May 2010 April 2015. Adjusted logistic regressions were applied to examine odd case status changed: (1) (2) different use groups. Psychosis declined (β = -0.002; 95% CI -0.004 0.000; P 0.067). When accounting for duration use, this effect remained -0.003; -0.005 -0.001; 0.013). However, models adjusting frequency potency result was not significant. Analysis groups indicated that ex-users who stopped 1 4 weeks previously had highest disorder compared never (OR 6.89; 3.91-12.14; < 0.001); those 5 12 2.70; 1.73-4.21; 0.001) 13 36 1.53; 1.00-2.33; 0.050). Ex-users 37 96 1.01; 0.66-1.57; 0.949), 97 180 0.73; 0.45-1.19; 0.204), 181 or more 1.18; 0.76-1.83; 0.456) similar never-used cannabis. Risk appears decline cessation, receding have used after abstinence. Although, preliminary results suggest frequent high types might maintain an elevated even when abstaining longer than weeks.

Language: Английский

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Integrating HiTOP and RDoC Frameworks Part II: Shared and Distinct Biological Mechanisms of Externalizing and Internalizing Psychopathology

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 6, 2025

Abstract Background The Hierarchical Taxonomy of Psychopathology (HiTOP) and Research Domain Criteria (RDoC) frameworks emphasize transdiagnostic mechanistic aspects psychopathology, respectively. We used a multi-omics approach to examine how externalizing (EXT), internalizing (INT), shared EXT+INT liability map onto these models. Methods conducted analyses across five RDoC units analysis: genes, molecules, cells, circuits, physiology. Using genome-wide association studies from the companion Part I article, we identified genes tissue-specific expression patterns. drug repurposing that integrate gene annotations identify potential therapeutic targets single-cell RNA sequencing data implicate brain cell types. then magnetic resonance imaging regions circuits associated with each psychopathology spectrum. Finally, tested causal relationships between spectrum physical health conditions. Results identification methods, EXT was 1,759 INT 454 1,138 genes. Drug targets, including those affect dopamine serotonin pathways. Expression enriched in GABAergic, cortical, hippocampal neurons, while were more narrowly linked GABAergic neurons. reduced gray matter volume amygdala subcallosal cortex. Mendelian randomization, showed stronger effects on health—including chronic pain cardiovascular diseases—than EXT. Conclusions Our findings revealed distinct pathways underlying psychopathology. Integrating genomic insights HiTOP advanced our understanding mechanisms underlie

Language: Английский

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