Neurogenetic and multi‐omic sources of overlap among sensation seeking, alcohol consumption, and alcohol use disorder

Addiction Biology, Journal Year: 2024, Volume and Issue: 29(2)

Published: Jan. 29, 2024

Sensation seeking is bidirectionally associated with levels of alcohol consumption in both adult and adolescent samples, shared neurobiological genetic influences may part explain these associations. Links between sensation use disorder (AUD) primarily manifest via increased rather than through direct effects on increasing problems consequences. Here the overlap among seeking, consumption, AUD was examined using multivariate modelling approaches for genome-wide association study (GWAS) summary statistics conjunction neurobiologically informed analyses at multiple investigation. Meta-analytic genomic structural equation (GenomicSEM) were used to conduct GWAS AUD. Resulting downstream examine brain tissue enrichment heritability evidence (e.g., stratified GenomicSEM, RRHO, correlations neuroimaging phenotypes), identify regions likely contributing observed across traits H-MAGMA LAVA). Across approaches, results supported neurogenetic architecture characterised by overlapping genes expressed midbrain striatal tissues variants cortical surface area. Alcohol evidenced relation decreased frontocortical thickness. Finally, mediation models provided mediating associations This extends previous research examining critical sources multi-omic which underlie phenotypic

Language: Английский

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Genetic Loci Influencing Cue‐Reactivity in Heterogeneous Stock Rats

Genes Brain & Behavior, Journal Year: 2025, Volume and Issue: 24(2)

Published: March 6, 2025

Addiction vulnerability is associated with the tendency to attribute incentive salience reward predictive cues. Both addiction and attribution of are influenced by environmental genetic factors. To characterize contributions attribution, we performed a genome-wide association study (GWAS) in cohort 1596 heterogeneous stock (HS) rats. Rats underwent Pavlovian conditioned approach task that characterized responses food-associated stimuli ("cues"). Responses ranged from cue-directed "sign-tracking" behavior food-cup directed "goal-tracking" (12 measures, SNP heritability: 0.051-0.215). Next, rats novel operant for unrewarded presentations cue using reinforcement procedure. GWAS identified 14 quantitative trait loci (QTLs) 11 12 traits across both tasks. Interval sizes these QTLs varied widely. Seven shared QTL on chromosome 1 contained few genes (e.g., Tenm4, Mir708) have been substance use disorders other psychiatric humans. Other candidate Wnt11, Pak1) this region had coding variants expression-QTLs mesocorticolimbic regions brain. We also conducted Phenome-Wide Association Study (PheWAS) addiction-related behaviors HS found was nicotine self-administration separate These results provide starting point molecular dissection motivational processes further support relationship between drug abuse-related traits.

Language: Английский

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The Genetically Informed Neurobiology of Addiction (GINA) model

Nature reviews. Neuroscience, Journal Year: 2022, Volume and Issue: 24(1), P. 40 - 57

Published: Nov. 29, 2022

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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Genome-wide association studies of coffee intake in UK/US participants of European ancestry uncover cohort-specific genetic associations

Neuropsychopharmacology, Journal Year: 2024, Volume and Issue: 49(10), P. 1609 - 1618

Published: June 11, 2024

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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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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Impulsivity facets and substance use involvement: insights from genomic structural equation modeling

Psychological Medicine, Journal Year: 2025, Volume and Issue: 55

Published: Jan. 1, 2025

Abstract Background Impulsivity is a multidimensional trait associated with substance use disorders (SUDs), but the relationship between distinct impulsivity facets and stages of involvement remains unclear. Methods We used genomic structural equation modeling genome-wide association studies ( N = 79,729–903,147) to examine latent genetic architecture nine traits seven (SU) SUD traits. Results found that SU factors were strongly genetically inter-correlated r G =0.77) their associations differed. Lack premeditation, negative positive urgency equally positively correlated both =.0.30–0.50) 0.38–0.46) factors; sensation seeking was more factor =0.27 versus =0.10); delay discounting =0.31 =0.21); lack perseverance only weakly =0.10). After controlling for correlation SU/SUD, we premeditation independently (β=0.42) (β=0.21); (β=0.48, β=0.33, respectively); (β=0.33, β=0.36, respectively). Conclusions Our findings show specific confer risk involvement, potential implications SUDs prevention treatment.

Language: Английский

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Genetic Propensity for Delay Discounting and Educational Attainment in Adults Are Associated With Delay Discounting in Preadolescents: Findings From the Adolescent Brain Cognitive Development Study

Genes Brain & Behavior, Journal Year: 2025, Volume and Issue: 24(2)

Published: March 27, 2025

Higher delay discounting (DD) (i.e., propensity to devalue larger, delayed rewards over immediate, smaller rewards) is a transdiagnostic marker underpinning multiple health behaviors. Although genetic influences account for some of the variability in DD among adults, less known about contributors preadolescents. We examined whether polygenic scores (PGS) DD, educational attainment, and behavioral traits impulsivity, inhibition, externalizing behavior) were associated with phenotypic Participants included youth (N = 8982, 53% male) from Adolescent Brain Cognitive Development Study who completed an Adjusting Delay Discounting Task at 1-year follow-up had valid data. PGS behaviors created based on largest GWAS available. Separate linear mixed effects models conducted individuals most genetically similar European (EUR; n 4972), African (AFR; 1769), Admixed American (AMR; 2241) reference panels. After adjusting age, sex, income, top ten ancestry principal components, greater lower attainment (but not or externalizing) higher rates preference sooner, participants EUR Findings provide insight into influence tendencies preadolescents, particularly those samples, thereby advancing our understanding etiology choice this population.

Language: Английский

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