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

---

Genome-wide association study of problematic opioid prescription use in 132,113 23andMe research participants of European ancestry

Molecular Psychiatry, Journal Year: 2021, Volume and Issue: 26(11), P. 6209 - 6217

Published: Nov. 1, 2021

Abstract The growing prevalence of opioid use disorder (OUD) constitutes an urgent health crisis. Ample evidence indicates that risk for OUD is heritable. As a surrogate (or proxy) OUD, we explored the genetic basis using prescription opioids ‘not as prescribed’. We hypothesized misuse opiates might be heritable factor OUD. To test this hypothesis, performed genome-wide association study (GWAS) problematic (POU) in 23andMe research participants European ancestry ( N = 132,113; 21% cases). identified two significant loci (rs3791033, intronic variant KDM4A ; rs640561, intergenic near LRRIQ3 ). POU showed positive correlations with largest available GWAS and dependence r g 0.64, 0.80, respectively). also numerous additional POU, including alcohol 0.74), smoking initiation 0.63), pain relief medication intake 0.49), major depressive 0.44), chronic 0.42), insomnia 0.39), loneliness 0.28). Although was positively genetically correlated risk-taking 0.38), conditioning on did not substantially alter magnitude or direction these correlations, suggesting does simply reflect tendency towards risky behavior. Lastly, phenome- lab-wide analyses, which uncovered phenotypes were associated respiratory failure, insomnia, ischemic heart disease, metabolic blood-related biomarkers. conclude can measured population-based cohorts provides cost-effective complementary strategy understanding

Language: Английский

---

Genetics of substance use disorders: a review

Psychological Medicine, Journal Year: 2021, Volume and Issue: 51(13), P. 2189 - 2200

Published: April 21, 2021

Substance use disorders (SUDs) are prevalent and result in an array of negative consequences. They influenced by genetic factors (h2 = ~50%). Recent years have brought substantial progress our understanding the etiology SUDs related traits. The present review covers current state field for SUD genetics, including epidemiology SUDs, findings from first-generation genome-wide association studies (GWAS), cautions about translating GWAS to clinical settings, suggested prioritizations next wave genetics efforts. advances been facilitated assembly large samples, development state-of-the-art methods modeling aggregate effect variation. These confirmed that highly polygenic with many variants across genome conferring risk, vast majority which small effect. Downstream analyses enabled finer resolution architecture revealed insights into their relationship other psychiatric disorders. efforts also prioritized a closer examination non-uniform influences measures substance (e.g. consumption) problematic SUD). Additional highlights recent include robust confirmation loci alcohol metabolizing genes ADH1B ALDH2) affecting alcohol-related traits, within CHRNA5-CHRNA3-CHRNB4 gene cluster influencing nicotine-related Similar successes expected cannabis, opioid, cocaine as sample sizes approach those assembled nicotine.

Language: Английский

---

The relationship between cannabis and schizophrenia: a genetically informed perspective

Addiction, Journal Year: 2021, Volume and Issue: 116(11), P. 3227 - 3234

Published: May 6, 2021

Abstract Background and Aims While epidemiological studies support a role for heavy, high‐potency cannabis use on first‐episode psychosis, genetic models of causation suggest reverse causal effects schizophrenia liability. We estimated the relationship between disorder (CUD) (SCZ) tested whether liability CUD is causally associated with increased to SCZ while adjusting tobacco smoking. Design This study used summary statistics from published genome‐wide association (GWAS). genomic structural equation modeling, latent variable analysis, multivariable Mendelian randomization examine relationships CUD, ever‐use, ever‐smoked regularly, nicotine dependence SCZ, test SCZ. Setting Genome‐wide were previously as part international consortia. Participants Sample sizes GWAS in this ranged 161 405 357 806 individuals European ancestry. Measurements primary measurements, regularly included additional variables analyses. Findings Genetic was significantly [β = 0.29, 95% confidence interval (CI) 0.11, 0.46, P 0.001], even when accounting simultaneous predictors. found mixed evidence relationship, analysis finding no causality (genetic proportion −0.08, CI −0.40, 0.23, 0.87) but analyses suggesting significant, risk‐increasing effect (β 0.10, 0.02, 0.18, 0.02), risk factors (cannabis dependence). Conclusions appears be robustly schizophrenia, above beyond smoking schizophrenia.

Language: Английский

---

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

---

Multivariate genome-wide association meta-analysis of over 1 million subjects identifies loci underlying multiple substance use disorders

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: Jan. 12, 2022

Genetic liability to substance use disorders can be parsed into loci conferring general and substance-specific addiction risk. We report a multivariate genome-wide association study that disaggregates for problematic alcohol use, tobacco cannabis opioid in sample of 1,025,550 individuals European 92,630 African descent. Nineteen were significant the risk factor (addiction-rf), which showed high polygenicity. Across ancestries PDE4B was (among others), suggesting dopamine regulation as cross-trait vulnerability. The addiction-rf polygenic score associated with disorders, psychopathologies, somatic conditions, environments onset addictions. Substance-specific (9 alcohol, 32 tobacco, 5 cannabis, 1 opioids) included metabolic receptor genes. These findings provide insight genetic architecture disorder may leveraged treatment targets.

Language: Английский

---

Chromatin architecture in addiction circuitry identifies risk genes and potential biological mechanisms underlying cigarette smoking and alcohol use traits

Molecular Psychiatry, Journal Year: 2022, Volume and Issue: 27(7), P. 3085 - 3094

Published: April 14, 2022

Language: Английский

---

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

---

Estimating Addiction-Related Brain Connectivity by Prior-Embedding Graph Generative Adversarial Networks

IEEE Transactions on Cybernetics, Journal Year: 2024, Volume and Issue: 54(9), P. 5026 - 5039

Published: Feb. 7, 2024

The study of nicotine addiction mechanism is great significance in both withdrawal and brain science. detection addiction-related connectivity using functional magnetic resonance imaging (fMRI) a critical step this mechanism. However, it challenging to accurately estimate due the low-signal-to-noise ratio fMRI issue small sample size. In work, prior-embedding graph generative adversarial network (PG-GAN) proposed capture accurately. By designing dual-generator-based scheme, generator employed learn feature map connection, while reconstruction used for reconstruction. Moreover, bidirectional mapping designed maintain consistency distribution latent space so that can be estimated more model utilizes prior knowledge embeddings reduce search better understand Experimental results demonstrate effectiveness PG-GAN.

Language: Английский

---

Familial Risks and Proportions Describing Population Landscape of Familial Cancer

Cancers, Journal Year: 2021, Volume and Issue: 13(17), P. 4385 - 4385

Published: Aug. 30, 2021

Background: Familial cancer can be defined through the occurrence of same in two or more family members. We describe a nationwide landscape familial cancer, including its frequency and risk that it conveys, by using largest database world with complete structures medically confirmed cancers. Patients/methods: employed standardized incidence ratios (SIRs) to estimate risks for concordant among first-degree relatives Swedish Cancer Registry from years 1958 2016. Results: 20–84 year old population conferred affected parents siblings were about two-fold compared individuals unaffected relatives. For small intestinal, testicular, thyroid bone cancers Hodgkin disease, higher, five-to-eight-fold. Novel associations included adult bone, lip, pharyngeal, connective tissue found 13.2% families cancer; prostate proportion was 26.4%. High-risk accounted 6.6% all families. Discussion/Conclusion: history should exceedingly considered management, targeted genetic testing. major clustering, where testing may not feasible, medical behavioral intervention indicated patient their members, screening recommendations avoidance carcinogenic exposure.

Language: Английский

---