Genome-wide association study in individuals of European and African ancestry and multi-trait analysis of opioid use disorder identifies 19 independent genome-wide significant risk loci

Molecular Psychiatry, Journal Year: 2022, Volume and Issue: 27(10), P. 3970 - 3979

Published: July 25, 2022

Abstract Despite the large toll of opioid use disorder (OUD), genome-wide association studies (GWAS) OUD to date have yielded few susceptibility loci. We performed a large-scale GWAS in individuals European (EUR) and African (AFR) ancestry, optimizing genetic informativeness by performing MTAG (Multi-trait analysis GWAS) with genetically correlated substance disorders (SUDs). Meta-analysis included seven cohorts: Million Veteran Program, Psychiatric Genomics Consortium, iPSYCH, FinnGen, Partners Biobank, BioVU, Yale-Penn 3, resulting total N = 639,063 ( cases 20,686;N effective 77,026) across ancestries. were defined as having lifetime diagnosis, controls anyone not known meet criteria. estimated SNP-heritability (h 2 SNP ) correlations (r g ). Based on correlation, we OUD, alcohol (AUD), cannabis (CanUD). A leave-one-out polygenic risk score (PRS) was compare OUD-MTAG PRS predictors case status 3. The EUR meta-analysis identified three significant (GWS; p ≤ 5 × 10 − 8 lead SNPs—one at FURIN (rs11372849; 9.54 two OPRM1 variants (rs1799971, 4.92 09 ; rs79704991, 1.11 08 r 0.02). Rs1799971 (p 4.91 another variant (rs9478500; 1.95 0.03) cross-ancestry meta-analysis. Estimated h 12.75%, strong CanUD 0.82; 1.14 47 AUD 0.77; 6.36 78 resulted equivalent 128,748 18 independent GWS loci, some mapping genes or gene regions that previously been associated psychiatric addiction phenotypes. accounted for 3.81% variance (beta 0.61;s.e. 0.066; 2.00 16 compared 2.41% 0.45; s.e. 0.058; 2.90 13 explained PRS. current study associations , single OUD-MTAG. architecture is likely influenced both OUD-specific loci shared SUDs.

Language: Английский

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CADM2 is implicated in impulsive personality and numerous other traits by genome- and phenome-wide association studies in humans and mice

Translational Psychiatry, Journal Year: 2023, Volume and Issue: 13(1)

Published: May 12, 2023

Abstract Impulsivity is a multidimensional heritable phenotype that broadly refers to the tendency act prematurely and associated with multiple forms of psychopathology, including substance use disorders. We performed genome-wide association studies (GWAS) eight impulsive personality traits from Barratt Impulsiveness Scale short UPPS-P Impulsive Personality ( N = 123,509–133,517 23andMe research participants European ancestry), measure Drug Experimentation 130,684). Because these GWAS implicated gene CADM2 , we next single-SNP phenome-wide (PheWAS) several variants in multi-ancestral cohort 3,229,317, European; 579,623, Latin American; 199,663, African American). Finally, produced Cadm2 mutant mice used them perform Mouse-PheWAS (“MouseWAS”) by testing battery relevant behavioral tasks. In humans, showed modest chip-heritability (~6–11%), moderate genetic correlations r g 0.20–0.50) other traits, various psychiatric medical traits. identified significant associations proximal genes such as TCF4 PTPRF also nominal DRD2 CRHR1 . PheWAS for 378 participants, 47 American replicating risky behaviors, cognition BMI, revealing novel allergies, anxiety, irritable bowel syndrome, migraine. Our MouseWAS recapitulated some found impulsivity, cognition, BMI. results further delineate role impulsivity numerous somatic across ancestries species.

Language: Английский

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Multi-ancestry meta-analysis of tobacco use disorder identifies 461 potential risk genes and reveals associations with multiple health outcomes

Nature Human Behaviour, Journal Year: 2024, Volume and Issue: 8(6), P. 1177 - 1193

Published: April 17, 2024

Language: Английский

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Cross-ancestry meta-analysis of opioid use disorder uncovers novel loci with predominant effects in brain regions associated with addiction

Nature Neuroscience, Journal Year: 2022, Volume and Issue: 25(10), P. 1279 - 1287

Published: Sept. 28, 2022

Language: Английский

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Multi-trait genome-wide association study of opioid addiction: OPRM1 and beyond

Scientific Reports, Journal Year: 2022, Volume and Issue: 12(1)

Published: Oct. 7, 2022

Abstract Opioid addiction (OA) is moderately heritable, yet only rs1799971, the A118G variant in OPRM1 , has been identified as a genome-wide significant association with OA and independently replicated. We applied genomic structural equation modeling to conduct GWAS of new Genetics Addiction Consortium (GENOA) data together published studies (Psychiatric Genomics Consortium, Million Veteran Program, Partners Health), comprising 23,367 cases effective sample size 88,114 individuals European ancestry. Genetic correlations among various phenotypes were uniformly high (r g > 0.9). observed strongest evidence date for : lead SNP rs9478500 ( p = 2.56 × 10 –9 ). Gene-based analyses novel associations PPP6C FURIN . Variants within these loci appear be pleiotropic related traits.

Language: Английский

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Utility of Candidate Genes From an Algorithm Designed to Predict Genetic Risk for Opioid Use Disorder

JAMA Network Open, Journal Year: 2025, Volume and Issue: 8(1), P. e2453913 - e2453913

Published: Jan. 9, 2025

Importance Recently, the US Food and Drug Administration gave premarketing approval to an algorithm based on its purported ability identify individuals at genetic risk for opioid use disorder (OUD). However, clinical utility of candidate variants included in has not been independently demonstrated. Objective To assess 15 from intended predict OUD risk. Design, Setting, Participants This case-control study examined association with using electronic health record data December 20, 1992, September 30, 2022. Electronic data, including pharmacy records, were accrued participants Million Veteran Program across exposure (n = 452 664). Cases identified International Classification Diseases, Ninth Revision , or Tenth diagnostic codes, controls no diagnosis. Exposures Number alleles present variants. Main Outcome Measures Performance identifying assessed via logistic regression machine learning models. Results A total 664 (including 33 669 OUD) had a mean (SD) age 61.15 (13.37) years, 90.46% male; sample was ancestrally diverse (with genetically inferred European, African, admixed American ancestries). Using Nagelkerke R 2 collectively, genes accounted 0.40% variation In comparison, sex alone 3.27% variation. The ensemble learning. model as predictive factors correctly classified 52.83% (95% CI, 52.07%-53.59%) independent testing sample. Conclusions Relevance this suggest that approved do meet reasonable standards efficacy Given algorithm’s limited accuracy, care would lead high rates both false-positive false-negative findings. More clinically useful models are needed developing OUD.

Language: Английский

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Neuroimmune Mechanisms of Opioid Use Disorder and Recovery: Translatability to Human Studies, and Future Research Directions

Neuroscience, Journal Year: 2023, Volume and Issue: 528, P. 102 - 116

Published: Aug. 9, 2023

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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A Shared Genetic Signature for Common Chronic Pain Conditions and its Impact on Biopsychosocial Traits

Journal of Pain, Journal Year: 2022, Volume and Issue: 24(3), P. 369 - 386

Published: Oct. 14, 2022

Language: Английский

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3D genomic features across >50 diverse cell types reveal insights into the genomic architecture of childhood obesity

eLife, Journal Year: 2025, Volume and Issue: 13

Published: Jan. 15, 2025

The prevalence of childhood obesity is increasing worldwide, along with the associated common comorbidities type 2 diabetes and cardiovascular disease in later life. Motivated by evidence for a strong genetic component, our prior genome-wide association study (GWAS) efforts revealed 19 independent signals trait; however, mechanism action these loci remains to be elucidated. To molecularly characterize loci, we sought determine underlying causal variants corresponding effector genes within diverse cellular contexts. Integrating GWAS summary statistics existing 3D genomic datasets 57 human cell types, consisting high-resolution promoter-focused Capture-C/Hi-C, ATAC-seq, RNA-seq, applied stratified LD score regression calculated proportion SNP heritability attributable type-specific features, revealing pancreatic alpha enrichment as most statistically significant. Subsequent chromatin contact-based fine-mapping was carried out significant their linkage disequilibrium proxies implicate genes, yielded abundant number candidate target at BDNF , ADCY3 TMEM18, FTO skeletal muscle myotubes beta-cell line, EndoC-BH1. One novel implicated gene, ALKAL2 – an inflammation-responsive gene nerve nociceptors observed key TMEM18 locus across multiple immune types. Interestingly, this observation also supported through colocalization analysis using expression quantitative trait (eQTL) derived from Genotype-Tissue Expression (GTEx) dataset, supporting inflammatory neurologic component pathogenesis obesity. Our comprehensive appraisal generated myriad different types provides insights into pediatric pathogenesis.

Language: Английский

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