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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Circular RNAs in the human brain are tailored to neuron identity and neuropsychiatric disease

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Sept. 18, 2023

Little is known about circular RNAs (circRNAs) in specific brain cells and human neuropsychiatric disease. Here, we systematically identify over 11,039 circRNAs expressed vulnerable dopamine pyramidal neurons laser-captured from 190 brains non-neuronal using ultra-deep, total RNA sequencing. 1526 3308 are custom-tailored to the cell identity of enriched synapse pathways. 29% Parkinson's 12% Alzheimer's disease-associated genes produced validated circRNAs. circDNAJC6, which transcribed a juvenile-onset gene, already dysregulated during prodromal, onset stages common disease neuropathology. Globally, addiction-associated preferentially produce neurons, autism-associated cancers cells. This study shows that tailored neuron implicate circRNA-regulated synaptic specialization diseases.

Language: Английский

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Shared genetic liability for alcohol consumption, alcohol problems, and suicide attempt: Evaluating the role of impulsivity

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

Published: March 10, 2023

Abstract Heavy drinking and diagnosis with alcohol use disorder (AUD) are consistently associated risk for suicide attempt (SA). Though the shared genetic architecture among consumption problems (ACP) SA remains largely uncharacterized, impulsivity has been proposed as a heritable, intermediate phenotype both suicidal behavior. The present study investigated extent to which liability ACP is genetically related five dimensions of impulsivity. Analyses incorporated summary statistics from genome-wide association studies ( N = 160,824), dependence 46,568), alcoholic drinks per week 537,349), 513,497), 22,861), extraversion 63,030). We used genomic structural equation modeling (Genomic SEM) to, first, estimate common factor model consumption, problems, dependence, week, included indicators. Next, we evaluated correlations between this factors representing negative urgency, positive lack premeditation, sensation-seeking, perseverance. Common was significantly correlated all impulsive personality traits examined rs 0.24–0.53, p s < 0.002), largest correlation though supplementary analyses suggested that these findings were potentially more strongly influenced by than SA. These have potential implications screening prevention: Impulsivity can be comprehensively assessed in childhood, whereas heavy quite rare prior adolescence. Our provide preliminary evidence features may serve early indicators suicidality.

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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Rapidly evolved genomic regions shape individual language abilities in present-day humans

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

Published: March 11, 2025

1 Summary Minor genetic changes have produced profound differences in cognitive abilities between humans and our closest relatives, particularly language. Despite decades of research, ranging from single-gene studies to broader evolutionary analyses[1, 2, 3, 4, 5], key questions about the genomic foundations human language persisted, including which sequences are involved, how they evolved, whether similar occur other vocal learning species. Here we provide first evidence directly linking rapidly evolved regions contemporary humans. Through extensive analysis 65 million years events over 30,000 individuals, demonstrate that Human Ancestor Quickly Evolved Regions (HAQERs)[5] - accumulated mutations after human-chimpanzee split specifically influence but not general cognition. These shape development by altering binding Forkhead domain transcription factors, FOXP2 . Strikingly, language-associated HAQER variants show higher prevalence Neanderthals than modern humans, been stable throughout recent history, convergent evolution across mammalian learners. An unexpected pattern balancing selection acting on these apparently beneficial alleles is explained their pleiotropic effects prenatal brain contributing birth complications, reflecting an trade-off capability reproductive fitness. By developing Evolution Stratified-Polygenic Score analysis, capabilities likely emerged before human-Neanderthal far earlier previously thought[3, 6, 7]. Our findings establish direct link ancient divergence present-day variation abilities, while revealing constraints continue development.

Language: Английский

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Convergent Pathways Identified for Cannabis Use Disorder Across Diverse Ancestry Populations

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

Published: March 17, 2025

ABSTRACT Large disparities in the prevalence of cannabis use disorder (CUD) exist across ethnic groups U.S. Despite large GWAS meta-analyses identifying numerous genome-wide significant loci for CUD European descents, little is known about other groups. While most and SNP-heritability studies focus on common genomic variants, rare low-frequency particularly those altering proteins, are to be enriched heritability complex traits may contribute disease different ways populations, either through converging or alternative pathways. In this study, we examined three populations including Americans (EA) two understudied populations: American Indians (AI) Mexican (MA). We focused low frequency functional variants genes pathways, performed association analysis with severity. identified 10 AI, ARSA gene MA, pathways one EA associated Notably, related arylsulfatases activation heparan sulfate degradation were supported by both additional evidence from AI. The integrin beta-1 cell surface interaction pathway, involved adhesion, was uniquely MA. Several immune-related also found, an autoimmune condition MA as well, a p38-gamma/delta mediated signaling pathway all cohorts. Although each population displayed distinct linked CUD, overlapping top suggested shared genetic factors, further highlighting importance considering diverse research disorder.

Language: Английский

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Novel Biological Insights Into the Common Heritable Liability to Substance Involvement: A Multivariate Genome-wide Association Study

Biological Psychiatry, Journal Year: 2022, Volume and Issue: 93(6), P. 524 - 535

Published: Aug. 10, 2022

Language: Английский

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Leveraging related health phenotypes for polygenic prediction of impulsive choice, impulsive action, and impulsive personality traits in 1534 European ancestry community adults

Genes Brain & Behavior, Journal Year: 2023, Volume and Issue: 22(3)

Published: April 14, 2023

Abstract Impulsivity refers to a number of conceptually related phenotypes reflecting self‐regulatory capacity that are considered promising endophenotypes for mental and physical health. Measures impulsivity can be broadly grouped into three domains, namely, impulsive choice, action, personality traits. In community‐based sample ancestral Europeans ( n = 1534), we conducted genome‐wide association studies (GWASs) choice (delay discounting), action (behavioral inhibition), traits (UPPS‐P), evaluated 11 polygenic risk scores (PRSs) previously linked self‐regulation. Although there were no individual significant hits, the neuroticism PRS was positively associated with negative urgency (adjusted R 2 1.61%, p 3.6 × 10 −7 ) educational attainment inversely delay discounting 1.68%, 2.2 ). There also evidence implicating PRSs attention‐deficit/hyperactivity disorder, externalizing, risk‐taking, smoking cessation, initiation, body mass index one or more s: 0.35%–1.07%; FDR adjusted s 0.05–0.0006). These associations between consistent established genetic correlations. The combined explained 0.91%–2.46% phenotypic variance measures, corresponding 8.7%–32.5% their reported single‐nucleotide polymorphism (SNP)‐based heritability, suggesting non‐negligible portion SNP‐based heritability recovered by PRSs. results support predictive validity utility PRSs, even derived from phenotypes, inform genetics phenotypes.

Language: Английский

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Identifying potential risk genes and pathways for neuropsychiatric and substance use disorders using intermediate molecular mediator information

Frontiers in Genetics, Journal Year: 2023, Volume and Issue: 14

Published: June 21, 2023

Neuropsychiatric and substance use disorders (NPSUDs) have a complex etiology that includes environmental polygenic risk factors with significant cross-trait genetic correlations. Genome-wide association studies (GWAS) of NPSUDs yield numerous signals. However, for most these regions, we do not yet firm understanding either the specific variants or effects variants. Post-GWAS methods allow researchers to GWAS summary statistics molecular mediators (transcript, protein, methylation abundances) infer effect on disorders. One group post-GWAS approaches is commonly referred as transcriptome/proteome/methylome-wide studies, which are abbreviated T/P/MWAS (or collectively XWAS). Since biological mediators, multiple testing burden reduced number genes (∼20,000) instead millions SNPs, leads increased signal detection. In this work, our aim uncover likely by performing XWAS analyses in two tissues-blood brain. First, identify putative causal genes, performed an using Summary-data-based Mendelian randomization, uses statistics, reference xQTL data, LD panel. Second, given large comorbidities among shared cis-xQTLs between blood brain, improved detection underpowered joint concordance results i) across tissues ii) NPSUDs. All signals were adjusted heterogeneity dependent instruments (HEIDI) (non-causality) p-values used test pathway enrichment. The suggest there widely gene/protein within major histocompatibility region chromosome 6 (BTN3A2 C4A) elsewhere genome (FURIN, NEK4, RERE, ZDHHC5). identification pathways underlying may offer new targets therapeutic development. Our study revealed enrichment vitamin D omega-3 gene sets. So, including treatment plans modest but beneficial patients bipolar disorder.

Language: Английский

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Biospecimens in the HEALthy Brain and Child Development Study (HBCD) Study: Rationale and Protocol

Developmental Cognitive Neuroscience, Journal Year: 2024, Volume and Issue: 70, P. 101451 - 101451

Published: Sept. 18, 2024

Language: Английский

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