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 mapping in Collaborative Cross mouse strains identifies loci that affect initial sensitivity to cocaine

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

Published: Jan. 12, 2025

ABSTRACT We identified two Collaborative Cross (CC) strains, CC004/TauUncJ (CC004) and CC041/TauUncJ (CC041), that differ significantly for locomotor response self-administration of cocaine. In the current study, we crossed each these strains to C57BL/6NJ (B6N) mice produce F2 populations identify genetic loci influence three significant on chromosomes 7, 11 14 in CC041 mapping cross collectively explain 14% phenotypic variance used a bioinformatic approach high quality candidate genes are genetically plausible, have functional relevance suitable further exploration. Our study is first use CC perform QTL addiction-related phenotypes proposes several follow-up analyses.

Language: Английский

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Multi-trait genome-wide association analyses leveraging alcohol use disorder findings identify novel loci for smoking behaviors in the Million Veteran Program

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

Published: May 5, 2023

Smoking behaviors and alcohol use disorder (AUD), both moderately heritable traits, commonly co-occur in the general population. Single-trait genome-wide association studies (GWAS) have identified multiple loci for smoking AUD. However, GWASs that aimed to identify contributing co-occurring AUD used small samples thus not been highly informative. Applying multi-trait analysis of (MTAG), we conducted a joint GWAS with data from Million Veteran Program (N = 318,694). By leveraging summary statistics AUD, MTAG 21 significant (GWS) associated initiation 17 cessation compared 16 8 loci, respectively, by single-trait GWAS. The novel included those previously psychiatric or substance traits. Colocalization 10 shared status all which achieved GWS MTAG, including variants on SIX3, NCAM1, near DRD2. Functional annotation highlighted biologically important regions ZBTB20, DRD2, PPP6C, GCKR contribute behaviors. In contrast, consumption (AC) did enhance discovery We conclude using augment power enables identification genetic co-occuring phenotypes, providing new insights into their pleiotropic effects behavior

Language: Английский

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Cross-ancestry genetic investigation of schizophrenia, cannabis use disorder, and tobacco smoking

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

Published: Jan. 18, 2024

Abstract Individuals with schizophrenia frequently experience co-occurring substance use, including tobacco smoking and heavy cannabis use disorders. There is interest in understanding the extent to which these relationships are causal, what shared genetic factors play a role. We explored between (Scz), disorder (CanUD), ever-regular (Smk) using largest available genome-wide studies of phenotypes individuals African European ancestries. All three were positively genetically correlated (r g s = 0.17 – 0.62).Causal inference analyses suggested presence horizontal pleiotropy, but evidence for bidirectional causal was also found all even after correcting pleiotropy. identified 439 pleiotropic loci ancestry data, 150 novel (i.e., not significant original studies). Of loci, 202 had lead variants showed convergent effects same direction effect) on Scz, CanUD, Smk. Genetic across strong correlations risk-taking, executive function, several mental health conditions. Our results suggest that both pleiotropy mechanisms may role relationship Smk, longitudinal, prospective needed confirm relationship.

Language: Английский

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Genome-wide association studies of lifetime and frequency cannabis use in 131,895 individuals

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

Published: June 16, 2024

Cannabis is one of the most widely used drugs globally. Decriminalization cannabis further increasing consumption. We performed genome-wide association studies (GWASs) lifetime (N=131,895) and frequency (N=73,374) use. Lifetime use GWAS identified two loci, near CADM2 (rs11922956, p=2.40E-11) another GRM3 (rs12673181, p=6.90E-09). Frequency locus (rs4856591, p=8.10E-09; r2 =0.76 with rs11922956). Both traits were heritable genetically correlated previous GWASs disorder (CUD), as well other substance cognitive traits. Polygenic scores (PGSs) for associated phenotypes in AllofUs participants. Phenome-wide study PGS a hospital cohort replicated associations mood disorders, uncovered celiac infectious diseases. This work demonstrates value CUD transition risk factors.

Language: Английский

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Multi-trait genome-wide association studies reveal novel pleiotropic loci associated with yield and yield-related traits in rice

Journal of Integrative Agriculture, Journal Year: 2024, Volume and Issue: unknown

Published: July 1, 2024

Rice yield is a complex trait affected by many related traits. Traditional single-trait genome-wide association studies (GWAS) have limitations when studying traits, as they cannot account for the genetic relationships among multiple Multi-trait GWAS, which can consider traits and identify pleiotropic loci, more suitable such rice than GWAS. In this study, we conducted multi-trait GWAS on 11 two-trait combinations of yield-related with 575 hybrid varieties across two environments. All these showed significant correlation (YD), including filled grains per panicle (FGPP), kilo-grain weight (KGW), tillers plant (TP), primary branch number (PB), secondary (SB) main length (MPL). total identified 44 quantitative loci (pQTLs), 29 new pQTLs not found in We then screened 23 showing common effects key pQTLs. These were subsequently analyzed haplotype analysis 13 candidate genes. Finally, optimal yield-enhancing allele pyraming superior haplotypes: GS3-GL3.1-OsCIPK17 YD-KGW combination GNP12 YD-FGPP YD-SB combinations. This study provides genes that exhibit differences both offering valuable information future high-yielding breeding.

Language: Английский

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Application of polygenic scores to a deeply phenotyped sample enriched for substance use disorders reveals extensive pleiotropy with psychiatric and somatic traits

Neuropsychopharmacology, Journal Year: 2024, Volume and Issue: 49(13), P. 1958 - 1967

Published: July 23, 2024

Co-occurring psychiatric, medical, and substance use disorders (SUDs) are common, but the complex pathways leading to such comorbidities poorly understood. A greater understanding of genetic influences on this phenomenon could inform precision medicine efforts. We used Yale-Penn dataset, a cross-sectional sample enriched for individuals with SUDs, examine pleiotropic effects liability psychiatric somatic traits. Participants completed an in-depth interview that provides information demographics, environment, medical illnesses, SUDs. Polygenic scores (PGS) traits were calculated in European-ancestry (EUR; n = 5691) participants and, when discovery datasets available, African-ancestry (AFR; 4918) participants. Phenome-wide association studies (PheWAS) then conducted. In AFR participants, only PGS significant associations was bipolar disorder (BD), all which phenotypes. EUR major depressive (MDD), generalized anxiety (GAD), post-traumatic stress (PTSD), schizophrenia (SCZ), body mass index (BMI), coronary artery disease (CAD), type 2 diabetes (T2D) showed associations, majority phenotypes categories. For instance,

Language: Английский

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Cross-ancestry genetic investigation of schizophrenia, cannabis use disorder, and tobacco smoking

Neuropsychopharmacology, Journal Year: 2024, Volume and Issue: 49(11), P. 1655 - 1665

Published: June 21, 2024

Individuals with schizophrenia frequently experience co-occurring substance use, including tobacco smoking and heavy cannabis use disorders. There is interest in understanding the extent to which these relationships are causal, what shared genetic factors play a role. We explored between (Scz; European ancestry N = 161,405; African 15,846), disorder (CanUD; 886,025; 120,208), ever-regular (Smk; 805,431; 24,278) using largest available genome-wide studies of phenotypes individuals ancestries. All three were positively genetically correlated (r

Language: Английский

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Genome-wide meta-analyses of cross substance use disorders in European, African, and Latino ancestry populations

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: July 16, 2024

Genetic risks for substance use disorders (SUDs) are due to both SUD-specific and SUD-shared genes. We performed the largest multivariate analyses date search genes using samples of European (EA), African (AA), Latino (LA) ancestries. By focusing on variants having cross-SUD cross-ancestry concordant effects, we identified 45 loci. Through gene-based analyses, gene mapping, prioritization, 250 These highly expressed in amygdala, cortex, hippocampus, hypothalamus, thalamus, primarily neuronal cells. Cross-SUD explained ~ 50% heritability each SUD EA. The top 5% individuals highest polygenic scores were approximately twice as likely have SUDs others EA LA. Polygenic had higher predictability females than males Using real-world data, five drugs targeting that may be repurposed treat SUDs.

Language: Английский

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Considerations for the application of polygenic scores to clinical care of individuals with substance use disorders

Journal of Clinical Investigation, Journal Year: 2024, Volume and Issue: 134(20)

Published: Oct. 14, 2024

Substance use disorders (SUDs) are highly prevalent and associated with excess morbidity, mortality, economic costs. Thus, there is considerable interest in the early identification of individuals who may be more susceptible to developing SUDs improving personalized treatment decisions for those have SUDs. known influenced by both genetic environmental factors. Polygenic scores (PGSs) provide a single measure liability that could used as biomarker predicting disease development, progression, response. Although PGSs rapidly being integrated into clinical practice, little information guide clinicians their responsible interpretation. In this Review, we discuss potential benefits pitfalls care SUDs, highlighting current research. We also suggestions important considerations prior implementing recommend future directions

Language: Английский

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