Identifying genetic loci and phenomic associations of substance use traits: A multi‐trait analysis of GWAS (MTAG) study

Xu, Heng; Toikumo, Sylvanus; Crist, Richard C.; Glogowska, Klaudia; Jinwala, Zeal; Deak, Joseph D.; Justice, Amy C.; Johnson, Emma C.; Kranzler, Henry R.; Kember, Rachel L.

doi:10.1111/add.16229

Cited by 9 publications

(16 citation statements)

References 57 publications

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“…There were 114 genomic risk loci and 143 lead SNPs for the CanUD ∩ Smk | Scz subset (Table S9). The strongest meta-analytic effect was at lead SNP rs4620159 on chromosome 6 (chr6:111744735, p = 1.8e-28); this locus was previously associated with Smk and CanUD 47,48 .…”

Section: Cross-trait Loci: European Ancestrymentioning

confidence: 91%

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

Johnson,

Austin-Zimmerman,

Thorpe

et al. 2024

Preprint

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

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Section: Cross-trait Loci: European Ancestrymentioning

confidence: 91%

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

Johnson,

Austin-Zimmerman,

Thorpe

et al. 2024

Preprint

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“…However, the locus has been associated with alcohol consumption, tobacco-related traits, opioid use disorder, and cannabis use disorder in EUR and cross-ancestry studies. [64][65][66] The SNP exhibited chromatin interaction with two genes: BLID and C11orf63. A PheWAS of the lead SNP in the GWAS Atlas identified significant associations with regular smoking, past-month stomach pain, and tobacco-related conditions, such as atrial fibrillation and respiratory function (i.e., forced vital capacity and peak expiratory flow).…”

Section: First-order Common Factors: Suds Psychotic and Mood Disordersmentioning

confidence: 99%

“…One lead QSNP, rs10489130, identified on chromosome 4, exhibited significant associations with AUD only and was GWS in a previous AUD GWAS in AFR individuals, suggesting that this SNP may display specificity for AUD rather than influencing SUDs broadly. 66 For the SUD factor, gene expression was significantly enriched in brain tissues involved in emotion processing, reward signaling, and cognitive control, including the putamen, amygdala, caudate, and hippocampus (Supplementary Figure 11). No significant variants were identified for the psychiatric disorders factor (Supplementary Figure 12).…”

Section: First-order Common Factors: Suds Psychotic and Mood Disordersmentioning

confidence: 99%

“…This locus has, however, been previously implicated in alcohol, tobacco, cannabis, and opioid-related traits in EUR and cross-ancestry GWAS. [64][65][66] Our ability to identify this lead SNP was facilitated by the use of gSEM, which allowed us to leverage power across multiple SUDs. In doing so, we were able to overcome some of the limitations posed by the relatively low statistical power of existing GWAS in AFR populations.…”

Section: Identification Of Suds Psychotic and Mood Disorder Factorsmentioning

confidence: 99%

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Combining Transdiagnostic and Disorder-Level GWAS Enhances Precision of Psychiatric Genetic Risk Profiles in a Multi-Ancestry Sample

Khan,

Davis,

Jinwala

et al. 2024

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The etiology of substance use disorders (SUDs) and psychiatric disorders reflects a combination of both transdiagnostic (i.e., common) and disorder-level (i.e., independent) genetic risk factors. We applied genomic structural equation modeling to examine these genetic factors across SUDs, psychotic, mood, and anxiety disorders using genome-wide association studies (GWAS) of European-(EUR) and African-ancestry (AFR) individuals. In EUR individuals, transdiagnostic genetic factors represented SUDs (143 lead single nucleotide polymorphisms [SNPs]), psychotic (162 lead SNPs), and mood/anxiety disorders (112 lead SNPs). We identified two novel SNPs for mood/anxiety disorders that have probable regulatory roles onFOXP1,NECTIN3, andBTLAgenes. In AFR individuals, genetic factors represented SUDs (1 lead SNP) and psychiatric disorders (no significant SNPs). The SUD factor lead SNP, although previously significant in EUR- and cross-ancestry GWAS, is a novel finding in AFR individuals. Shared genetic variance accounted for overlap between SUDs and their psychiatric comorbidities, with second-order GWAS identifying up to 12 SNPs not significantly associated with either first-order factor in EUR individuals. Finally, common and independent genetic effects showed different associations with psychiatric, sociodemographic, and medical phenotypes. For example, the independent components of schizophrenia and bipolar disorder had distinct associations with affective and risk-taking behaviors, and phenome-wide association studies identified medical conditions associated with tobacco use disorder independent of the broader SUDs factor. Thus, combining transdiagnostic and disorder-level genetic approaches can improve our understanding of co-occurring conditions and increase the specificity of genetic discovery, which is critical for psychiatric disorders that demonstrate considerable symptom and etiological overlap.

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“…Problematic cannabis use is estimated to be 51-78% heritable based on twin studies [17][18][19] and recent genome-wide association studies (GWASs) have implicated hundreds of loci associated with CUD [20][21][22][23] . While CUD GWASs are of paramount importance, they come with three major caveats.…”

Section: Introductionmentioning

confidence: 99%

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

Thorpe,

Fontanillas,

Meredith

et al. 2024

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SummaryCannabis is one of the most widely used drugs globally. Decriminalization of cannabis is further increasing cannabis consumption. We performed genome-wide association studies (GWASs) of lifetime (N=131,895) and frequency (N=73,374) of cannabis use. Lifetime cannabis use GWAS identified two loci, one nearCADM2(rs11922956,p=2.40E-11) and another nearGRM3(rs12673181,p=6.90E-09). Frequency of use GWAS identified one locus nearCADM2(rs4856591,p=8.10E-09;r2=0.76 with rs11922956). Both traits were heritable and genetically correlated with previous GWASs of lifetime use and cannabis use disorder (CUD), as well as other substance use and cognitive traits. Polygenic scores (PGSs) for lifetime and frequency of cannabis use associated cannabis use phenotypes inAllofUsparticipants. Phenome-wide association study of lifetime cannabis use PGS in a hospital cohort replicated associations with substance use and mood disorders, and uncovered associations with celiac and infectious diseases. This work demonstrates the value of GWASs of CUD transition risk factors.

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Identifying genetic loci and phenomic associations of substance use traits: A multi‐trait analysis of GWAS (MTAG) study

Cited by 9 publications

References 57 publications

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

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

Combining Transdiagnostic and Disorder-Level GWAS Enhances Precision of Psychiatric Genetic Risk Profiles in a Multi-Ancestry Sample

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

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