The Addiction Risk Factor: A Unitary Genetic Vulnerability Characterizes Substance Use Disorders and Their Associations with Common Correlates

Hatoum, Alexander S.; Johnson, Emma C.; Polimanti, Renato; Zhou, Hang; Walters, Raymond; Edenberg, Howard J.; Bogdan, Ryan; Agrawal, Arpana

doi:10.1101/2021.01.26.21250498

Cited by 11 publications

(11 citation statements)

References 47 publications

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“…Consistent with recent reports demonstrating broad levels of pleiotropy amongst psychiatric disorders (Lee et al, 2019), including substance use disorders (Hatoum et al, 2021), we found that 22 of the 55 top convergent SNPs and 3 of the 8 divergent SNPs showed at least nominal significance across one or more of the six psychiatric disorders and substance use traits that we assessed. Depression showed the greatest extent of overlap with the convergent SNPs, with 10 of the 55 convergent SNPs having p < 0.0009 in the depression GWAS and only one of those exerting a different direction of effect relative to AUD and SCZ.…”

Section: Discussionsupporting

confidence: 91%

Investigation of convergent and divergent genetic influences underlying schizophrenia and alcohol use disorder

et al. 2021

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Background Alcohol use disorder (AUD) and schizophrenia (SCZ) frequently co-occur, and large-scale genome-wide association studies (GWAS) have identified significant genetic correlations between these disorders. Methods We used the largest published GWAS for AUD (total cases = 77 822) and SCZ (total cases = 46 827) to identify genetic variants that influence both disorders (with either the same or opposite direction of effect) and those that are disorder specific. Results We identified 55 independent genome-wide significant single nucleotide polymorphisms with the same direction of effect on AUD and SCZ, 8 with robust effects in opposite directions, and 98 with disorder-specific effects. We also found evidence for 12 genes whose pleiotropic associations with AUD and SCZ are consistent with mediation via gene expression in the prefrontal cortex. The genetic covariance between AUD and SCZ was concentrated in genomic regions functional in brain tissues (p = 0.001). Conclusions Our findings provide further evidence that SCZ shares meaningful genetic overlap with AUD.

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Section: Discussionsupporting

confidence: 91%

Investigation of convergent and divergent genetic influences underlying schizophrenia and alcohol use disorder

et al. 2021

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“…substance-specific genetic influences, reporting evidence to suggest the presence of a common unitary addiction factor that can account for risk across SUDs, in addition to substance-specific influences (46). Larger-scale studies of OUD will be needed to advance OUD genetic discovery and parse genomic influences specific to OUD from those underlying risk for SUDs more broadly.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide association study and multi-trait analysis of opioid use disorder identifies novel associations in 639,709 individuals of European and African ancestry

Deak

Zhou

Galimberti

et al. 2021

Preprint

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BackgroundDespite the large toll of opioid use disorder (OUD), genome-wide association studies (GWAS) of OUD to date have yielded few susceptibility loci.MethodsWe performed a large-scale GWAS of OUD in individuals of European (EUR) and African (AFR) ancestry, optimizing genetic informativeness by performing MTAG (Multi-trait analysis of GWAS) with genetically correlated substance use disorders (SUDs). Meta-analysis included seven cohorts: the Million Veteran Program (MVP), Psychiatric Genomics Consortium (PGC), iPSYCH, FinnGen, Partners Biobank, BioVU, and Yale-Penn 3, resulting in a total N=639,709 (Ncases=20,858) across ancestries. OUD cases were defined as having lifetime OUD diagnosis, and controls as anyone not known to meet OUD criteria. We estimated SNP-heritability (h2SNP) and genetic correlations (rg). Based on genetic correlation, we performed MTAG on OUD, alcohol use disorder (AUD), and cannabis use disorder (CanUD).ResultsThe EUR meta-analysis identified three genome-wide significant (GWS; p≤5×10−8) lead SNPs—one at FURIN (rs11372849; p=9.54×10−10) and two OPRM1 variants (rs1799971, p=4.92×10−09 ; rs79704991, p=1.37×10−08; r2=0.02). Rs1799971 (p=4.91×10−08) and another OPRM1 variant (rs9478500; p=1.95×10−8; r2=0.03) were identified in the cross-ancestry meta-analysis. Estimated h2SNP was 12.75%, with strong rg with CanUD (rg =0.82; p=1.14×10−47) and AUD (rg=0.77; p=6.36×10−78). The OUD-MTAG resulted in 18 GWS loci, all of which map to genes or gene regions that have previously been associated with psychiatric or addiction phenotypes.ConclusionsWe identified multiple OUD variant associations at OPRM1, single variant associations with FURIN, and 18 GWS associations in the OUD-MTAG. OUD is likely influenced by both OUD-specific loci and loci shared across SUDs.

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“…Summary statistics for the SUDs came from four independent studies, which to our knowledge are the largest available GWAS for each phenotype. We chose to use these phenotypes specifically as their contributions to a common genetic addictions factor are well-studied (Hatoum et al, 2021).…”

Section: Methodsmentioning

confidence: 99%

“…Heterogeneity amongst SUDs and their distinct genetic relationships with other dimensions of mental health are becoming increasingly better understood (Abdellaoui et al, 2021; Hatoum et al, 2021). Recently, Hatoum et al (preprint; 2021) proposed a unidimensional factor for characterizing substance use disorders, specifically problematic alcohol use (PAU), cannabis use disorder (CUD), opioid use disorder (OUD) and problematic tobacco use.…”

Section: Introductionmentioning

confidence: 99%

Exploring the genetic overlap of suicide-related behaviors and substance use disorders

Colbert¹,

Hatoum²,

Shabalin

et al. 2021

Preprint

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Background: Suicide-related behaviors are heterogeneous and transdiagnostic, and may demonstrate varying levels of genetic overlap with different substance use disorders (SUDs). Methods: We used linkage disequilibrium score regression and genomic structural equation models to examine the genetic relationships between several SUDs and suicide-related behaviors. Our analyses incorporated summary statistics from the largest genome-wide association studies (GWAS) of problematic alcohol use (PAU), the Fagerstrom Test for Nicotine Dependence (FTND), cannabis use disorder (CUD), and opioid use disorder (OUD; Ns ranging from 46,213-435,563) and GWAS of ever self-harmed, suicide attempt, and suicide death (Ns ranging from 18,223-117,733). We also accounted for genetic liability to depression (N=500,199) and risk tolerance (N=315,894). Results: Ever self-harmed correlated most strongly with CUD (rg=0.60) and suicide death correlated most strongly with OUD (rg=0.53). Suicide attempt correlated similarly with all SUDs. Simultaneously correlating a common SUD factor with each specific suicide indicator while controlling for depression and risk tolerance revealed significant, positive genetic correlations between all SUDs and suicide-related behaviors (rg=0.26-0.46). Discussion: Our findings suggest that genetic and behavioral contributions to suicide death may somewhat differ from non-lethal suicide-related behaviors. Additionally, we identify a general level of genetic overlap between SUDs and suicide-related behaviors which is independent of depression and risk tolerance.

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The Addiction Risk Factor: A Unitary Genetic Vulnerability Characterizes Substance Use Disorders and Their Associations with Common Correlates

Cited by 11 publications

References 47 publications

Investigation of convergent and divergent genetic influences underlying schizophrenia and alcohol use disorder

Investigation of convergent and divergent genetic influences underlying schizophrenia and alcohol use disorder

Genome-wide association study and multi-trait analysis of opioid use disorder identifies novel associations in 639,709 individuals of European and African ancestry

Exploring the genetic overlap of suicide-related behaviors and substance use disorders

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