Browsing by Author "Nunez, Yaira Z."

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    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
    (Springer, 2022-10) Deak, Joseph D.; Zhou, Hang; Galimberti, Marco; Levey, Daniel F.; Wendt, Frank R.; Sanchez-Roige, Sandra; Hatoum, Alexander S.; Johnson, Emma C.; Nunez, Yaira Z.; Demontis, Ditte; Børglum, Anders D.; Rajagopal, Veera M.; Jennings, Mariela V.; Kember, Rachel L.; Justice, Amy C.; Edenberg, Howard J.; Agrawal, Arpana; Polimanti, Renato; Kranzler, Henry R.; Gelernter, Joel; Biochemistry and Molecular Biology, School of Medicine
    Despite the large toll of opioid use disorder (OUD), genome-wide association studies (GWAS) of OUD to date have yielded few susceptibility loci. We 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, Psychiatric Genomics Consortium, iPSYCH, FinnGen, Partners Biobank, BioVU, and Yale-Penn 3, resulting in a total N = 639,063 (Ncases = 20,686;Neffective = 77,026) across ancestries. OUD cases were defined as having a 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). A leave-one-out polygenic risk score (PRS) analysis was performed to compare OUD and OUD-MTAG PRS as predictors of OUD case status in Yale-Penn 3. The 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 = 1.11 × 10−08; r2 = 0.02). Rs1799971 (p = 4.91 × 10−08) and another OPRM1 variant (rs9478500; p = 1.95 × 10−08; 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 a GWAS Nequivalent = 128,748 and 18 independent GWS loci, some mapping to genes or gene regions that have previously been associated with psychiatric or addiction phenotypes. The OUD-MTAG PRS accounted for 3.81% of OUD variance (beta = 0.61;s.e. = 0.066; p = 2.00 × 10−16) compared to 2.41% (beta = 0.45; s.e. = 0.058; p = 2.90 × 10−13) explained by the OUD PRS. The current study identified OUD variant associations at OPRM1, single variant associations with FURIN, and 18 GWS associations in the OUD-MTAG. The genetic architecture of OUD is likely influenced by both OUD-specific loci and loci shared across SUDs.
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    Multi-ancestral genome-wide association study of clinically defined nicotine dependence reveals strong genetic correlations with other substance use disorders and health-related traits
    (medRxiv, 2025-02-03) Johnson, Emma C.; Lai, Dongbing; Miller, Alex P.; Hatoum, Alexander S.; Deak, Joseph D.; Balbona, Jared V.; Baranger, David A. A.; Galimberti, Marco; Sanichwankul, Kittipong; Thorgeirsson, Thorgeir; McColbert, Sarah; Sanchez-Roige, Sandra; Adhikari, Keyrun; Docherty, Anna; Degenhardt, Louisa; Edwards, Tobias; Fox, Louis; Giannelis, Alexandros; Jeffries, Paul; Korhonen, Tellervo; Morrison, Claire; Nunez, Yaira Z.; Palviainen, Teemu; Su, Mei-Hsin; Romero Villela, Pamela N.; Wetherill, Leah; Willoughby, Emily A.; Zellers, Stephanie; Bierut, Laura; Buchwald, Jadwiga; Copeland, William; Corley, Robin; Friedman, Naomi P.; Foroud, Tatiana M.; Gillespie, Nathan A.; Gizer, Ian R.; Heath, Andrew C.; Hickie, Ian B.; Kaprio, Jaakko A.; Keller, Matthew C.; Lee, James L.; Lind, Penelope A.; Madden, Pamela A.; Maes, Hermine H. M.; Martin, Nicholas G.; McGue, Matt; Medland, Sarah E.; Nelson, Elliot C.; Pearson, John V.; Porjesz, Bernice; Stallings, Michael; Vrieze, Scott; Wilhelmsen, Kirk C.; Walters, Raymond K.; Polimanti, Renato; Malison, Robert T.; Zhou, Hang; Stefansson, Kari; Potenza, Marc N.; Mutirangura, Apiwat; Shotelersuk, Vorasuk; Kalayasiri, Rasmon; Edenberg, Howard J.; Gelernter, Joel; Agrawal, Arpana; Medical and Molecular Genetics, School of Medicine
    Genetic research on nicotine dependence has utilized multiple assessments that are in weak agreement. We conducted a genome-wide association study of nicotine dependence defined using the Diagnostic and Statistical Manual of Mental Disorders (DSM-NicDep) in 61,861 individuals (47,884 of European ancestry, 10,231 of African ancestry, 3,746 of East Asian ancestry) and compared the results to other nicotine-related phenotypes. We replicated the well-known association at the CHRNA5 locus (lead SNP: rs147144681, p =1.27E-11 in European ancestry; lead SNP = rs2036527, p = 6.49e-13 in cross-ancestry analysis). DSM-NicDep showed strong positive genetic correlations with cannabis use disorder, opioid use disorder, problematic alcohol use, lung cancer, material deprivation, and several psychiatric disorders, and negative correlations with respiratory function and educational attainment. A polygenic score of DSM-NicDep predicted DSM-5 tobacco use disorder and 6 of 11 individual diagnostic criteria, but none of the Fagerström Test for Nicotine Dependence (FTND) items, in the independent NESARC-III sample. In genomic structural equation models, DSM-NicDep loaded more strongly on a previously identified factor of general addiction liability than did a "problematic tobacco use" factor (a combination of cigarettes per day and nicotine dependence defined by the FTND). Finally, DSM-NicDep was strongly genetically correlated with a GWAS of tobacco use disorder as defined in electronic health records, suggesting that combining the wide availability of diagnostic EHR data with nuanced criterion-level analyses of DSM tobacco use disorder may produce new insights into the genetics of this disorder.
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    Multi-ancestry genome-wide association study of cannabis use disorder yields insight into disease biology and public health implications
    (Springer Nature, 2023) Levey, Daniel F.; Galimberti, Marco; Deak, Joseph D.; Wendt, Frank R.; Bhattacharya, Arjun; Koller, Dora; Harrington, Kelly M.; Quaden, Rachel; Johnson, Emma C.; Gupta, Priya; Biradar, Mahantesh; Lam, Max; Cooke, Megan; Rajagopal, Veera M.; Empke, Stefany L. L.; Zhou, Hang; Nunez, Yaira Z.; Kranzler, Henry R.; Edenberg, Howard J.; Agrawal, Arpana; Smoller, Jordan W.; Lencz, Todd; Hougaard, David M.; Børglum, Anders D.; Demontis, Ditte; Veterans Affairs Million Veteran Program; Gaziano, J. Michael; Gandal, Michael J.; Polimanti, Renato; Stein, Murray B.; Gelernter, Joel; Biochemistry and Molecular Biology, School of Medicine
    As recreational use of cannabis is being decriminalized in many places and medical use widely sanctioned, there are growing concerns about increases in cannabis use disorder (CanUD), which is associated with numerous medical comorbidities. Here we performed a genome-wide association study of CanUD in the Million Veteran Program (MVP), followed by meta-analysis in 1,054,365 individuals (ncases = 64,314) from four broad ancestries designated by the reference panel used for assignment (European n = 886,025, African n = 123,208, admixed American n = 38,289 and East Asian n = 6,843). Population-specific methods were applied to calculate single nucleotide polymorphism-based heritability within each ancestry. Statistically significant single nucleotide polymorphism-based heritability for CanUD was observed in all but the smallest population (East Asian). We discovered genome-wide significant loci unique to each ancestry: 22 in European, 2 each in African and East Asian, and 1 in admixed American ancestries. A genetically informed causal relationship analysis indicated a possible effect of genetic liability for CanUD on lung cancer risk, suggesting potential unanticipated future medical and psychiatric public health consequences that require further study to disentangle from other known risk factors such as cigarette smoking.