Browsing by Author "Bierut, Laura"
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Item A meta-analysis of two genome-wide association studies to identify novel loci for maximum number of alcoholic drinks(Springer, 2013) Kapoor, Manav; Wang, Jen-Chyong; Wetherill, Leah; Le, Nhung; Bertelsen, Sarah; Hinrichs, Anthony L.; Budde, John; Agrawal, Arpana; Bucholz, Kathleen; Dick, Danielle; Harari, Oscar; Hesselbrock, Victor; Kramer, John; Nurnberger, John I., Jr.; Rice, John; Saccone, Nancy; Schuckit, Marc; Tischfield, Jay; Porjesz, Bernice; Edenberg, Howard J.; Bierut, Laura; Foroud, Tatiana; Goate, Alison; Medical and Molecular Genetics, School of MedicineMaximum number of alcoholic drinks consumed in a 24-h period (maxdrinks) is a heritable (>50 %) trait and is strongly correlated with vulnerability to excessive alcohol consumption and subsequent alcohol dependence (AD). Several genome-wide association studies (GWAS) have studied alcohol dependence, but few have concentrated on excessive alcohol consumption. We performed two GWAS using maxdrinks as an excessive alcohol consumption phenotype: one in 118 extended families (N = 2,322) selected from the Collaborative Study on the Genetics of Alcoholism (COGA), and the other in a case-control sample (N = 2,593) derived from the Study of Addiction: Genes and Environment (SAGE). The strongest association in the COGA families was detected with rs9523562 (p = 2.1 × 10(-6)) located in an intergenic region on chromosome 13q31.1; the strongest association in the SAGE dataset was with rs67666182 (p = 7.1 × 10(-7)), located in an intergenic region on chromosome 8. We also performed a meta-analysis with these two GWAS and demonstrated evidence of association in both datasets for the LMO1 (p = 7.2 × 10(-7)) and PLCL1 genes (p = 4.1 × 10(-6)) with maxdrinks. A variant in AUTS2 and variants in INADL, C15orf32 and HIP1 that were associated with measures of alcohol consumption in a meta-analysis of GWAS studies and a GWAS of alcohol consumption factor score also showed nominal association in the current meta-analysis. The present study has identified several loci that warrant further examination in independent samples. Among the top SNPs in each of the dataset (p ≤ 10(-4)) far more showed the same direction of effect in the other dataset than would be expected by chance (p = 2 × 10(-3), 3 × 10(-6)), suggesting that there are true signals among these top SNPs, even though no SNP reached genome-wide levels of significance.Item Development of Alcohol Use Disorder as a Function of Age, Severity, and Comorbidity with Externalizing and Internalizing Disorders in a Young Adult Cohort(Hapres Limited, 2019) Nurnberger Jr., John I.; Yang, Ziyi; Zang, Yong; Acion, Laura; Bierut, Laura; Bucholz, Kathleen; Chan, Grace; Dick, Danielle M.; Edenberg, Howard J.; Kramer, John; Kuperman, Samuel; Rice, John P.; Schuckit, Marc; Psychiatry, School of MedicineBackground: As part of the ongoing Collaborative Study of the Genetics of Alcoholism, we performed a longitudinal study of a high risk cohort of adolescents/young adults from families with a proband with an alcohol use disorder, along with a comparison group of age-matched controls. The intent was to compare the development of alcohol problems in subjects at risk with and without comorbid externalizing and internalizing psychiatric disorders. Methods: Subjects (N = 3286) were assessed with a structured psychiatric interview at 2 year intervals over 10 years (2004–2017). The age range at baseline was 12–21. Results: Subjects with externalizing disorders (with or without accompanying internalizing disorders) were at increased risk for the onset of an alcohol use disorder during the observation period. Subjects with internalizing disorders were at greater risk than those without comorbid disorders for onset of a moderate or severe alcohol use disorder. The statistical effect of comorbid disorders was greater in subjects with more severe alcohol use disorders. The developmental trajectory of drinking milestones and alcohol use disorders was also accelerated in those with more severe disorders. Conclusions: These results may be useful for counseling of subjects at risk who present for clinical care, especially those subjects manifesting externalizing and internalizing disorders in the context of a positive family history of an alcohol use disorder. We confirm and extend findings that drinking problems in subjects at greatest risk will begin in early adolescence.Item Exome chip meta-analysis fine maps causal variants and elucidates the genetic architecture of rare coding variants in smoking and alcohol use(Elsevier, 2018) Brazel, David M.; Jiang, Yu; Hughey, Jordan M.; Turcot, Valérie; Zhan, Xiaowei; Gong, Jian; Batini, Chiara; Weissenkampen, J. Dylan; Liu, MengZhen; Barnes, Daniel R.; Bertelsen, Sarah; Chou, Yi-Ling; Erzurumluoglu, A. Mesut; Faul, Jessica D.; Haessler, Jeff; Hammerschlag, Anke R.; Hsu, Chris; Kapoor, Manav; Lai, Dongbing; Le, Nhung; de Leeuw, Christiaan A.; Loukola, Anu; Mangino, Massimo; Melbourne, Carl A.; Pistis, Giorgio; Qaiser, Beenish; Rohde, Rebecca; Shao, Yaming; Stringham, Heather; Wetherill, Leah; Zhao, Wei; Agrawal, Arpana; Bierut, Laura; Chen, Chu; Eaton, Charles B.; Goate, Alison; Haiman, Christopher; Heath, Andrew; Iacono, William G.; Martin, Nicholas G.; Polderman, Tinca J.; Reiner, Alex; Rice, John; Schlessinger, David; Scholte, H. Steven; Smith, Jennifer A.; Tardif, Jean-Claude; Tindle, Hilary A.; van der Leij, Andries R.; Boehnke, Michael; Chang-Claude, Jenny; Cucca, Francesco; David, Sean P.; Foroud, Tatiana; Howson, Joanna M. M.; Kardia, Sharon L. R.; Kooperberg, Charles; Laakso, Markku; Lettre, Guillaume; Madden, Pamela; McGue, Matt; North, Kari; Posthuma, Danielle; Spector, Timothy; Stram, Daniel; Tobin, Martin D.; Weir, David R.; Kaprio, Jaakko; Abecasis, Gonçalo R.; Liu, Dajiang J.; Vrieze, Scott; Medical and Molecular Genetics, School of MedicineBackground Smoking and alcohol use have been associated with common genetic variants in multiple loci. Rare variants within these loci hold promise in the identification of biological mechanisms in substance use. Exome arrays and genotype imputation can now efficiently genotype rare nonsynonymous and loss of function variants. Such variants are expected to have deleterious functional consequences, and contribute to disease risk. Methods We analyzed ∼250,000 rare variants from 16 independent studies genotyped with exome arrays and augmented this dataset with imputed data from the UK Biobank. Associations were tested for five phenotypes: cigarettes per day, pack years, smoking initiation, age of smoking initiation, and alcoholic drinks per week. We conducted stratified heritability analyses, single-variant tests, and gene-based burden tests of nonsynonymous/loss of function coding variants. We performed a novel fine mapping analysis to winnow the number of putative causal variants within associated loci. Results Meta-analytic sample sizes ranged from 152,348-433,216, depending on the phenotype. Rare coding variation explained 1.1-2.2% of phenotypic variance, reflecting 11%-18% of the total SNP heritability of these phenotypes. We identified 171 genome-wide associated loci across all phenotypes. Fine mapping identified putative causal variants with double base-pair resolution at 24 of these loci, and between 3 and 10 variants for 65 loci. 20 loci contained rare coding variants in the 95% credible intervals. Conclusions Rare coding variation significantly contributes to the heritability of smoking and alcohol use. Fine mapping GWAS loci identifies specific variants contributing to the biological etiology of substance use behavior.Item Genes associated with alcohol outcomes show enrichment of effects with broad externalizing and impulsivity phenotypes in an independent sample(JSAD, 2015-01) Aliev, Fazil; Wetherill, Leah; Bierut, Laura; Bucholz, Kathleen K.; Edenberg, Howard; Foroud, Tatiana; Dick, Danielle M.; Department of Medical and Molecular Genetics, IU School of MedicineOBJECTIVE: The purpose of this study was to evaluate evidence for association with a panel of genes previously associated with alcohol-related traits in a new sample of adolescent and young adult individuals (N = 2,128; 51% female) collected as part of the Collaborative Study on the Genetics of Alcoholism (COGA). We tested for association with phenotypes related to externalizing behavior, including diagnostic symptom counts for disorders on the externalizing spectrum (alcohol dependence, conduct disorder, adult antisocial personality disorder, and illicit drug dependence), and related behavioral/personality traits (Achenbach Externalizing, NEO Extraversion, NEO Conscientiousness, Zuckerman's Sensation Seeking, and the Barratt Impulsivity Scale) based on the substantial literature suggesting that these behaviors may be alternate manifestations of a shared genetic liability. METHOD: We tested for overall enrichment of the set of 215 genotyped single-nucleotide polymorphisms (SNPs) for each of the phenotypes. We conducted secondary analyses comparing results for sensation seeking with results for the other phenotypes. RESULTS: For all phenotypes, there was significant enrichment of association results (p < .05) compared with chance expectations. The greatest number of significant results was observed with the phenotype Sensation Seeking. Secondary analyses indicated that the number of SNPs yielding p < .05 with Sensation Seeking was significantly greater than that observed for each of the other phenotypes. CONCLUSIONS: We find evidence for enrichment of association results across a spectrum of externalizing phenotypes with a panel of candidate genes/SNPs selected based on previous suggestion of association with alcohol-related outcomes. In particular, we find significant enrichment of effects with sensation seeking, suggesting that this may be a particularly salient behavior associated with risk for alcohol-related problems.Item Genetic and neurophysiological correlates of the age of onset of alcohol use disorders in adolescents and young adults(Springer, 2013) Chorlian, David B.; Rangaswamy, Madhavi; Manz, Niklas; Wang, Jen-Chyong; Dick, Danielle; Almasy, Laura; Bauer, Lance; Bucholz, Kathleen; Foroud, Tatiana; Hesselbrock, Victor; Kang, Sun J.; Kramer, John; Kuperman, Sam; Nurnberger, John, Jr.; Rice, John; Schuckit, Marc; Tischfield, Jay; Edenberg, Howard J.; Goate, Alison; Bierut, Laura; Porjesz, Bernice; Medical and Molecular Genetics, School of MedicineDiscrete time survival analysis was used to assess the age-specific association of event-related oscillations (EROs) and CHRM2 gene variants on the onset of regular alcohol use and alcohol dependence. The subjects were 2,938 adolescents and young adults ages 12-25. Results showed that the CHRM2 gene variants and ERO risk factors had hazards which varied considerably with age. The bulk of the significant age-specific associations occurred in those whose age of onset was under 16. These associations were concentrated in those subjects who at some time took an illicit drug. These results are consistent with studies which associate greater rates of alcohol dependence among those who begin drinking at an early age. The age specificity of the genetic and neurophysiological factors is consistent with recent studies of adolescent brain development, which locate an interval of heightened vulnerability to substance use disorders in the early to mid teens.Item High Polygenic Risk Scores Are Associated With Early Age of Onset of Alcohol Use Disorder in Adolescents and Young Adults at Risk(Elsevier, 2022-10) Nurnberger, John I., Jr.; Wang, Yumin; Zang, Yong; Lai, Dongbing; Wetherill, Leah; Edenberg, Howard J.; Aliev, Fazil; Plawecki, Martin H.; Chorlian, David; Chan, Grace; Bucholz, Kathleen; Bauer, Lance; Kamarajan, Chella; Salvatore, Jessica E.; Kapoor, Manav; Hesselbrock, Victor; Dick, Danielle; Bierut, Laura; McCutcheon, Vivia; Meyers, Jacquelyn L.; Porjesz, Bernice; Kramer, John; Kuperman, Samuel; Kinreich, Sivan; Anokhin, Andrey P.; Collaborative Study on the Genetics of Alcoholism; Psychiatry, School of MedicineBackground Genome-wide association studies have been conducted in alcohol use disorder (AUD), and they permit the use of polygenic risk scores (PRSs), in combination with clinical variables, to predict the onset of AUD in vulnerable populations. Methods A total of 2794 adolescent/young adult subjects from the Collaborative Study on the Genetics of Alcoholism were followed, with clinical assessments every 2 years. Subjects were genotyped using a genome-wide chip. Separate PRS analyses were performed for subjects of European ancestry and African ancestry. Age of onset of DSM-5 AUD was evaluated using the Cox proportional hazard model. Predictive power was assessed using receiver operating characteristic curves and by analysis of the distribution of PRS. Results European ancestry subjects with higher than median PRSs were at greater risk for onset of AUD than subjects with lower than median PRSs (p = 3 × 10–7). Area under the curve for the receiver operating characteristic analysis peaked at 0.88 to 0.95 using PRS plus sex, family history, comorbid disorders, age at first drink, and peer drinking; predictive power was primarily driven by clinical variables. In this high-risk sample, European ancestry subjects with a PRS score in the highest quartile showed a 72% risk for developing AUD and a 35% risk of developing severe AUD (compared with risks of 54% and 16%, respectively, in the lowest quartile). Conclusions Predictive power for PRSs in the extremes of the distribution suggests that these may have future clinical utility. Uncertainties in interpretation at the individual level still preclude current application.Item How Phenotype and Developmental Stage Affect the Genes We Find: GABRA2 and Impulsivity(Cambridge University Press, 2013) Dick, Danielle M.; Aliev, Fazil; Latendresse, Shawn; Porjesz, Bernice; Schuckit, Marc; Rangaswamy, Madhavi; Hesselbrock, Victor; Edenberg, Howard; Nurnberger, John, Jr.; Agrawal, Arpana; Bierut, Laura; Wang, Jen; Bucholz, Kathy; Kuperman, Samuel; Kramer, John; Biochemistry and Molecular Biology, School of MedicineContext: The detection and replication of genes involved in psychiatric outcome has been notoriously difficult. Phenotypic measurement has been offered as one explanation, although most of this discussion has focused on problems with binary diagnoses. Objective: This article focuses on two additional components of phenotypic measurement that deserve further consideration in evaluating genetic associations: (1) the measure used to reflect the outcome of interest, and (2) the developmental stage of the study population. We focus our discussion of these issues around the construct of impulsivity and externalizing disorders, and the association of these measures with a specific gene, GABRA2. Design, setting, and participants: Data were analyzed from the Collaborative Study on the Genetics of Alcoholism Phase IV assessment of adolescents and young adults (ages 12-26; N = 2,128). Main outcome measures: Alcohol dependence, illicit drug dependence, childhood conduct disorder, and adult antisocial personality disorder symptoms were measured by psychiatric interview; Achenbach youth/adult self-report externalizing scale; Zuckerman Sensation-Seeking scale; Barratt Impulsivity scale; NEO extraversion and consciousness. Results: GABRA2 was associated with subclinical levels of externalizing behavior as measured by the Achenbach in both the adolescent and young adult samples. Contrary to previous associations in adult samples, it was not associated with clinical-level DSM symptom counts of any externalizing disorders in these younger samples. There was also association with sensation-seeking and extraversion, but only in the adolescent sample. There was no association with the Barratt impulsivity scale or conscientiousness. Conclusions: Our results suggest that the pathway by which GABRA2 initially confers risk for eventual alcohol problems begins with a predisposition to sensation-seeking early in adolescence. The findings support the heterogeneous nature of impulsivity and demonstrate that both the measure used to assess a construct of interest and the age of the participants can have profound implications for the detection of genetic associations.Item Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci(Springer Nature, 2019-01-07) Erzurumluoglu, A. Mesut; Liu, Mengzhen; Jackson, Victoria E.; Barnes, Daniel R.; Datta, Gargi; Melbourne, Carl A.; Young, Robin; Batini, Chiara; Surendran, Praveen; Jiang, Tao; Adnan, Sheikh Daud; Afaq, Saima; Agrawal, Arpana; Altmaier, Elisabeth; Antoniou, Antonis C.; Asselbergs, Folkert W.; Baumbach, Clemens; Bierut, Laura; Bertelsen, Sarah; Boehnke, Michael; Bots, Michiel L.; Brazel, David M.; Chambers, John C.; Chang-Claude, Jenny; Chen, Chu; Corley, Janie; Chou, Yi-Ling; David, Sean P.; Boer, Rudolf A. de; Leeuw, Christiaan A. de; Dennis, Joe G.; Dominiczak, Anna F.; Dunning, Alison M.; Easton, Douglas F.; Eaton, Charles; Elliott, Paul; Evangelou, Evangelos; Faul, Jessica D.; Foroud, Tatiana; Goate, Alison; Gong, Jian; Grabe, Hans J.; Haessler, Jeff; Haiman, Christopher; Hallmans, Göran; Hammerschlag, Anke R.; Harris, Sarah E.; Hattersley, Andrew; Heath, Andrew; Hsu, Chris; Iacono, William G.; Kanoni, Stavroula; Kapoor, Manav; Kaprio, Jaakko; Kardia, Sharon L.; Karpe, Fredrik; Kontto, Jukka; Kooner, Jaspal S.; Kooperberg, Charles; Kuulasmaa, Kari; Laakso, Markku; Lai, Dongbing; Langenberg, Claudia; Le, Nhung; Lettre, Guillaume; Loukola, Anu; Luan, Jian’an; Madden, Pamela A. F.; Mangino, Massimo; Marioni, Riccardo E.; Marouli, Eirini; Marten, Jonathan; Martin, Nicholas G.; McGue, Matt; Michailidou, Kyriaki; Mihailov, Evelin; Moayyeri, Alireza; Moitry, Marie; Müller-Nurasyid, Martina; Naheed, Aliya; Nauck, Matthias; Neville, Matthew J.; Nielsen, Sune Fallgaard; North, Kari; Perola, Markus; Pharoah, Paul D. P.; Pistis, Giorgio; Polderman, Tinca J.; Posthuma, Danielle; Poulter, Neil; Qaiser, Beenish; Rasheed, Asif; Reiner, Alex; Renström, Frida; Rice, John; Rohde, Rebecca; Rolandsson, Olov; Samani, Nilesh J.; Samuel, Maria; Schlessinger, David; Scholte, Steven H.; Scott, Robert A.; Sever, Peter; Shao, Yaming; Shrine, Nick; Smith, Jennifer A.; Starr, John M.; Stirrups, Kathleen; Stram, Danielle; Stringham, Heather M.; Tachmazidou, Ioanna; Tardif, Jean-Claude; Thompson, Deborah J.; Tindle, Hilary A.; Tragante, Vinicius; Trompet, Stella; Turcot, Valerie; Tyrrell, Jessica; Vaartjes, Ilonca; Leij, Andries R. van der; Meer, Peter van der; Varga, Tibor V.; Verweij, Niek; Völzke, Henry; Wareham, Nicholas J.; Warren, Helen R.; Weir, David R.; Weiss, Stefan; Wetherill, Leah; Yaghootkar, Hanieh; Yavas, Ersin; Jiang, Yu; Chen, Fang; Zhan, Xiaowei; Zhang, Weihua; Zhao, Wei; Zhao, Wei; Zhou, Kaixin; Amouyel, Philippe; Blankenberg, Stefan; Caulfield, Mark J.; Chowdhury, Rajiv; Cucca, Francesco; Deary, Ian J.; Deloukas, Panos; Angelantonio, Emanuele Di; Ferrario, Marco; Ferrières, Jean; Franks, Paul W.; Frayling, Tim M.; Frossard, Philippe; Hall, Ian P.; Hayward, Caroline; Jansson, Jan-Håkan; Jukema, J. Wouter; Kee, Frank; Männistö, Satu; Metspalu, Andres; Munroe, Patricia B.; Nordestgaard, Børge Grønne; Palmer, Colin N. A.; Salomaa, Veikko; Sattar, Naveed; Spector, Timothy; Strachan, David Peter; Harst, Pim van der; Zeggini, Eleftheria; Saleheen, Danish; Butterworth, Adam S.; Wain, Louise V.; Abecasis, Goncalo R.; Danesh, John; Tobin, Martin D.; Vrieze, Scott; Liu, Dajiang J.; Howson, Joanna M. M.; Medical and Molecular Genetics, School of MedicineSmoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P < 5 × 10−8 in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P < 5 × 10−8) in the discovery samples. Ten novel SNVs, including rs12616219 near TMEM182, were followed-up and five of them (rs462779 in REV3L, rs12780116 in CNNM2, rs1190736 in GPR101, rs11539157 in PJA1, and rs12616219 near TMEM182) replicated at a Bonferroni significance threshold (P < 4.5 × 10−3) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, in CCDC141 and two low-frequency SNVs in CEP350 and HDGFRP2. Functional follow-up implied that decreased expression of REV3L may lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation.Item 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 MedicineGenetic 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.Item Multi-trait genome-wide association study of opioid addiction: OPRM1 and beyond(Springer Nature, 2022-10-07) Gaddis, Nathan; Mathur, Ravi; Marks, Jesse; Zhou, Linran; Quach, Bryan; Waldrop, Alex; Levran, Orna; Agrawal, Arpana; Randesi, Matthew; Adelson, Miriam; Jeffries, Paul W.; Martin, Nicholas G.; Degenhardt, Louisa; Montgomery, Grant W.; Wetherill, Leah; Lai, Dongbing; Bucholz, Kathleen; Foroud, Tatiana; Porjesz, Bernice; Runarsdottir, Valgerdur; Tyrfingsson, Thorarinn; Einarsson, Gudmundur; Gudbjartsson, Daniel F.; Webb, Bradley Todd; Crist, Richard C.; Kranzler, Henry R.; Sherva, Richard; Zhou, Hang; Hulse, Gary; Wildenauer, Dieter; Kelty, Erin; Attia, John; Holliday, Elizabeth G.; McEvoy, Mark; Scott, Rodney J.; Schwab, Sibylle G.; Maher, Brion S.; Gruza, Richard; Kreek, Mary Jeanne; Nelson, Elliot C.; Thorgeirsson, Thorgeir; Stefansson, Kari; Berrettini, Wade H.; Gelernter, Joel; Edenberg, Howard J.; Bierut, Laura; Hancock, Dana B.; Johnson, Eric Otto; Medical and Molecular Genetics, School of MedicineOpioid addiction (OA) is moderately heritable, yet only rs1799971, the A118G variant in OPRM1, has been identified as a genome-wide significant association with OA and independently replicated. We applied genomic structural equation modeling to conduct a GWAS of the new Genetics of Opioid Addiction Consortium (GENOA) data together with published studies (Psychiatric Genomics Consortium, Million Veteran Program, and Partners Health), comprising 23,367 cases and effective sample size of 88,114 individuals of European ancestry. Genetic correlations among the various OA phenotypes were uniformly high (rg > 0.9). We observed the strongest evidence to date for OPRM1: lead SNP rs9478500 (p = 2.56 × 10-9). Gene-based analyses identified novel genome-wide significant associations with PPP6C and FURIN. Variants within these loci appear to be pleiotropic for addiction and related traits.