Multi-ancestral genome-wide association study of clinically defined nicotine dependence reveals strong genetic correlations with other substance use disorders and health-related traits.
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Johnson Emma C, Lai Dongbing, Balbona Jared V, Miller Alex P, Hatoum Alexander S, Deak Joseph D, Jennings Mariela, Baranger David A A, Galimberti Marco, Sanichwankul Kittipong, Thorgeirsson Thorgeir, Colbert Sarah M C, Adhikari Keyrun, Docherty Anna R, Degenhardt Louisa, Edwards Tobias, Fox Louis, Giannelis Alexandros, Jeffries Paul W, Korhonen Tellervo, Morrison Claire L, Nunez Yaira Z, Palviainen Teemu, Su Mei-Hsin, Romero Villela Pamela N, Wetherill Leah, Willoughby Emily A, Zellers Stephanie M, Bierut Laura J, Buchwald Jadwiga, Copeland William E, Corley Robin P, Friedman Naomi P, Foroud Tatiana M, Gillespie Nathan A, Gizer Ian R, Heath Andrew C, Hickie Ian B, Kaprio Jaakko, Keller Matthew C, Lee James J, Lind Penelope, Madden Pamela A, Maes Hermine H M, Martin Nicholas G, McGue Matt, Medland Sarah E, Nelson Elliot C, Pearson John, Porjesz Bernice, Stallings Michael C, Vrieze Scott, Wilhelmson Kirk C, Kranzler Henry R, Walters Raymond K, Polimanti Renato, Malison Robert, Zhou Hang, Stefansson Kari, Sanchez-Roige Sandra, Potenza Marc, Mutirangura Apiwat, Shotelersuk Vorasuk, Kalayasiri Rasmon, Edenberg Howard J, Gelernter Joel, Agrawal Arpana
Аннотация
METHODS: We conducted a genome-wide association study (GWAS) of nicotine dependence defined using the Diagnostic and Statistical Manual of Mental Disorders (DSM-NicDep) in 61,861 individuals (47,884 of European ancestry [EUR], 10,231 of African ancestry, and 3,746 of East Asian ancestry) and compared the results to other nicotine-related phenotypes.
RESULTS: We replicated the well-known association at the CHRNA5 locus (lead single-nucleotide polymorphism [SNP]: rs147144681, p = 1.27E-11 in EUR; 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 criterion count and all 11 individual diagnostic criteria in the independent National Epidemiologic Survey on Alcohol and Related Conditions-III sample. In genomic structural equation models, DSM-NicDep loaded more strongly on a previously identified factor of general addiction liability than a "problematic tobacco use" factor (a combination of cigarettes per day and nicotine dependence defined by the Fagerström Test for Nicotine Dependence). Finally, DSM-NicDep showed a strong genetic correlation with a GWAS of tobacco use disorder as defined in electronic health records (EHRs).
CONCLUSIONS: Our results suggest 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.