Expanding the genetic architecture of nicotine dependence and its shared genetics with multiple traits

Bryan C. Quach, Michael J. Bray, Nathan C. Gaddis, Mengzhen Liu, Teemu Palviainen, Camelia C. Minica, Stephanie Zellers, Richard Sherva, Fazil Aliev, Michael Nothnagel, Kendra A. Young, Jesse A. Marks, Hannah Young, Megan U. Carnes, Yuelong Guo, Alex Waldrop, Nancy Y.A. Sey, Maria T. Landi, Daniel W. McNeil, Dmitriy DrichelLindsay A. Farrer, Christina A. Markunas, Jacqueline M. Vink, Jouke Jan Hottenga, William G. Iacono, Henry R. Kranzler, Nancy L. Saccone, Michael C. Neale, Pamela Madden, Marcella Rietschel, Mary L. Marazita, Matthew McGue, Hyejung Won, Georg Winterer, Richard Grucza, Danielle M. Dick, Joel Gelernter, Neil E. Caporaso, Timothy B. Baker, Dorret I. Boomsma, Jaakko Kaprio, John E. Hokanson, Scott Vrieze, Laura J. Bierut, Eric O. Johnson, Dana B. Hancock

Research output: Contribution to journalArticlepeer-review

48 Scopus citations


Cigarette smoking is the leading cause of preventable morbidity and mortality. Genetic variation contributes to initiation, regular smoking, nicotine dependence, and cessation. We present a Fagerström Test for Nicotine Dependence (FTND)-based genome-wide association study in 58,000 European or African ancestry smokers. We observe five genome-wide significant loci, including previously unreported loci MAGI2/GNAI1 (rs2714700) and TENM2 (rs1862416), and extend loci reported for other smoking traits to nicotine dependence. Using the heaviness of smoking index from UK Biobank (N = 33,791), rs2714700 is consistently associated; rs1862416 is not associated, likely reflecting nicotine dependence features not captured by the heaviness of smoking index. Both variants influence nearby gene expression (rs2714700/MAGI2-AS3 in hippocampus; rs1862416/TENM2 in lung), and expression of genes spanning nicotine dependence-associated variants is enriched in cerebellum. Nicotine dependence (SNP-based heritability = 8.6%) is genetically correlated with 18 other smoking traits (rg = 0.40–1.09) and co-morbidities. Our results highlight nicotine dependence-specific loci, emphasizing the FTND as a composite phenotype that expands genetic knowledge of smoking.

Original languageEnglish (US)
Article number5562
JournalNature communications
Issue number1
StatePublished - Dec 1 2020

Bibliographical note

Funding Information:
This work was supported by the National Institute on Drug Abuse grant numbers R01 DA042090 (PI: DBH) and R01 DA036583 (PI: LJB) and by National Cancer Institute grant number U19 CA203654 (LJB; PI: Amos). The authors thank deCODE Genetics / Amgen and its investigators (Gunnar W. Reginsson, Thorgeir E. Thorgeirsson, and Kari Stefansson) for their data contributions, which were supported in part by NIDA R01 DA017932 (PI: Kari Stefansson). Acknowledgments for all other ND studies, which were contributed by the authors and/or made publicly available, are included in Supplementary Note 1. UK Biobank Resource data were obtained under Application Number 24603.

Publisher Copyright:
© 2020, The Author(s).


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