Journal Article

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

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

2020

Overview

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 ( r g  = 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. There is strong genetic evidence for cigarette smoking behaviors, yet little is known on nicotine dependence (ND). Here, the authors perform a genome-wide association study on ND in 58,000 smokers, identifying five genome-wide significant loci.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 45 / 45/43 / 631/208/1515 / 631/208/205/2138 / Cerebellum / Cigarette smoking / Cigarettes / Dependence / Drug dependence / Gene expression / Genetic diversity / Genetic Loci / Genetic Predisposition to Disease / Genetics / Genome-wide association studies / Genome-Wide Association Study / Genomes / Heritability / Humanities and Social Sciences / Humans / Inheritance Patterns - genetics / Linkage Disequilibrium - genetics / Loci / Meta-Analysis as Topic / Molecular Sequence Annotation / Morbidity / multidisciplinary / Nicotine / Phenotype / Phenotypes / Polymorphism, Single Nucleotide - genetics / Quantitative Trait, Heritable / Science / Science (multidisciplinary) / Single-nucleotide polymorphism / Smoking / Tobacco Use Disorder - genetics