PT  - JOURNAL ARTICLE
AU  - Bryan C. Quach
AU  - Michael J. Bray
AU  - Nathan C. Gaddis
AU  - Mengzhen Liu
AU  - Teemu Palviainen
AU  - Camelia C. Minica
AU  - Stephanie Zellers
AU  - Richard Sherva
AU  - Fazil Aliev
AU  - Michael Nothnagel
AU  - Kendra A. Young
AU  - Jesse A. Marks
AU  - Hannah Young
AU  - Megan U. Carnes
AU  - Yuelong Guo
AU  - Alex Waldrop
AU  - Nancy Y.A. Sey
AU  - Maria T. Landi
AU  - Daniel W. McNeil
AU  - Dmitriy Drichel
AU  - Lindsay A. Farrer
AU  - Christina A. Markunas
AU  - Jacqueline M. Vink
AU  - Jouke-Jan Hottenga
AU  - William G. Iacono
AU  - Henry R. Kranzler
AU  - Nancy L. Saccone
AU  - Michael C. Neale
AU  - Pamela Madden
AU  - Marcella Rietschel
AU  - Mary L. Marazita
AU  - Matthew McGue
AU  - Hyejung Won
AU  - Georg Winterer and the German Nicotine Cohort Study
AU  - Richard Grucza
AU  - Danielle M. Dick
AU  - Joel Gelernter
AU  - Neil E. Caporaso
AU  - Timothy B. Baker
AU  - Dorret I. Boomsma
AU  - Jaakko Kaprio
AU  - John E. Hokanson
AU  - Scott Vrieze
AU  - Laura J. Bierut
AU  - Eric O. Johnson
AU  - Dana B. Hancock
TI  - Expanding the Genetic Architecture of Nicotine Dependence and its Shared Genetics with Multiple Traits: Findings from the Nicotine Dependence GenOmics (iNDiGO) Consortium
AID  - 10.1101/2020.01.15.898858
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.01.15.898858
4099  - http://biorxiv.org/content/early/2020/07/09/2020.01.15.898858.short
4100  - http://biorxiv.org/content/early/2020/07/09/2020.01.15.898858.full
AB  - Cigarette smoking is the leading cause of preventable morbidity and mortality. Knowledge is evolving on genetics underlying initiation, regular smoking, nicotine dependence (ND), and cessation. We performed a genome-wide association study using the Fagerström Test for ND (FTND) in 58,000 smokers of European or African ancestry. Five genome-wide significant loci, including two novel loci MAGI2/GNAI1 (rs2714700) and TENM2 (rs1862416) were identified, and loci reported for other smoking traits were extended to ND. Using the heaviness of smoking index (HSI) in the UK Biobank (N=33,791), rs2714700 was consistently associated, but rs1862416 was not associated, likely reflecting ND features not captured by the HSI. Both variants were cis-eQTLs (rs2714700 for MAGI2-AS3 in hippocampus, rs1862416 for TENM2 in lung), and expression of genes spanning ND-associated variants was enriched in cerebellum. SNP-based heritability of ND was 8.6%, and ND was genetically correlated with 17 other smoking traits (rg=0.40–0.95) and co-morbidities. Our results emphasize the FTND as a composite phenotype that expands genetic knowledge of smoking, including loci specific to ND.Competing Interest StatementL.J.B. and the spouse of N.L.S. are listed as inventors on U.S. Patent 8,080,371, 'Markers for Addiction' covering the use of certain SNPs in determining the diagnosis, prognosis, and treatment of addiction. Y.G. is an employee of GeneCentric Therapeutics. Although unrelated to this research, H.R.K. is an advisory board member for Dicerna and a member of the American Society of Clinical Psychopharmacology's Alcohol Clinical Trials Initiative, which was supported in the last 3 years by AbbVie, Alkermes, Ethypharm, Indivior, Lilly, Lundbeck, Otsuka, Pfizer, Arbor and Amygdala Neurosciences. H.R.K. and J.G. are named as inventors on PCT patent application #15/878,640 entitled: "Genotype-guided dosing of opioid agonists," filed January 24, 2018. J.K. consulted for Pfizer in 2012-2015 on ND. All other authors declare no conflict of interest.