Expanding the Genetic Architecture of Nicotine Dependence and its Shared Genetics with Multiple Traits: Findings from the Nicotine Dependence GenOmics (iNDiGO) Consortium

Bryan C. Quach; Michael A. Bray; Nathan Gaddis; Mengzhen Liu; Teemu Palviainen; Camelia C. Minică; Stephanie M. Zellers; Richard Sherva; Fazil Alıev; Michael Nothnagel; Kendra A. Young; Jesse A. Marks; Hannah E. Young; Megan Ulmer Carnes; Yuelong Guo; Alex Waldrop; Nancy Y. A. Sey; Maria Teresa Landi; Daniel W. McNeil; Dmitriy Drichel; Lindsay A. Farrer; Christina A. Markunas; Jacqueline M. Vink; Jouke‐Jan Hottenga; William G. Iacono; Henry R. Kranzler; Nancy L. Saccone; Michael Churton Neale; Pamela A. F. Madden; Marcella Rietschel

doi:10.1038/s41467-020-19265-z

GenomicsNature CommunicationsNov 3, 2020

Peer-reviewed journal article

Expanding the Genetic Architecture of Nicotine Dependence and its Shared Genetics with Multiple Traits: Findings from the Nicotine Dependence GenOmics (iNDiGO) Consortium

Bryan C. Quach iD, Michael A. Bray iD, Nathan Gaddis iD, Mengzhen Liu iD, Teemu Palviainen iD, Camelia C. Minică iD, Stephanie M. Zellers iD, Richard Sherva iD, Fazil Alıev iD, Michael Nothnagel iD, Kendra A. Young iD, Jesse A. Marks iD, Hannah E. Young iD, Megan Ulmer Carnes iD, Yuelong Guo iD, Alex Waldrop iD, Nancy Y. A. Sey iD, Maria Teresa Landi iD, Daniel W. McNeil iD, Dmitriy Drichel iD, Lindsay A. Farrer iD, Christina A. Markunas iD, Jacqueline M. Vink iD, Jouke‐Jan Hottenga iD, William G. Iacono iD, , Dana B. Hancock iD

Abstract

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 Fagerstrom 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.

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