Multi-ancestry meta-analysis of tobacco use disorder identifies 461 potential risk genes and reveals associations with multiple health outcomes

Sylvanus Toikumo, Mariela V. Jennings, Benjamin K. Pham, Hyunjoon Lee, Travis T. Mallard, Sevim B. Bianchi, John J. Meredith, Laura Vilar-Ribó, Heng Xu, Alexander S. Hatoum, Emma C. Johnson, Vanessa K. Pazdernik, Zeal Jinwala, Shreya R. Pakala, Brittany S. Leger, Maria Niarchou, Michael Ehinmowo, Greg D. Jenkins, Anthony Batzler, Richard Pendegraft, Abraham A. Palmer, Hang Zhou, Joanna M. Biernacka, Brandon J. Coombes, Joel Gelernter, Ke Xu, Dana B. Hancock, Nancy J. Cox, Jordan W. Smoller, Lea K. Davis, Amy C. Justice, Henry R. Kranzler, Rachel L. Kember and Sandra Sanchez-Roige ()
Additional contact information
Sylvanus Toikumo: Crescenz VAMC
Mariela V. Jennings: University of California San Diego
Benjamin K. Pham: University of California San Diego
Hyunjoon Lee: Vanderbilt University Medical Center
Travis T. Mallard: Massachusetts General Hospital
Sevim B. Bianchi: University of California San Diego
John J. Meredith: University of California San Diego
Laura Vilar-Ribó: Universitat Autònoma de Barcelona
Heng Xu: University of California San Diego
Alexander S. Hatoum: Washington University in St. Louis
Emma C. Johnson: Washington University in St. Louis
Vanessa K. Pazdernik: Mayo Clinic
Zeal Jinwala: University of Pennsylvania Perelman School of Medicine
Shreya R. Pakala: University of California San Diego
Brittany S. Leger: University of California San Diego
Maria Niarchou: Vanderbilt University
Michael Ehinmowo: University of Ibadan
Greg D. Jenkins: Mayo Clinic
Anthony Batzler: Mayo Clinic
Richard Pendegraft: Mayo Clinic
Abraham A. Palmer: University of California San Diego
Hang Zhou: Yale University School of Medicine
Joanna M. Biernacka: Mayo Clinic
Brandon J. Coombes: Mayo Clinic
Joel Gelernter: Yale University School of Medicine
Ke Xu: Yale University School of Medicine
Dana B. Hancock: RTI International
Nancy J. Cox: Vanderbilt University Medical Center
Jordan W. Smoller: Massachusetts General Hospital
Lea K. Davis: Vanderbilt University Medical Center
Amy C. Justice: Veterans Affairs Connecticut Healthcare System
Henry R. Kranzler: Crescenz VAMC
Rachel L. Kember: Crescenz VAMC
Sandra Sanchez-Roige: University of California San Diego

Nature Human Behaviour, 2024, vol. 8, issue 6, 1177-1193

Abstract: Abstract Tobacco use disorder (TUD) is the most prevalent substance use disorder in the world. Genetic factors influence smoking behaviours and although strides have been made using genome-wide association studies to identify risk variants, most variants identified have been for nicotine consumption, rather than TUD. Here we leveraged four US biobanks to perform a multi-ancestral meta-analysis of TUD (derived via electronic health records) in 653,790 individuals (495,005 European, 114,420 African American and 44,365 Latin American) and data from UK Biobank (ncombined = 898,680). We identified 88 independent risk loci; integration with functional genomic tools uncovered 461 potential risk genes, primarily expressed in the brain. TUD was genetically correlated with smoking and psychiatric traits from traditionally ascertained cohorts, externalizing behaviours in children and hundreds of medical outcomes, including HIV infection, heart disease and pain. This work furthers our biological understanding of TUD and establishes electronic health records as a source of phenotypic information for studying the genetics of TUD.

Date: 2024
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DOI: 10.1038/s41562-024-01851-6

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