Multi-ancestry meta-analysis of tobacco use disorder prioritizes novel candidate risk genes and reveals associations with numerous health outcomes

Abstract

Tobacco use disorder (TUD) is the most prevalent substance use disorder in the world. Genetic factors influence smoking behaviors, and although strides have been made using genome-wide association studies (GWAS) to identify risk variants, the majority of variants identified have been for nicotine consumption, rather than TUD. We leveraged five biobanks to perform a multi-ancestral meta-analysis of TUD (derived via electronic health records, EHR) in 898,680 individuals (739,895 European, 114,420 African American, 44,365 Latin American). We identified 72 independent risk loci; integration with functional genomic tools uncovered 330 potential risk genes, primarily expressed in the brain. TUD was genetically correlated with smoking and psychiatric traits from traditionally ascertained cohorts, externalizing behaviors in children, and hundreds of medical outcomes, including HIV infection, heart disease, and pain. This work furthers our biological understanding of TUD and establishes EHR as a source of phenotypic information for studying the genetics of TUD.

Genetic Insights into Externalizing and Internalizing Traits through Integration of the Research Domain Criteria and Hierarchical Taxonomy of Psychopathology

“…Ten sets of summary statistics in European-ancestry (EUR) individuals were selected based on existing theory regarding the externalizing spectrum (Supplementary Table 1). We included summary statistics from the largest available GWAS of the following externalizing disorders: attention deficit hyperactivity disorder (ADHD; n = 225,534), 26 four substance use disorders [SUDs; i.e., alcohol (AUD; n = 753,248), 27 cannabis (CanUD; n = 886,025), 28 opioid (OUD; n = 425,944), 29 and tobacco (TUD; n = 495,005) 30 ]. We also included broader measures of externalizing psychopathology [age of first sexual intercourse (AgeSex; reverse-coded; n = 317,694), 14 general risk tolerance (Risk; n = 431,126), 14,31 number of sexual partners (NumSex; n = 370,711), 14,31 antisocial behavior (ASB; n = 16,400), 32 and automobile speeding propensity (n = 404,291) 31 ].…”

A Multivariate Genome-Wide Association Study Reveals Neural Correlates and Common Biological Mechanisms of Psychopathology Spectra

“…Ten sets of summary statistics in European-ancestry (EUR) individuals were selected based on existing theory regarding the externalizing spectrum (Supplementary Table 1). We included summary statistics from the largest available GWAS of the following externalizing disorders: attention de cit hyperactivity disorder (ADHD; n = 225,534), 26 four substance use disorders [SUDs; i.e., alcohol (AUD; n = 753,248), 27 cannabis (CanUD; n = 886,025), 28 opioid (OUD; n = 425,944), 29 and tobacco (TUD; n = 495,005) 30 ]. We also included broader measures of externalizing psychopathology [age of rst sexual intercourse (AgeSex; reverse-coded; n = 317,694), 14 general risk tolerance (Risk; n = 431,126), 14,31 number of sexual partners (NumSex; n = 370,711), 14,31 antisocial behavior (ASB; n = 16,400), 32 and automobile speeding propensity (n = 404,291) 31 ].…”

A single-nucleus transcriptomic atlas of medium spiny neurons in the rat nucleus accumbens

“…Cleaned data from mouse and human NAc can be obtained at GEO accession number GSE118020 and https://github.com/LieberInstitute/10xPilot_snRNAseq-human, respectively. Gene-level summary statistics from SUD GWAS are available from their respective groups [35][36][37] .…”

“…Expression patterns for glutamate, GABA, and acetylcholine receptor genes are presented to further phenotype these subclusters. Finally, MSNs from rat, mouse 26 , and human 25 were integrated together and cells scored using genome-wide association study (GWAS) summary statistics for substance use disorder (SUD) phenotypes [35][36][37] , revealing potentially differential roles for MSN subpopulations in alcohol use disorder (AUD), alcohol consumption (AUDIT-C), opioid use disorder (OUD), and tobacco use disorder (TUD).…”