Multi-ancestral genome-wide association study of clinically defined nicotine dependence reveals strong genetic correlations with other substance use disorders and health-related traits.

Comparing genetic correlations (r g) for DSM-NicDep, FTND, ICD-TUD, and CPD with other traits in European ancestry data. Traits include other substance use disorders (CanUD, cannabis use disorder [Levey et al., 2023]; OUD, opioid use disorder [Deak et al., 2022]; PAU, problematic alcohol use [Zhou et al., 2023]; ICD-TUD, ICD-based tobacco use disorder [Toikumo et al., 2024]), substance use behaviors (CanUse, cannabis ever-use [Pasman et al., 2018]; DPW, drinks per week [Saunders et al., 2022]; SmkInit, smoking initiation [Saunders et al., 2022]; SmkCessation, smoking cessation [Saunders et al., 2022]), psychiatric disorders and other mental health phenotypes (ADHD, attention deficit hyperactivity disorder [Demontis et al., 2023]; PTSD, post-traumatic stress disorder [Nievergelt et al., 2019]), biomarkers (Cot + HC, cotinine +3-hydroxycotinine [Buchwald et al., 2021]), lung health-related traits (FEV1, forced expiratory volume in 1 s), risk tolerance (Linnér et al., 2019), socioeconomic status-related traits (Edu attainment, educational attainment [Lee et al., 2018]; TDI, Townsend Deprivation Index]), executive function (EF [Hatoum, Morrison, et al., 2023]), and anthropometric measures (BMI, body mass index [Yengo et al., 2018]; height [Yengo et al., 2022]). * indicates r gs that significantly differ between DSM-NicDep and FTND at 𝛼 = 0.002 (Bonferroni correction for 24 comparisons).

A modified Addiction-Risk-Factor model. This model is patterned upon the common factor model in Figure 1A of Hatoum et al., 2022, but updated with new, larger versions of the OUD (Deak et al., 2022), PAU (Zhou et al., 2023), and CanUD GWAS (Levey et al., 2023) and using three different phenotypes for tobacco GWAS. (a) DSM-NicDep. (b) PTU (Hatoum et al., 2022) GWAS. (c) ICD-TUD (Toikumo et al., 2024). *Significant loadings at p < 0.05. Addiction-rf, the Addiction-Risk-Factor; CanUD, cannabis use disorder; DSM-NicDep, nicotine dependence; ICD-TUD, ICD-based tobacco use disorder; OUD, opioid use disorder; PAU, problematic alcohol use.

Polygenic scores (PGSs) for DSM-NicDep (a), FTND (b), and DSM-NicDep, FTND, ICD-TUD, and CPD (c) predict individual DSM-5 nicotine use disorder and FTND criteria and total criterion or item counts, respectively, in the European ancestry subset of the NESARC-III sample. Filled circles represent estimates that were significant after FDR correction, while open circles represent estimates that were not significant after FDR correction. Hazardous = Recurrent use in physically hazardous situations; Fail = Recurrent use resulting in failure to fulfill major role obligations at work, school, or home; Tolerance = Marked need for increased amount to get the same effect or diminished effect of the same amount; TimeSpent = Great deal of time spent in activities necessary to obtain or use; GiveUp = Important recreational, social, or occupational activities given up or reduced; Problems = Use despite knowledge of persistent/recurrent physical/psychological problems; Larger = Taken over larger amounts/longer periods than intended; Withdrawal = Withdrawal syndrome or use to relieve/avoid syndrome; Cutdown = Persistent desire or unsuccessful attempts to cut down or control use; Crave = Craving or strong urge or desire to use; Social = Persistent use despite recurring social/interpersonal problems caused or exacerbated by use; FTND1_within30min = How soon after you wake up do you smoke your first cigarette?; FTND2_prohibited = Do you find it difficult to refrain from smoking in places where it is forbidden?; FTND3_morning = Which cigarette would you hate most to give up?; FTND5_waking = Do you smoke more frequently during the first hours after waking than during the rest of the day?