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Introduction Tobacco use disorder is a complex behavior with a strong genetic component. Genome-wide association studies (GWAS) on smoking behaviors allow for the creation of polygenic risk scores (PRSs) to approximate genetic vulnerability. However, the utility of smoking-related PRSs in predicting smoking cessation in clinical trials remains unknown. Aims and Methods We evaluated the association between polygenic risk scores and bioverified smoking abstinence in a meta-analysis of two randomized, placebo-controlled smoking cessation trials. PRSs of smoking behaviors were created using the GWAS and Sequencing Consortium of Alcohol and Nicotine use (GSCAN) consortium summary statistics. We evaluated the utility of using individual PRS of specific smoking behavior versus a combined genetic risk that combines PRS of all four smoking behaviors. Study participants came from the Transdisciplinary Tobacco Use Research Centers (TTURCs) Study (1091 smokers of European descent), and the Genetically Informed Smoking Cessation Trial (GISC) Study (501 smokers of European descent). Results PRS of later age of smoking initiation (OR [95% CI]: 1.20, [1.04–1.37], p = .0097) was significantly associated with bioverified smoking abstinence at end of treatment. In addition, the combined PRS of smoking behaviors also significantly predicted bioverified smoking abstinence (OR [95% CI] 0.71 [0.51–0.99], p = .045). Conclusions PRS of later age at smoking initiation may be useful in predicting smoking cessation at the end of treatment. A combined PRS may be a useful predictor for smoking abstinence by capturing the genetic propensity for multiple smoking behaviors. Implications There is a potential for polygenic risk scores to inform future clinical medicine, and a great need for evidence on whether these scores predict clinically meaningful outcomes. Our meta-analysis provides early evidence for potential utility of using polygenic risk scores to predict smoking cessation amongst smokers undergoing quit attempts, informing further work to optimize the use of polygenic risk scores in clinical care.

Background: Variation in liability to cannabis use disorder has a strong genetic component (estimated twin and family heritability about 50–70%) and is associated with negative outcomes, including increased risk of psychopathology. The aim of the study was to conduct a large genome-wide association study (GWAS) to identify novel genetic variants associated with cannabis use disorder. Methods: To conduct this GWAS meta-analysis of cannabis use disorder and identify associations with genetic loci, we used samples from the Psychiatric Genomics Consortium Substance Use Disorders working group, iPSYCH, and deCODE (20 916 case samples, 363 116 control samples in total), contrasting cannabis use disorder cases with controls. To examine the genetic overlap between cannabis use disorder and 22 traits of interest (chosen because of previously published phenotypic correlations [eg, psychiatric disorders] or hypothesised associations [eg, chronotype] with cannabis use disorder), we used linkage disequilibrium score regression to calculate genetic correlations. Findings: We identified two genome-wide significant loci: a novel chromosome 7 locus (FOXP2, lead single-nucleotide polymorphism [SNP] rs7783012; odds ratio [OR] 1·11, 95% CI 1·07–1·15, p=1·84 × 10 −9) and the previously identified chromosome 8 locus (near CHRNA2 and EPHX2, lead SNP rs4732724; OR 0·89, 95% CI 0·86–0·93, p=6·46 × 10 −9). Cannabis use disorder and cannabis use were genetically correlated (r g 0·50, p=1·50 × 10 −21), but they showed significantly different genetic correlations with 12 of the 22 traits we tested, suggesting at least partially different genetic underpinnings of cannabis use and cannabis use disorder. Cannabis use disorder was positively genetically correlated with other psychopathology, including ADHD, major depression, and schizophrenia. Interpretation: These findings support the theory that cannabis use disorder has shared genetic liability with other psychopathology, and there is a distinction between genetic liability to cannabis use and cannabis use disorder. Funding: National Institute of Mental Health; National Institute on Alcohol Abuse and Alcoholism; National Institute on Drug Abuse; Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing; The European Commission, Horizon 2020; National Institute of Child Health and Human Development; Health Research Council of New Zealand; National Institute on Aging; Wellcome Trust Case Control Consortium; UK Research and Innovation Medical Research Council (UKRI MRC); The Brain & Behavior Research Foundation; National Institute on Deafness and Other Communication Disorders; Substance Abuse and Mental Health Services Administration (SAMHSA); National Institute of Biomedical Imaging and Bioengineering; National Health and Medical Research Council (NHMRC) Australia; Tobacco-Related Disease Research Program of the University of California; Families for Borderline Personality Disorder Research (Beth and Rob Elliott) 2018 NARSAD Young Investigator Grant; The National Child Health Research Foundation (Cure Kids); The Canterbury Medical Research Foundation; The New Zealand Lottery Grants Board; The University of Otago; The Carney Centre for Pharmacogenomics; The James Hume Bequest Fund; National Institutes of Health: Genes, Environment and Health Initiative; National Institutes of Health; National Cancer Institute; The William T Grant Foundation; Australian Research Council; The Virginia Tobacco Settlement Foundation; The VISN 1 and VISN 4 Mental Illness Research, Education, and Clinical Centers of the US Department of Veterans Affairs; The 5th Framework Programme (FP-5) GenomEUtwin Project; The Lundbeck Foundation; NIH-funded Shared Instrumentation Grant S10RR025141; Clinical Translational Sciences Award grants; National Institute of Neurological Disorders and Stroke; National Heart, Lung, and Blood Institute; National Institute of General Medical Sciences.

Background: There is mixed evidence about the relations of current versus past cancer with severe COVID-19 outcomes and how they vary by patient and cancer characteristics. Methods: Electronic health record data of 104,590 adult hospitalized patients with COVID-19 were obtained from 21 United States health systems from February 2020 through September 2021. In-hospital mortality and ICU admission were predicted from current and past cancer diagnoses. Moderation by patient characteristics, vaccination status, cancer type, and year of the pandemic was examined. Results: 6.8% of the patients had current (n = 7,141) and 6.5% had past (n = 6,749) cancer diagnoses. Current cancer predicted both severe outcomes but past cancer did not; adjusted odds ratios (aOR) for mortality were 1.58 [95% confidence interval (CI), 1.46–1.70] and 1.04 (95% CI, 0.96–1.13), respectively. Mortality rates decreased over the pandemic but the incremental risk of current cancer persisted, with the increment being larger among younger vs. older patients. Prior COVID-19 vaccination reduced mortality generally and among those with current cancer (aOR, 0.69; 95% CI, 0.53–0.90). Conclusions: Current cancer, especially among younger patients, posed a substantially increased risk for death and ICU admission among patients with COVID-19; prior COVID-19 vaccination mitigated the risk associated with current cancer. Past history of cancer was not associated with higher risks for severe COVID-19 outcomes for most cancer types. Impact: This study clarifies the characteristics that modify the risk associated with cancer on severe COVID-19 outcomes across the first 20 months of the COVID-19 pandemic. See related commentary by Egan et al., p. 3

Introduction Available evidence is mixed concerning associations between smoking status and COVID-19 clinical outcomes. Effects of nicotine replacement therapy (NRT) and vaccination status on COVID-19 outcomes in smokers are unknown. Methods Electronic health record data from 104 590 COVID-19 patients hospitalized February 1, 2020 to September 30, 2021 in 21 U.S. health systems were analyzed to assess associations of smoking status, in-hospital NRT prescription, and vaccination status with in-hospital death and ICU admission. Results Current (n = 7764) and never smokers (n = 57 454) did not differ on outcomes after adjustment for age, sex, race, ethnicity, insurance, body mass index, and comorbidities. Former (vs never) smokers (n = 33 101) had higher adjusted odds of death (aOR, 1.11; 95% CI, 1.06–1.17) and ICU admission (aOR, 1.07; 95% CI, 1.04–1.11). Among current smokers, NRT prescription was associated with reduced mortality (aOR, 0.64; 95% CI, 0.50–0.82). Vaccination effects were significantly moderated by smoking status; vaccination was more strongly associated with reduced mortality among current (aOR, 0.29; 95% CI, 0.16–0.66) and former smokers (aOR, 0.47; 95% CI, 0.39–0.57) than for never smokers (aOR, 0.67; 95% CI, 0.57, 0.79). Vaccination was associated with reduced ICU admission more strongly among former (aOR, 0.74; 95% CI, 0.66–0.83) than never smokers (aOR, 0.87; 95% CI, 0.79–0.97). Conclusions Former but not current smokers hospitalized with COVID-19 are at higher risk for severe outcomes. SARS-CoV-2 vaccination is associated with better hospital outcomes in COVID-19 patients, especially current and former smokers. NRT during COVID-19 hospitalization may reduce mortality for current smokers. Implications Prior findings regarding associations between smoking and severe COVID-19 disease outcomes have been inconsistent. This large cohort study suggests potential beneficial effects of nicotine replacement therapy on COVID-19 outcomes in current smokers and outsized benefits of SARS-CoV-2 vaccination in current and former smokers. Such findings may influence clinical practice and prevention efforts and motivate additional research that explores mechanisms for these effects.

Despite major advancements in genomic medicine, research to optimize the design and communication of genetically informed interventions in behavioral health has lagged. The goal of this study was to engage potential end users in participatory codesign of a personalized genetically informed risk tool to intervene on high-risk health behaviors. We used structured interviews to examine end-user attitudes and interest in personalized genetics, qualitative interviews to guide iterative design of a genetically informed tool, and questionnaires to assess acceptability and potential utility of the tool. Participants expressed strong demand for using personal genetics to inform smoking and alcohol-related disease risk and guide treatment (78%–95% agreed). Via iterative design feedback, we cocreated a genetically informed risk profile featuring (i) explanation of genetic and phenotypic markers used to construct a risk algorithm, (ii) personalized risks and benefits of healthy behavior change, and (iii) recommended actions with referral to freely available resources. Participants demonstrated sufficient understanding and cited motivating behavior change as the most useful purpose of the tool. In three phases, we confirmed strong desire for personalized genetics on high-risk health behaviors; codesigned a genetically informed profile with potential end users; and found high acceptability, comprehensibility, and perceived usefulness of the profile. As scientific discovery of genomic medicine advances in behavioral health, we must develop the tools to communicate these discoveries to consumers who stand to benefit. The potential of genomic medicine to engage populations and personalize behavioral health treatment depends, in part, on preparatory studies to design for the future implementation of genetically informed interventions.

Purpose The objective of this study is to identify how predisposing characteristics, enabling factors, and health needs are jointly and individually associated with epidemiological patterns of outpatient healthcare utilization for patients who already interact and engage with a large healthcare system. Methods We retrospectively analyzed electronic medical record data from 1,423,166 outpatient clinic visits from 474,674 patients in a large healthcare system from June 2018-March 2019. We evaluated patients who exclusively visited rural clinics versus patients who exclusively visited urban clinics using Chi-square tests and the generalized estimating equation Poisson regression methodology. The outcome was healthcare use defined by the number of outpatient visits to clinics within the healthcare system and independent variables included age, gender, race, ethnicity, smoking status, health status, and rural or urban clinic location. Supplementary analyses were conducted observing healthcare use patterns within rural and urban clinics separately and within primary care and specialty clinics separately. Findings Patients in rural clinics vs. urban clinics had worse health status [χ2 = 935.1, df = 3, p Conclusions Within the large healthcare system, patients in rural clinics had lower outpatient healthcare utilization compared to their urban counterparts despite having potentially elevated health needs reflected by a higher number of unique health diagnoses documented in their electronic health records after adjusting for multiple factors. This work can inform future studies exploring the roots and ramifications of rural-urban healthcare utilization differences and rural healthcare disparities.

Main objective There is limited information on how patient outcomes have changed during the COVID-19 pandemic. This study characterizes changes in mortality, intubation, and ICU admission rates during the first 20 months of the pandemic. Study design and methods University of Wisconsin researchers collected and harmonized electronic health record data from 1.1 million COVID-19 patients across 21 United States health systems from February 2020 through September 2021. The analysis comprised data from 104,590 adult hospitalized COVID-19 patients. Inclusion criteria for the analysis were: (1) age 18 years or older; (2) COVID-19 ICD-10 diagnosis during hospitalization and/or a positive COVID-19 PCR test in a 14-day window (+/- 7 days of hospital admission); and (3) health system contact prior to COVID-19 hospitalization. Outcomes assessed were: (1) mortality (primary), (2) endotracheal intubation, and (3) ICU admission. Results and significance The 104,590 hospitalized participants had a mean age of 61.7 years and were 50.4% female, 24% Black, and 56.8% White. Overall risk-standardized mortality (adjusted for age, sex, race, ethnicity, body mass index, insurance status and medical comorbidities) declined from 16% of hospitalized COVID-19 patients (95% CI: 16% to 17%) early in the pandemic (February-April 2020) to 9% (CI: 9% to 10%) later (July-September 2021). Among subpopulations, males (vs. females), those on Medicare (vs. those on commercial insurance), the severely obese (vs. normal weight), and those aged 60 and older (vs. younger individuals) had especially high mortality rates both early and late in the pandemic. ICU admission and intubation rates also declined across these 20 months. Conclusions Mortality, intubation, and ICU admission rates improved markedly over the first 20 months of the pandemic among adult hospitalized COVID-19 patients although gains varied by subpopulation. These data provide important information on the course of COVID-19 and identify hospitalized patient groups at heightened risk for negative outcomes. Trial registration ClinicalTrials.gov Identifier: NCT04506528 (https://clinicaltrials.gov/ct2/show/NCT04506528).

Background: Tobacco cessation after a cancer diagnosis can extend patient survival by improving outcomes for primary cancer and preventing secondary cancers. However, smoking is often unaddressed in cancer care, highlighting the need for strategies to increase treatment reach and cessation. This study examined a low-burden, point-of-care tobacco treatment program (ELEVATE) featuring an electronic health record–enabled smoking module and decision support tools to increase the reach and effectiveness of evidence-based smoking cessation treatment. Methods: This study included adult outpatient tobacco smokers (n=13,651) in medical oncology, internal medicine, and surgical oncology clinics from a large midwestern healthcare system. We examined reach and effectiveness of ELEVATE with 2 comparisons: (1) preimplementation versus postimplementation of ELEVATE and (2) ELEVATE versus usual care. Data were evaluated during 2 time periods: preimplementation (January through May 2018) and postimplementation (June through December 2018), with smoking cessation assessed at the last follow-up outpatient encounter during the 6 months after these periods. Results: The proportion of current tobacco smokers receiving cessation treatment increased from pre-ELEVATE to post-ELEVATE (1.6%–27.9%; difference, 26.3%; relative risk, 16.9 [95% CI, 9.8–29.2]; PP=.002). Compared with 17.2% smoking cessation with ELEVATE in the postimplementation time period, achievement of cessation within usual care clinics ranged from 8.2% to 9.9% during this same period. Conclusions: A low-burden, point-of-care tobacco treatment strategy increased tobacco treatment and cessation, thereby improving access to and the impact of evidence-based cessation treatment. Using implementation strategies to embed tobacco treatment in every healthcare encounter promises to engage more smokers in evidence-based treatment and facilitate smoking cessation, thereby improving care cancer for patients who smoke.

Smoking at the time of surgical treatment for lung cancer increases the risk for perioperative morbidity and mortality. The prevalence of persistent smoking in the postoperative period and its association with long-term oncologic outcomes are poorly described.What is the relationship between persistent smoking and long-term outcomes in early-stage lung cancer after surgical treatment?We performed a retrospective cohort study using a uniquely compiled Veterans Health Administration dataset of patients with clinical stage I non-small cell lung cancer (NSCLC) undergoing surgical treatment between 2006 and 2016. We defined persistent smoking as individuals who continued smoking 1 year after surgery and characterized the relationship between persistent smoking and disease-free survival and overall survival.This study included 7,489 patients undergoing surgical treatment for clinical stage I NSCLC. Of 4,562 patients (60.9%) who were smoking at the time of surgery, 2,648 patients (58.0%) continued to smoke at 1 year after surgery. Among 2,927 patients (39.1%) who were not smoking at the time of surgical treatment, 573 (19.6%) relapsed and were smoking at 1 year after surgery. Persistent smoking at 1 year after surgery was associated with significantly shorter overall survival (adjusted hazard ration [aHR], 1.291; 95% CI, 1.197-1.392; P .001). However, persistent smoking was not associated with inferior disease-free survival (aHR, 0.989; 95% CI, 0.884-1.106; P = .84).Persistent smoking after surgery for stage I NSCLC is common and is associated with inferior overall survival. Providers should continue to assess smoking habits in the postoperative period given its disproportionate impact on long-term outcomes after potentially curative treatment for early-stage lung cancer.

Supplemental Digital Content is available in the text., Background Rare variants (minor allele frequency < 1% or 5 %) can help researchers to deal with the confounding issue of ‘missing heritability’ and have a proven role in dissecting the etiology for human diseases and complex traits. Methods We extended the combined multivariate and collapsing (CMC) and weighted sum statistic (WSS) methods and accounted for the effects of population stratification and subgroup effects using stratified analyses by the principal component analysis, named here as ‘str-CMC’ and ‘str-WSS’. To evaluate the validity of the extended methods, we analyzed the Genetic Architecture of Smoking and Smoking Cessation database, which includes African Americans and European Americans genotyped on Illumina Human Omni2.5, and we compared the results with those obtained with the sequence kernel association test (SKAT) and its modification, SKAT-O that included population stratification and subgroup effect as covariates. We utilized the Cochran–Mantel–Haenszel test to check for possible differences in single nucleotide polymorphism allele frequency between subgroups within a gene. We aimed to detect rare variants and considered population stratification and subgroup effects in the genomic region containing 39 acetylcholine receptor-related genes. Results The Cochran–Mantel–Haenszel test as applied to GABRG2 (P = 0.001) was significant. However, GABRG2 was detected both by str-CMC (P= 8.04E-06) and str-WSS (P= 0.046) in African Americans but not by SKAT or SKAT-O. Conclusions Our results imply that if associated rare variants are only specific to a subgroup, a stratified analysis might be a better approach than a combined analysis.

Introduction Reducing adverse events from pharmacologic treatment is an important goal of precision medicine and identifying genetic predictors of adverse events is a step toward this goal. In 2012, King et al. reported associations between genetic variants and adverse events in a placebo-controlled smoking cessation trial of varenicline and bupropion. Strong associations were found between gastrointestinal adverse events and 11 variants in the CHRNA5–CHRNA3–CHRNB4 region of chromosome 15, a region repeatedly associated with smoking-related phenotypes. Our goal was to replicate, in an independent sample, the impact of variants in the CHRNA5–CHRNA3–CHRNB4 region on gastrointestinal adverse events and to extend the analyses to adherence and smoking cessation. Methods The University of Wisconsin Transdisciplinary Tobacco Use Research Center (TTURC) conducted a multiarmed, placebo-controlled smoking cessation trial of bupropion and nicotine replacement therapy that included 985 genotyped European-ancestry participants. We evaluated relationships between our key variables using logistic regression. Results Gastrointestinal adverse events were experienced by 31.6% TTURC participants. Each of the CHRNA5–CHRNA3–CHRNB4 associations from the King et al. study was found in TTURC, with the same direction of effect. Neither these variants nor the gastrointestinal adverse events themselves were associated with adherence to medication or successful smoking cessation. Conclusions Variants in the CHRNA5–CHRNA3–CHRNB4 region of chromosome 15 are associated with gastrointestinal adverse events in smoking cessation. Additional independent variants in this region strengthen the association. The consistency between the results of these two independent studies supports the conclusion that these findings reflect biological response to the use of smoking cessation medication. Implications The fact that our findings from the TTURC smoking cessation trial support the independent findings of King et al. suggest that associations of variants in the CHRNA5–CHRNA3–CHRNB4 region of chromosome 15 with gastrointestinal adverse events while taking medications for smoking cessation reflect biology. However, although adherence to medication was a strong predictor of successful smoking cessation in TTURC, neither adverse events nor the genetic variants associated with them predicted either adherence or successful cessation in this study. Thus, although we should strive to minimize adverse events during treatment, we should not expect that to increase successful smoking cessation substantially.

Aim: This study tests whether polygenic risk scores (PRSs) for nicotine metabolism predict smoking behaviors in independent data. Materials & methods: Linear regression, logistic regression and survival analyses were used to analyze nicotine metabolism PRSs and nicotine metabolism, smoking quantity and smoking cessation. Results: Nicotine metabolism PRSs based on two genome wide association studies (GWAS) meta-analyses significantly predicted nicotine metabolism biomarkers (R2 range: 9.2–16%; minimum p = 7.6 × 10-8). The GWAS top hit variant rs56113850 significantly predicted nicotine metabolism biomarkers (R2 range: 14–17%; minimum p = 4.4 × 10-8). There was insufficient evidence for these PRSs predicting smoking quantity and smoking cessation. Conclusion: Results suggest that nicotine metabolism PRSs based on GWAS meta-analyses predict an individual's nicotine metabolism, so does use of the top hit variant. We anticipate that PRSs will enter clinical medicine, but additional research is needed to develop a more comprehensive genetic score to predict smoking behaviors.

Tobacco cessation treatment for cancer patients is essential to providing comprehensive oncologic care. We have implemented a point of care tobacco treatment care model enabled by electronic health record (EHR) modifications in a comprehensive cancer center. Data are needed on the sustainability of both reach of treatment and effectiveness over time, including the COVID-19 pandemic.Using EHR data from the pre-implementation (P: 5 months) and post-implementation periods (6 month-blocks, T1-T5 for a total of 30 months), we compared two primary outcomes: 1) reach of treatment among those smoking and 2) effectiveness assessed by smoking cessation among those smoking in the subsequent 6 month period. We analyzed the data using generalized estimation equation regression models.With the point of care tobacco treatment care model, reach of treatment increased from pre to post T5 (3.2 % vs. 48.4 %, RR 15.50, 95 % CI 10.56-22.74, p0.0001). Reach of treatment in all post periods (T1-T5 including the COVID-19 pandemic time) remained significantly higher than the pre period. Effectiveness, defined by smoking cessation among those smoking, increased from pre to post T2 before the pandemic (12.4 % vs. 21.4 %, RR 1.57, 95 % CI 1.31-1.87, p0.0001). However, effectiveness, while higher in later post periods (T3, T4), was no longer significantly increased compared with the pre period.A point of care EHR-enabled tobacco treatment care model demonstrates sustained reach up to 30 months following implementation, even during the COVID-19 pandemic and changes in healthcare prioritization. Effectiveness was sustained for 12 months, but did not sustain through the subsequent 12 months.

Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa (BN) and problem alcohol use (genetic correlation [rg], twin-based=0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge-eating, AN without binge-eating, and a BN factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder (MDD). Total sample sizes per phenotype ranged from ~2,400 to ~537,000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (rg=0.18; false discovery rate q=0.0006), cannabis initiation and AN (rg=0.23; qwith binge-eating (rg=0.27; q=0.0016). Conversely, significant negative genetic correlations were observed between three non-diagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge-eating (rgs=-0.19 to −0.23; qs

Because tobacco use remains one of the leading causes of disease, disability, and mortality, tobacco treatment programs should be integrated into medical systems such as hospitals and outpatient centers. Medical providers have a unique, high-impact opportunity to initiate smoking cessation treatment with patients. However, there are several barriers that may hinder the development and implementation of these programs. The purpose of this review was to address such barriers by illustrating several examples of successful tobacco treatment programs in US health-care systems that were contributed by the authors. This includes describing treatment models, billing procedures, and implementation considerations. Using an illustrative review of vignettes from existing programs, various models are outlined, emphasizing commonalities and unique features, strengths and limitations, resources necessary, and other relevant considerations. In addition, clinical research and dissemination trials from each program are described to provide evidence of feasibility and efficacy from these programs. This overview of example treatment models designed for hospitals and outpatient centers provides guidelines for any emerging tobacco cessation services within these contexts. For existing treatment programs, this review provides additional insight and ideas about improving these programs within their respective medical systems.

Introduction The purpose of this study is to examine the predictive utility of polygenic risk scores (PRSs) for smoking behaviors. Aims and Methods Using summary statistics from the Sequencing Consortium of Alcohol and Nicotine use consortium, we generated PRSs of ever smoking, age of smoking initiation, cigarettes smoked per day, and smoking cessation for participants in the population-based Atherosclerosis Risk in Communities (ARIC) study (N = 8638), and the Collaborative Genetic Study of Nicotine Dependence (COGEND) (N = 1935). The outcomes were ever smoking, age of smoking initiation, heaviness of smoking, and smoking cessation. Results In the European ancestry cohorts, each PRS was significantly associated with the corresponding smoking behavior outcome. In the ARIC cohort, the PRS z-score for ever smoking predicted smoking (odds ratio [OR]: 1.37; 95% confidence interval [CI]: 1.31, 1.43); the PRS z-score for age of smoking initiation was associated with age of smoking initiation (OR: 0.87; 95% CI: 0.82, 0.92); the PRS z-score for cigarettes per day was associated with heavier smoking (OR: 1.17; 95% CI: 1.11, 1.25); and the PRS z-score for smoking cessation predicted successful cessation (OR: 1.24; 95% CI: 1.17, 1.32). In the African ancestry cohort, the PRSs did not predict smoking behaviors. Conclusions Smoking-related PRSs were associated with smoking-related behaviors in European ancestry populations. This improvement in prediction is greatest in the lowest and highest genetic risk categories. The lack of prediction in African ancestry populations highlights the urgent need to increase diversity in research so that scientific advances can be applied to populations other than those of European ancestry. Implications This study shows that including both genetic ancestry and PRSs in a single model increases the ability to predict smoking behaviors compared with the model including only demographic characteristics. This finding is observed for every smoking-related outcome. Even though adding genetics is more predictive, the demographics alone confer substantial and meaningful predictive power. However, with increasing work in PRSs, the predictive ability will continue to improve.

The implementation of pharmacogenomic (PGx) testing in psychiatry remains modest, in part due to divergent perceptions of the quality and completeness of the evidence base and diverse perspectives on the clinical utility of PGx testing among psychiatrists and other healthcare providers. Recognizing the current lack of consensus within the field, the International Society of Psychiatric Genetics assembled a group of experts to conduct a narrative synthesis of the PGx literature, prescribing guidelines, and product labels related to psychotropic medications as well as the key considerations and limitations related to the use of PGx testing in psychiatry. The group concluded that to inform medication selection and dosing of several commonly-used antidepressant and antipsychotic medications, current published evidence, prescribing guidelines, and product labels support the use of PGx testing for 2 cytochrome P450 genes (CYP2D6, CYP2C19). In addition, the evidence supports testing for human leukocyte antigen genes when using the mood stabilizers carbamazepine (HLA-A and HLA-B), oxcarbazepine (HLA-B), and phenytoin (CYP2C9, HLA-B). For valproate, screening for variants in certain genes (POLG, OTC, CSP1) is recommended when a mitochondrial disorder or a urea cycle disorder is suspected. Although barriers to implementing PGx testing remain to be fully resolved, the current trajectory of discovery and innovation in the field suggests these barriers will be overcome and testing will become an important tool in psychiatry.

Background Compared to white smokers, Black smokers are at disproportionately higher risk for smoking-related disease, despite consuming fewer cigarettes per day (CPD). To examine racial disparities in biobehavioral influences on smoking and disease risk, we analyzed the relationship between self-reported tobacco dependence and intensity of tobacco smoke exposure per cigarette, on the one hand, and intensity of nicotine intake per cigarette, on the other. Methods In 270 Black and 516 white smokers, smoke exposure was measured by expired carbon monoxide (CO), and nicotine intake was measured by plasma cotinine (COT) and cotinine+3′-hydroxycotinine ([COT + 3HC]). Using linear regression analyses, we analyzed how the Fagerstrom Test for Cigarette Dependence (FTCD) predicted intensity of smoke exposure per cigarette (CO/CPD) and intensity of nicotine intake per cigarette (COT/CPD; [COT + 3HC]/CPD), and how race moderated these relations. Results Overall, Black smokers consumed fewer CPD than white smokers and had higher levels of CO/CPD, COT/CPD, and [COT + 3HC]/CPD. These elevations were most pronounced at lower levels of dependence: amongst Black smokers, FTCD negatively predicted intensity of smoke exposure as measured by CO/CPD (B = −0.12, 95% CI = −0.18, −0.05, p = 0.0003) and intensity of nicotine intake as measured by [COT + 3HC]/CPD (B = −1.31, 95% CI = −2.15, −0.46, p = 0.002). Conclusions Low-dependence Black smokers had higher intensities of both smoke exposure and nicotine intake per cigarette compared to similarly dependent white smokers, suggesting that measures of dependence, exposure, and intake underestimate incremental risk of each cigarette to Black smokers.

Relatively little is known about the possible effects of personalized genetic risk information on smoking, the leading preventable cause of morbidity and mortality. We examined the acceptability and potential behavior change associated with a personalized genetically informed risk tool (RiskProfile) among current smokers. Current smokers (n = 108) were enrolled in a pre-post study with three visits. At visit 1, participants completed a baseline assessment and genetic testing via 23andMe. Participants’ raw genetic data (CHRNA5 variants) and smoking heaviness were used to create a tailored RiskProfile tool that communicated personalized risks of smoking-related diseases and evidence-based recommendations to promote cessation. Participants received their personalized RiskProfile intervention at visit 2, approximately 6 weeks later. Visit 3 involved a telephone-based follow-up assessment 30 days after intervention. Of enrolled participants, 83% were retained across the three visits. Immediately following intervention, acceptability of RiskProfile was high (M = 4.4; SD = 0.6 on scale of 1 to 5); at 30-day follow-up, 89% of participants demonstrated accurate recall of key intervention messages. In the full analysis set of this single-arm trial, cigarettes smoked per day decreased from intervention to 30-day follow-up [11.3 vs. 9.8; difference = 1.5; 95% confidence interval (0.6–2.4); P = 0.001]. A personalized genetically informed risk tool was found to be highly acceptable and associated with a reduction in smoking, although the absence of a control group must be addressed in future research. This study demonstrates proof of concept for translating key basic science findings into a genetically informed risk tool that was used to promote progress toward smoking cessation. Prevention Relevance: This study demonstrates that personal genetic information can be incorporated into a risk feedback tool that was highly acceptable to current smokers and associated with reductions in smoking. These findings may pave the way for effectiveness and implementation research on genetically-informed behavior change interventions to enhance cancer prevention efforts.

Smoking is a major contributor to lung cancer and chronic obstructive pulmonary disease (COPD). Two of the strongest genetic associations of smoking-related phenotypes are the chromosomal regions 15q25.1, encompassing the nicotinic acetylcholine receptor subunit genes CHRNA5-CHRNA3-CHRNB4, and 19q13.2, encompassing the nicotine metabolizing gene CYP2A6. In this study, we examined genetic relations between cigarettes smoked per day, smoking cessation, lung cancer, and COPD. Data consisted of genome-wide association study summary results. Genetic correlations were estimated using linkage disequilibrium score regression software. For each pair of outcomes, z-score-z-score (ZZ) plots were generated. Overall, heavier smoking and decreased smoking cessation showed positive genetic associations with increased lung cancer and COPD risk. The chromosomal region 19q13.2, however, showed a different correlational pattern. For example, the effect allele-C of the sentinel SNP (rs56113850) within CYP2A6 was associated with an increased risk of heavier smoking (z-score = 19.2; p = 1.10 × 10-81 ), lung cancer (z-score = 8.91; p = 5.02 × 10-19 ), and COPD (z-score = 4.04; p = 5.40 × 10-5 ). Surprisingly, this allele-C (rs56113850) was associated with increased smoking cessation (z-score = -8.17; p = 2.52 × 10-26 ). This inverse relationship highlights the need for additional investigation to determine how CYP2A6 variation could increase smoking cessation while also increasing the risk of lung cancer and COPD likely through increased cigarettes smoked per day.

The clinical translation of genetic research on nicotine dependence and treatment response requires acceptance of genetic testing by smokers. This study determines (1) which current smokers are receptive to genetic susceptibility testing for nicotine dependence and (2) to what potential extent smokers motivated to quit desire to take smoking cessation medication when hypothetical genetic results predict their pharmacogenetic medication response. Current smokers from a genetic nicotine dependence study (n = 1306) and an ongoing smoking cessation trial (n = 209) were surveyed on their hypothetical interest in seeing genetic testing results related to risk of nicotine dependence. Most current smokers (84.8%) reported high interest in receiving genetic testing results. Factors associated with high interest included age ≥ 40 years, having a college degree, and a positive medical history (≥1 medical condition). In the ongoing smoking cessation trial, current smokers motivated to quit (n = 474) were surveyed on their desire to take smoking cessation medication given hypothetical below or above average pharmacogenetic responses to the medication. When the hypothetical medication response changed from below to above average, significantly more smokers reported a desire to take medication (from 61.0% to 97.5%, p .0001). These preliminary findings suggest that genetic testing for personalized smoking cessation treatment is well-received by smokers and that a positive hypothetical pharmacogenetic response increases desire to take smoking cessation medication among current smokers motivated to quit. Graphical abstract ᅟ.

Nicotine dependence is highly comorbid with schizophrenia, and the etiology of the comorbidity is unknown. To determine whether there is a genetic correlation of smoking behavior with schizophrenia, genome-wide association study (GWAS) meta-analysis results from five smoking phenotypes (ever/never smoker (N=74,035), age of onset of smoking (N=28,647), cigarettes smoked per day (CPD, N=38,860), nicotine dependence (N=10,666), and current/former smoker (N=40,562)) were compared to GWAS meta-analysis results from schizophrenia (N=79,845) using linkage disequilibrium (LD) score regression. First, the SNP heritability (h(2)(g)) of each of the smoking phenotypes was computed using LD score regression (ever/never smoker h(2)(g) =0.08, age of onset of smoking h(2)(g)=0.06, CPD h(2)(g)=0.06, nicotine dependence h(2)(g)=0.15, current/former smoker h(2)(g)=0.07, p

Background Inflammatory bowel disease (IBD) is a chronic luminal disease with genetic and environmental factors affecting phenotype. This study evaluated the relationship between CHRNA5, a nicotinic receptor subunit gene, and smoking in predicting IBD-related surgery as well as the relationship between CHRNA5 and nicotine dependence. Methods Participants completed a smoking questionnaire and were genotyped for CHRNA5 rs16969968. Demographic and clinical data were obtained from medical records. Wilcoxon, ANOVA, Chi square, and Fisher’s exact tests were used for comparisons. Logistic regression was used to evaluate the effect of clinical and genetic predictors on surgery, stratified by disease subtype given paradoxical effects of smoking. Kaplan-Meier curves were used to examine the effect of smoking and genotype on time to surgery. (Significance: P < 0.05 for main effects; P < 0.2 for interaction terms) Results 400 (65.8%) patients had Crohn’s disease (CD) and 208 (34.2%) had ulcerative colitis (UC). 298 (49%) underwent an IBD-related surgery. There was a trend towards significance between rs16969968 and smoking behavior (smoking status [P = 0.05], nicotine dependence [AA > AG > GG; P = 0.08]). Smoking and genotype were not independently associated with surgery in UC or CD. However, interaction between rs16969968 and smoking in predicting surgery was observed for both UC (OR = 2.72; P = 0.05) and CD (OR = 2.88; P = 0.1). CHRNA5 genotype, but not smoking, predicted time to surgery in patients with UC (P = 0.007) but not in patients with CD. The interaction between smoking and genotype was not significantly associated with time to surgery in UC or CD. Conclusions The CHRNA5 rs16969968 A variant interacts with smoking to influence IBD-related surgery.

The incorporation of genomic information into routine care settings is a burgeoning area for investigation in behavioral medicine. The past decade has witnessed rapid advancements in knowledge of genetic biomarkers associated with smoking behaviors and tobacco-related morbidity and mortality, providing the basis for promising genomic applications in clinical and community settings. We assessed the current state of readiness for implementing genomic applications involving variation in the α5 nicotinic cholinergic receptor subunit gene CHRNA5 and smoking outcomes (behaviors and related diseases) using a process that could be translatable to a wide range of genomic applications in behavioral medicine. We reviewed the scientific literature involving CHRNA5 genetic variation and smoking cessation, and then summarized and synthesized a chain of evidence according to analytic validity, clinical validity, clinical utility, and ethical, legal, and social implications (ACCE), a well-established set of criteria used to evaluate genomic applications. Our review identified at least three specific genomic applications for which implementation may be considered, including the use of CHRNA5 genetic test results for informing disease risk, optimizing smoking cessation treatment, and motivating smoking behavior change. For these genomic applications, we rated analytic validity as convincing, clinical validity as adequate, and clinical utility and ethical, legal, and social implications as inadequate. For clinical genomic applications involving CHRNA5 variation and smoking outcomes, research efforts now need to focus on establishing clinical utility. This approach is compatible with pre-implementation research, which is also needed to accelerate translation, improve innovation design, and understand and refine system processes involved in implementation. This study informs the readiness to incorporate smoking-related genomic applications in real-world settings and facilitates cross-disciplinary collaboration to accelerate the integration of evidence-based genomics in behavioral medicine.

Liability to alcohol dependence (AD) is heritable, but little is known about its complex polygenic architecture or its genetic relationship with other disorders. To discover loci associated with AD and characterize the relationship between AD and other psychiatric and behavioral outcomes, we carried out the largest genome-wide association study to date of DSM-IV-diagnosed AD. Genome-wide data on 14,904 individuals with AD and 37,944 controls from 28 case–control and family-based studies were meta-analyzed, stratified by genetic ancestry (European, n = 46,568; African, n = 6,280). Independent, genome-wide significant effects of different ADH1B variants were identified in European (rs1229984; P = 9.8 × 10–13) and African ancestries (rs2066702; P = 2.2 × 10–9). Significant genetic correlations were observed with 17 phenotypes, including schizophrenia, attention deficit–hyperactivity disorder, depression, and use of cigarettes and cannabis. The genetic underpinnings of AD only partially overlap with those for alcohol consumption, underscoring the genetic distinction between pathological and nonpathological drinking behaviors.

Introduction: Human genetic research has succeeded in definitively identifying multiple genetic variants associated with risk for nicotine dependence and heavy smoking. To build on these advances, and to aid in reducing the prevalence of smoking and its consequent health harms, the next frontier is to identify genetic predictors of successful smoking cessation and also of the efficacy of smoking cessation treatments ("pharmacogenomics"). More broadly, additional biomarkers that can be quantified from biosamples also promise to aid "Precision Medicine" and the personalization of treatment, both pharmacological and behavioral. Aims and Methods: To motivate ongoing and future efforts, here we review several compelling genetic and biomarker findings related to smoking cessation and treatment. Results: These Key results involve genetic variants in the nicotinic receptor subunit gene CHRNA5, variants in the nicotine metabolism gene CYP2A6, and the nicotine metabolite ratio. We also summarize reports of epigenetic changes related to smoking behavior. Conclusions: The results to date demonstrate the value and utility of data generated from biosamples in clinical treatment trial settings. This article cross-references a companion paper in this issue that provides practical guidance on how to incorporate biosample collection into a planned clinical trial and discusses avenues for harmonizing data and fostering consortium-based, collaborative research on the pharmacogenomics of smoking cessation. Implications: Evidence is emerging that certain genotypes and biomarkers are associated with smoking cessation success and efficacy of smoking cessation treatments. We review key findings that open potential avenues for personalizing smoking cessation treatment according to an individual's genetic or metabolic profile. These results provide important incentive for smoking cessation researchers to collect biosamples and perform genotyping in research studies and clinical trials.

Patients with serious mental illness have high smoking prevalence and early mortality. Inadequate implementation of evidence-based smoking cessation treatment in community mental health centers (CMHCs) contributes to this disparity. This study evaluates the effects of quality improvement strategies on treatment and cessation outcomes. Low-burden strategies of decision support and academic detailing with data-driven feedback were implemented in 4 clinics from 2014 to 2016. Pre- and post-implementation data from pharmacy and medical records were analyzed. With these quality improvement strategies, we found an increase in patient receipt of cessation medication from 4.6% to 18.0% (p

Tobacco cessation after cancer diagnosis leads to better patient outcomes. However, tobacco treatment services are frequently unavailable in cancer care settings, and multilevel implementation challenges can impede uptake of new programs. The National Cancer Institute (NCI) dedicated Cancer Moonshot funding through the Cancer Center Cessation Initiative (C3I) for NCI-Designated Cancer Centers to implement or enhance the implementation of tobacco treatment services. We examined a pragmatic application of the RE-AIM framework (reach, effectiveness, adoption, implementation, and maintenance) to evaluate tobacco treatment programs implemented within Cancer Centers funded through C3I. Using three C3I-funded Centers as examples, we describe how each RE-AIM construct was operationalized to evaluate the implementation of a wide range of cessation services (e.g., tobacco use screening, counseling, Quitline referral, pharmacotherapy) in this heterogeneous group of cancer care settings. We discuss the practical challenges encountered in assessing RE-AIM constructs in real world situations, including using the electronic health record (EHR) to aid in assessment. Reach and effectiveness evaluation required that Centers define the setting(s) where cessation services were implemented (to determine the "denominator"), enumerate the patient population, report current patient tobacco use, patient engagement in tobacco treatment, and 6-month cessation outcomes. To reduce site heterogeneity, increase data accuracy, and reduce burden, reach was frequently captured via standardized EHR enhancements that improved the identification of current smokers and tobacco treatment referrals. Effectiveness was determined by cessation outcomes (30-day point prevalence abstinence at 6-months post-engagement) assessed through a variety of data collection approaches. Adoption was measured by the characteristics and proportion of targeted cancer care settings and clinicians engaged in cessation service delivery. Implementation was assessed by examining the delivery of tobacco screening assessments and intervention components across sites, and provider-level implementation consistency. Maintenance assessments identified whether tobacco treatment services continued in the setting after implementation and documented the sustainability plan and organizational commitment to continued delivery. In sum, this paper demonstrates a pragmatic approach to using RE-AIM as an evaluation framework that yields relevant outcomes on common implementation metrics across widely differing tobacco treatment approaches and settings.

Introduction Tobacco use is a current public health epidemic that puts individuals at risk for many health conditions and diseases, and adolescents are at high risk for the initiation and persistence of tobacco use behaviors partly due to engagement with social media content. The objective of this study is to examine the association between engaging in social media behaviors and patterns of electronic nicotine delivery systems (ENDS) and tobacco use at a 1-year follow-up among 11 279 adolescents from the PATH study. Methods Five social media variables were questioned at Wave 2 and then compared to ENDS and tobacco status transitions (i.e., initiation, persistence, and escalation) at a 1-year follow-up, respectively. Survey-weighted multivariable logistic regression models were used to calculate adjusted odds ratios and 95% confidence interval. Results Passive behaviors on social media were related to higher likelihoods of starting to use ENDS and other tobacco products. Additionally, active behaviors on social media were related to higher likelihoods for the initiation and persistence of tobacco use. In particular, sending tobacco content to other users was further associated with a higher likelihood of escalation of tobacco product use. Discussion Both exposure to and interactions with social media tobacco content had a significant impact on the patterns of ENDS and tobacco use in adolescents. Due to the amount of time adolescents spend engaging with online content, social media may be a critical place in which to intervene, possibly with the use of antitobacco or tobacco prevention messages. Implications The results of this study have implications for public health and the policies surrounding adolescents and their exposure to social media. Reducing the ENDS and tobacco content to which adolescents are exposed has the potential to decrease the instances of initiation and persistence of ENDS and tobacco use. Intervening on social media may prevent or slow the progression of ENDS and tobacco use, and increase motivation and actions toward the cessation of tobacco use in adolescents.

Tobacco smoking is an important risk factor for cancer incidence, an effect modifier for cancer treatment, and a negative prognostic factor for disease outcomes. Inadequate implementation of evidence-based smoking cessation treatment in cancer centers, a consequence of numerous patient-, provider-, and system-level barriers, contributes to tobacco-related morbidity and mortality. This study provides data for a paradigm shift from a frequently used specialist referral model to a point-of-care treatment model for tobacco use assessment and cessation treatment for outpatients at a large cancer center. The point-of-care model is enabled by a low-burden strategy, the Electronic Health Record-Enabled Evidence-Based Smoking Cessation Treatment program, which was implemented in the cancer center clinics on June 2, 2018. Five-month pre- and post-implementation data from the electronic health record (EHR) were analyzed. The percentage of cancer patients assessed for tobacco use significantly increased from 48% to 90% (z = 126.57, p < .001), the percentage of smokers referred for cessation counseling increased from 0.72% to 1.91% (z = 3.81, p < .001), and the percentage of smokers with cessation medication significantly increased from 3% to 17% (z = 17.20, p < .001). EHR functionalities may significantly address barriers to point-of-care treatment delivery, improving its consistent implementation and thereby increasing access to and quality of smoking cessation care for cancer center patients.

Background Whether medical or recreational cannabis legalization impacts alcohol or cigarette consumption is a key question as cannabis policy evolves, given the adverse health effects of these substances. Relatively little research has examined this question. The objective of this study was to examine whether medical or recreational cannabis legalization was associated with any change in state-level per capita alcohol or cigarette consumption. Methods Dependent variables included per capita consumption of alcohol and cigarettes from all 50 U.S. states, estimated from state tax receipts and maintained by the Centers for Disease Control and National Institute for Alcohol Abuse and Alcoholism, respectively. Independent variables included indicators for medical and recreational legalization policies. Three different types of indicators were separately used to model medical cannabis policies. Indicators for the primary model were based on the presence of active medical cannabis dispensaries. Secondary models used indicators based on either the presence of a more liberal medical cannabis policy (“non-medicalized”) or the presence of any medical cannabis policy. Difference-in-difference regression models were applied to estimate associations for each type of policy. Results Primary models found no statistically significant associations between medical or recreational cannabis legalization policies and either alcohol or cigarette sales per capita. In a secondary model, both medical and recreational policies were associated with significantly decreased per capita cigarette sales compared to states with no medical cannabis policy. However, post hoc analyses demonstrated that these reductions were apparent at least two years prior to policy adoption, indicating that they likely result from other time-varying characteristics of legalization states, rather than cannabis policy. Conclusion We found no evidence of a causal association between medical or recreational cannabis legalization and changes in either alcohol or cigarette sales per capita.

Little is known about patients' electronic cigarette use, interest in and use of smoking cessation treatments, and providers' attitude towards such treatment. We assessed patients (N = 231) and providers (45 psychiatrists, 97 case workers) in four Community Mental Health Centers. Interestingly, 50% of smokers reported interest in using electronic cigarettes to quit smoking, and 22% reported current use. While 82% of smokers reported wanting to quit or reduce smoking, 91% of psychiatrists and 84% of case workers reported that patients were not interested in quitting as the lead barrier, limiting the provision of cessation interventions. Providers' assumption of low patient interest in treatment may account for the low rate of smoking cessation treatment. In contrast, patients report interest and active use of electronic cigarettes to quit smoking. This study highlights the need for interventions targeting different phases of smoking cessation in these patients suffering disproportionately from tobacco dependence.

Background Recent meta-analyses show that individuals with high risk variants in CHRNA5 on chromosome 15q25 are likely to develop lung cancer earlier than those with low-risk genotypes. The same high-risk genetic variants also predict nicotine dependence and delayed smoking cessation. It is unclear whether smoking cessation confers the same benefits in terms of lung cancer risk reduction for those who possess CHRNA5 risk variants versus those who do not. Methods Meta-analyses examined the association between smoking cessation and lung cancer risk in 15 studies of individuals with European ancestry who possessed varying rs16969968 genotypes (N = 12,690 ever smokers, including 6988 cases of lung cancer and 5702 controls) in the International Lung Cancer Consortium. Results Smoking cessation (former vs. current smokers) was associated with a lower likelihood of lung cancer (OR = 0.48, 95%CI = 0.30–0.75, p = 0.0015). Among lung cancer patients, smoking cessation was associated with a 7-year delay in median age of lung cancer diagnosis (HR = 0.68, 95%CI = 0.61–0.77, p = 4.9 ∗ 10–10). The CHRNA5 rs16969968 risk genotype (AA) was associated with increased risk and earlier diagnosis for lung cancer, but the beneficial effects of smoking cessation were very similar in those with and without the risk genotype. Conclusion We demonstrate that quitting smoking is highly beneficial in reducing lung cancer risks for smokers regardless of their CHRNA5 rs16969968 genetic risk status. Smokers with high-risk CHRNA5 genotypes, on average, can largely eliminate their elevated genetic risk for lung cancer by quitting smoking- cutting their risk of lung cancer in half and delaying its onset by 7 years for those who develop it. These results: 1) underscore the potential value of smoking cessation for all smokers, 2) suggest that CHRNA5 rs16969968 genotype affects lung cancer diagnosis through its effects on smoking, and 3) have potential value for framing preventive interventions for those who smoke., Highlights • CHRNA5 rs16969968 confers risk for earlier lung cancer diagnosis, but quitting produces benefit regardless of genotype. • Smokers can cut their risk of lung cancer in half and delay its onset by 7 years among those diagnosed. • Precision prevention allows clinicians to provide personalized health benefits of smoking cessation. This is a report on whether smoking cessation confers the same benefits in terms of lung cancer risk reduction for those who possess CHRNA5 risk variants versus those who do not. We determined that quitting smoking is highly beneficial in reducing lung cancer risk levels for smokers regardless of their CHRNA5 rs16969968 genetic risk status. Although CHRNA5 rs16969968 increases risk for earlier lung cancer by 4 years, quitting produces essentially the same benefit for smokers with either high or low genetic risks. Smokers can cut their risk of lung cancer in half and delay its onset by 7 years among those diagnosed. These results are important for smokers to prevent cancer. On average, smokers at all genetic risk levels can largely eliminate their elevated risk for lung cancer by quitting smoking.

Several studies have reported that cigarette smoking is inversely associated with the risk of melanoma. This study further tested whether incorporating genetic factors will provide another level of evaluation of mechanisms underlying the association between smoking and risk of melanoma. We investigated the association between SNPs selected from genome-wide association studies (GWAS) on smoking behaviors and risk of melanoma using 2,298 melanoma cases and 6,654 controls. Among 16 SNPs, three (rs16969968 [A], rs1051730 [A] and rs2036534 [C] in the 15q25.1 region) reached significance for association with melanoma risk in men (0.01 < = P values < = 0.02; 0.85 < = Odds Ratios (ORs)

Rural populations face significant smoking-related health disparities, such as a higher prevalence of lung cancer and cancer mortality, higher prevalence of smoking, and lower likelihood of receiving cessation treatment than urban counterparts. A significant proportion of health disparities in rural populations could be eliminated with low-barrier, easy-access treatment delivery methods for smoking cessation. In this study, we assessed treatment engagement among patients in rural and urban settings. Then, we examined the effect of an electronic health record-based smoking cessation module on patient receipt of evidence-based cessation care. As part of a quality improvement project, we retrospectively observed 479,798 unique patients accounting for 1,426,089 outpatient clinical encounters from June 2018&ndash, March 2019 across 766 clinics in the greater St. Louis, southern Illinois, and mid-Missouri regions. Smoking prevalence was higher in rural versus urban clinics (20.7% vs. 13.9%, 6.7% [6.3, 7.1], odds ratio = 1.6 [1.6, 1.6], p &lt, 0.0001), and yet rural smokers were nearly three times less likely than their urban counterparts to receive any smoking cessation treatment after adjusting for patients clustering within clinics (9.6% vs. 25.8%, &minus, 16.2% [&minus, 16.9, &minus, 15.5], odds ratio = 0.304 [0.28, 0.33], p &lt, 0.0001). Although not yet scaled up in the rural setting, we examined the effects of a low-burden, point-of-care smoking module currently implemented in cancer clinics. After adjusting for patient clustering within clinics, patients were more likely to receive smoking treatment in clinics that implemented the module versus clinics that did not implement the module (31.2% vs. 17.5%, 13.7% [10.8, 16.6], odds ratio = 2.1 [1.8, 2.6], p &lt, 0.0001). The point-of-care treatment approach offers a promising solution for rural settings, both in and outside the context of cancer care.

In an era of Precision Medicine, it is vital to collect biological data within clinical trials and to integrate their analysis within the outcomes of the trial. The identification of genomic biomarkers that affect treatment response to smoking cessation treatment, both pharmacological and behavioral, or susceptibility to medication-related adverse reactions, holds real promise to improve treatment efficacy and to tailor the treatment approach to the individual. However, a clear challenge in identifying reliable biomarkers is in obtaining adequate sample sizes. Consortium-based approaches will likely be necessary to yield real successes. Thus, meta-analyses of data from individual smoking cessation trials will become crucial and will be facilitated by standardized trial designs, assessments, and outcomes and harmonizable measures. To foster increased collection of high-quality genetics data in clinical trials, we discuss (1) genetically informed trial design, (2) biological samples (collection requirements, storage, and analysis with a focus on genomic data) and genetics consortia, (3) participant consent and data sharing requirements for Institutional Review Board (IRB) approvals, and (4) information on phenotype characterization and meta-analysis. This work aligns with the objectives of the Precision Medicine Initiative and offers guidance for integrating treatment research and genetics/genomics within the nicotine and tobacco research community. It is intended to promote the collection and genotyping of biosamples in existing subject samples as well as the integration of genetic research elements into future study designs. This article crossreferences a companion paper in this issue that reviews current evidence on genetic and epigenetic markers in cessation trials. Implications: This article outlines a framework for the consistent integration of biological data/ samples into smoking cessation pharmacotherapy trials, aligned with the objectives of the recently unveiled Precision Medicine Initiative. Our goal is to encourage and provide support for treatment researchers to consider biosample collection and genotyping their existing samples as well as integrating genetic analyses into their study design in order to realize precision medicine in treatment of nicotine dependence.

The goal of this study was to examine participant responses to disclosure of genetic results in a minority population at high risk for depression and anxiety. Eighty-two subjects in a genetic study of nicotine dependence were offered personalized genetic results. All were nicotine-dependent and 64% self-identified as African American. Pathway Genomics was used to evaluate genetic risks for five complex diseases. Participants returned 4–8 weeks after enrollment for in-person genetic counseling interviews and evaluation of baseline measures. A telephone follow-up was performed 4–8 weeks later to assess responses to results. Fifty of the 82 subjects (61%) were interested in receiving genetic results. These participants had multiple risk factors, including high baseline measures of depression (66%) and anxiety (32%), as well as low rates of employment (46%), adequate health literacy (46%), and health insurance (45%). Pathway Genomics reported “increased risk” for at least one disease in 77% of subjects. Ninety-five percent of participants reported that they appreciated the genetic results, and receiving these results was not associated with changes in symptoms of depression or anxiety. Furthermore, after return of genetic results, smoking cessation attempts increased (P = 0.003). Even in an underserved population at high risk for adverse psychological reactions, subjects responded positively to personalized genetic results. Genet Med 17 5, 374–379.

Introduction Effective smoking cessation medications are readily available but may be underutilized in hospital settings. In our large, tertiary care hospital, we aimed to (1) characterize patient tobacco use prevalence across medical specialties, (2) determine smoking cessation pharmacotherapy prescription variation across specialties, and (3) identify opportunities for improvement in practice. Methods Using electronic health records at Barnes Jewish Hospital, we gathered demographic data, admitting service, admission route, length of stay, self-reported tobacco use, and smoking cessation prescriptions over a 6-year period, from 2010 to 2016. We then compared tobacco use prevalence and smoking cessation prescriptions across medical specialties using a cross-sectional, retrospective design. Results Past 12-month tobacco use was reported by patients in 27.9% of inpatient admissions; prescriptions for smoking cessation pharmacotherapy were provided during 21.5% of these hospitalizations. The proportion of patients reporting tobacco use was highest in psychiatry (55.3%) and lowest in orthopedic surgery (17.1%). Psychiatric patients who reported tobacco use were most likely to receive pharmacotherapy (71.8% of admissions), and plastic surgery patients were least likely (4.7% of admissions). Compared with Caucasian tobacco users, African American patients who used tobacco products were less likely to receive smoking cessation medications (adjusted odds ratio [aOR] = 0.65; 95% confidence interval [CI] = 0.62 to 0.68). Conclusions Among hospitalized tobacco users, safe and cost-effective pharmacotherapies are under-prescribed. We identified substantial variation in prescribing practices across different medical specialties and demographic groups, suggesting the need for an electronic medical record protocol that facilitates consistent tobacco use cessation pharmacotherapy treatment. Implications Tobacco use cessation pharmacotherapy is underutilized during hospitalization, and prescription rates vary greatly across medical specialties and patient characteristics. Hospitals may benefit from implementing policies and practices that standardize and automate the offer of smoking pharmacotherapy for all hospitalized patients who use tobacco.

INTRODUCTION: Genetic variants associated with nicotine dependence have previously been identified, primarily in European-ancestry populations. No genome-wide association studies (GWAS) have been reported for smoking behaviors in Hispanics/Latinos in the United States and Latin America, who are of mixed ancestry with European, African, and American Indigenous components. METHODS: We examined genetic associations with smoking behaviors in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) (N = 12 741 with smoking data, 5119 ever-smokers), using ~2.3 million genotyped variants imputed to the 1000 Genomes Project phase 3. Mixed logistic regression models accounted for population structure, sampling, relatedness, sex, and age. RESULTS: The known region of CHRNA5, which encodes the α5 cholinergic nicotinic receptor subunit, was associated with heavy smoking at genome-wide significance (p ≤ 5 × 10(–8)) in a comparison of 1929 ever-smokers reporting cigarettes per day (CPD) > 10 versus 3156 reporting CPD ≤ 10. The functional variant rs16969968 in CHRNA5 had a p value of 2.20 × 10(–7) and odds ratio (OR) of 1.32 for the minor allele (A); its minor allele frequency was 0.22 overall and similar across Hispanic/Latino background groups (Central American = 0.17; South American = 0.19; Mexican = 0.18; Puerto Rican = 0.22; Cuban = 0.29; Dominican = 0.19). CHRNA4 on chromosome 20 attained p < 10(–4), supporting prior findings in non-Hispanics. For nondaily smoking, which is prevalent in Hispanic/Latino smokers, compared to daily smoking, loci on chromosomes 2 and 4 achieved genome-wide significance; replication attempts were limited by small Hispanic/Latino sample sizes. CONCLUSIONS: Associations of nicotinic receptor gene variants with smoking, first reported in non-Hispanic European-ancestry populations, generalized to Hispanics/Latinos despite different patterns of smoking behavior. IMPLICATIONS: We conducted the first large-scale genome-wide association study (GWAS) of smoking behavior in a US Hispanic/Latino cohort, and the first GWAS of daily/nondaily smoking in any population. Results show that the region of the nicotinic receptor subunit gene CHRNA5, which in non-Hispanic European-ancestry smokers has been associated with heavy smoking as well as cessation and treatment efficacy, is also significantly associated with heavy smoking in this Hispanic/Latino cohort. The results are an important addition to understanding the impact of genetic variants in understudied Hispanic/Latino smokers.

BackgroundThere are high levels of comorbidity between schizophrenia and substance use disorder, but little is known about the genetic etiology of this comorbidity.MethodsHere, we test the hypothesis that shared genetic liability contributes to the high rates of comorbidity between schizophrenia and substance use disorder. To do this, polygenic risk scores for schizophrenia derived from a large meta-analysis by the Psychiatric Genomics Consortium were computed in three substance use disorder datasets: COGEND (ascertained for nicotine dependence n=918 cases, 988 controls), COGA (ascertained for alcohol dependence n=643 cases, 384 controls), and FSCD (ascertained for cocaine dependence n=210 cases, 317 controls). Phenotypes were harmonized across the three datasets and standardized analyses were performed. Genome-wide genotypes were imputed to 1000 Genomes reference panel.ResultsIn each individual dataset and in the mega-analysis, strong associations were observed between any substance use disorder diagnosis and the polygenic risk score for schizophrenia (mega-analysis pseudo R2 range 0.8%-3.7%, minimum p=4×10-23).ConclusionsThese results suggest that comorbidity between schizophrenia and substance use disorder is partially attributable to shared polygenic liability. This shared liability is most consistent with a general risk for substance use disorder rather than specific risks for individual substance use disorders and adds to increasing evidence of a blurred boundary between schizophrenia and substance use disorder.

ObjectivesTo generate system insights on patient and provider levers and strategies that must be activated to improve hospital-based smoking cessation treatment.DesignMixed methods study including a series of in-depth group model building sessions, which informed the design of an online survey completed by healthcare providers and a structured interview protocol administered at the bedside to patients who smoke.SettingLarge, tertiary care hospital in the Midwestern United States.ParticipantsGroup model building: 28 healthcare providers and 22 previously-hospitalised patients;Online survey: 308 healthcare providers;Bedside interviews: 205 hospitalised patients.Primary and secondary outcome measuresHypothesis-generating, participatory qualitative methods informed the examination of the following quantitative outcomes: patient interest versus provider perception of patient interest in smoking cessation and treatment; patient-reported receipt versus provider-reported offering of inpatient smoking cessation interventions; and priority ratings of importance and feasibility of strategies to improve treatment.ResultsSystem insightsincluded patients frequently leaving the floor to smoke, which created major workflow disruption.Leverage pointsincluded interventions to reduce withdrawal symptoms, andaction ideasincluded nurse-driven protocols for timely administration of nicotine replacement therapy. Quantitative data corroborated system insights; for instance, 80% of providers reported that patients frequently leave the floor to smoke, leading to safety risks, missed assessments and inefficient use of staff time. Patients reported significantly lower rates of receiving any smoking cessation interventions, compared with provider reports (mean difference=17.4%–33.7%, pConclusionsEngaging hospital providers and patients in participatory approaches to develop an implementation strategy revealed discrepant perceptions of patient interest and frequency of hospital-based treatment for smoking. These findings spurred adoption of standardised point-of-care treatment for cigarette smoking, which remains highly prevalent yet undertreated among hospitalised patients.

Introduction: Cigarette smoking is highly addictive and prevalent among individuals with mental illness. Modern genetic research has identified robust genetic influences on nicotine dependence. An important step in translating these genetic findings is to identify the genetic factors affecting smoking cessation in order to enhance current smoking cessation treatments. Methods We investigated the significant genetic variants that predict nicotine dependence, smoking cessation, and response to cessation pharmacotherapy using both large cohort studies of smokers and randomized controlled trials. Results We find that genetic risks may predict prognosis and response to pharmacological treatments. For prognosis, the nicotinic receptor genotypes predict delayed quitting and earlier lung cancer diagnoses after adjusting for smoking quantity in large meta-analyses of studies of lung cancer and nicotine dependence. For treatment response, some pharmacogenetic findings have been replicated in meta-analyses or multiple smoking cessation trials for both pharmacodynamic markers (e.g., CHRNA5) and pharmacokinetic marker (e.g., CYP2A6). The variation in efficacy between smokers with different genetic markers supports the notion that personalized smoking cessation intervention based upon genotype could maximize the efficiency of such treatment while minimizing side effects, thus influencing the number needed to treat (NNT) and the number needed to harm. Conclusion Current evidence strongly suggests that cessation failure and cessation pharmacotherapy effectiveness are modulated by biomarkers such as nicotinic receptor genotypes, nicotine metabolism ratio (NMR), or polygenic risk scores for nicotine dependence. These findings strengthen the case for further research on genetics of smoking cessation success, and the development and rigorous testing of treatments for smokers with different genetic risk profiles. Learning Objectives 1) human genetic studies can inform the biological mechanisms of nicotine dependence and health consequences such as lung cancer, 2) pharmacogenetic studies may inform personalized treatments for tobacco use disorder, possibly increasing efficacy and reducing risk of side effects.

Genome-wide significant associations with cigarettes per day (CPD) and risk for lung cancer and chronic obstructive pulmonary disease (COPD) were previously reported in a region of 19q13, including CYP2A6 (nicotine metabolism enzyme) and EGLN2 (hypoxia response). The associated single nucleotide polymorphisms (SNPs) were assumed to be proxies for functional variation in CYP2A6. Here, we demonstrate that when CYP2A6 and EGLN2 genotypes are analyzed together, the key EGLN2 variant, rs3733829, is not associated with nicotine metabolism independent of CYP2A6, but is nevertheless independently associated with CPD, and with breath carbon monoxide (CO), a phenotype associated with cigarette consumption and relevant to hypoxia. SNPs in EGLN2 are also associated with nicotine dependence and with smoking efficiency (CO/CPD). These results indicate a previously unappreciated novel mechanism behind genome-wide significant associations with cigarette consumption and disease risk unrelated to nicotine metabolism.

Introduction AQW051, an α7-nicotinic acetylcholine receptor partial agonist, enhanced cognitive function in rodent models of learning and memory. This study evaluated brain activation during performance of a working memory task (WMT) and an episodic memory task (EMT), and the effect of AQW051 on task-related brain activation and performance in subjects with schizophrenia. Methods This was a double-blind, randomized, placebo-controlled, multicenter, 2-period cross-over trial ( NCT00825539 ) in participants with chronic, stable schizophrenia. Participants, stratified according to smoking status, were randomized (1:1:1:1:1:1) to 1 of 6 sequence groups that determined the study drug dose (AQW051 7.5 mg, 50 mg or 100 mg) and order of administration versus placebo. The primary outcome was brain activation in a priori target regions of interest (ROIs) during performance of the WMT and EMT, measured using functional magnetic resonance imaging. The effect of AQW051 on task-related (EMT and WMT) brain activation and performance was also assessed, as were safety and tolerability. Results Overall, 60 of 68 enrolled participants completed the study (AQW051 then placebo: 7.5 mg n = 9; 50 mg n = 11; 100 mg n = 10. Placebo then AQW051: 7.5 mg n = 10; 50 mg n = 11; 100 mg n = 9). Significant task-related brain activation (5% significance level) was observed with placebo. During the WMT, a medium effect size was observed in the inferior prefrontal cortex with AQW051 100 mg versus placebo (0.431; p = 0.105). During the EMT encoding phase, a large effect size was observed in the anterior hippocampus (0.795; p = 0.007) and a medium effect size in the posterior hippocampus (0.476; p = 0.079) with AQW051 7.5 mg. No other medium/large effect sizes were observed with any dose on either task. Effects on brain activation were generally not associated with changes in cognitive performance. AQW051 was well tolerated with an acceptable safety profile. Conclusions Overall, no consistent effects of AQW051 on brain regions involved in the performance of a WMT or EMT were observed; however, this study presents a model for evaluating potential response to pharmacological interventions for cognitive impairment in schizophrenia.

Imputation, the process of inferring genotypes for untyped variants, is used to identify and refine genetic association findings. Inaccuracies in imputed data can distort the observed association between variants and a disease. Many statistics are used to assess accuracy; some compare imputed to genotyped data and others are calculated without reference to true genotypes. Prior work has shown that the Imputation Quality Score (IQS), which is based on Cohen's kappa statistic and compares imputed genotype probabilities to true genotypes, appropriately adjusts for chance agreement; however, it is not commonly used. To identify differences in accuracy assessment, we compared IQS with concordance rate, squared correlation, and accuracy measures built into imputation programs. Genotypes from the 1000 Genomes reference populations (AFR N = 246 and EUR N = 379) were masked to match the typed single nucleotide polymorphism (SNP) coverage of several SNP arrays and were imputed with BEAGLE 3.3.2 and IMPUTE2 in regions associated with smoking behaviors. Additional masking and imputation was conducted for sequenced subjects from the Collaborative Genetic Study of Nicotine Dependence and the Genetic Study of Nicotine Dependence in African Americans (N = 1,481 African Americans and N = 1,480 European Americans). Our results offer further evidence that concordance rate inflates accuracy estimates, particularly for rare and low frequency variants. For common variants, squared correlation, BEAGLE R2, IMPUTE2 INFO, and IQS produce similar assessments of imputation accuracy. However, for rare and low frequency variants, compared to IQS, the other statistics tend to be more liberal in their assessment of accuracy. IQS is important to consider when evaluating imputation accuracy, particularly for rare and low frequency variants.

Item does not contain fulltext BACKGROUND: Recent meta-analyses show strong evidence of associations among genetic variants in CHRNA5 on chromosome 15q25, smoking quantity, and lung cancer. This meta-analysis tests whether the CHRNA5 variant rs16969968 predicts age of smoking cessation and age of lung cancer diagnosis. METHODS: Meta-analyses examined associations between rs16969968, age of quitting smoking, and age of lung cancer diagnosis in 24 studies of European ancestry (n = 29 072). In each dataset, we used Cox regression models to evaluate the association between rs16969968 and the two primary phenotypes (age of smoking cessation among ever smokers and age of lung cancer diagnosis among lung cancer case patients) and the secondary phenotype of smoking duration. Heterogeneity across studies was assessed with the Cochran Q test. All statistical tests were two-sided. RESULTS: The rs16969968 allele (A) was associated with a lower likelihood of smoking cessation (hazard ratio [HR] = 0.95, 95% confidence interval [CI] = 0.91 to 0.98, P = .0042), and the AA genotype was associated with a four-year delay in median age of quitting compared with the GG genotype. Among smokers with lung cancer diagnoses, the rs16969968 genotype (AA) was associated with a four-year earlier median age of diagnosis compared with the low-risk genotype (GG) (HR = 1.08, 95% CI = 1.04 to 1.12, P = 1.1*10(-5)). CONCLUSION: These data support the clinical significance of the CHRNA5 variant rs16969968. It predicts delayed smoking cessation and an earlier age of lung cancer diagnosis in this meta-analysis. Given the existing evidence that this CHRNA5 variant predicts favorable response to cessation pharmacotherapy, these findings underscore the potential clinical and public health importance of rs16969968 in CHRNA5 in relation to smoking cessation success and lung cancer risk.

The mu1 opioid receptor gene, OPRM1, has long been a high-priority candidate for human genetic studies of addiction. Because of its potential functional significance, the non-synonymous variant rs1799971 (A118G, Asn40Asp) in OPRM1 has been extensively studied, yet its role in addiction has remained unclear, with conflicting association findings. To resolve the question of what effect, if any, rs1799971 has on substance dependence risk, we conducted collaborative meta-analyses of 25 datasets with over 28,000 European-ancestry subjects. We investigated non-specific risk for “general” substance dependence, comparing cases dependent on any substance to controls who were non-dependent on all assessed substances. We also examined five specific substance dependence diagnoses: DSM-IV alcohol, opioid, cannabis, and cocaine dependence, and nicotine dependence defined by the proxy of heavy/light smoking (cigarettes-per-day >20 vs. ≤10). The G allele showed a modest protective effect on general substance dependence (OR = 0.90, 95 % C.I. [0.83–0.97], p value = 0.0095, N = 16,908). We observed similar effects for each individual substance, although these were not statistically significant, likely because of reduced sample sizes. We conclude that rs1799971 contributes to mechanisms of addiction liability that are shared across different addictive substances. This project highlights the benefits of examining addictive behaviors collectively and the power of collaborative data sharing and meta-analyses.

Objective Recent evidence suggests that the efficacy of smoking cessation pharmacotherapy can vary across patients based on their genotypes. This study tests whether the coding variant rs16969968 in the CHRNA5 nicotinic receptor gene predicts the effects of combination nicotine replacement therapy (cNRT) and varenicline on treatment outcomes. Method In two randomized smoking cessation trials comparing cNRT vs. placebo, and varenicline vs. placebo, we used logistic regression to model associations between CHRNA5 rs16969968 and abstinence at end of treatment. Results For abstinence at end of treatment, there was an interaction between cNRT and rs16969968 (X2 = 8.15, df = 2, omnibus-p = 0.017 for the interaction); individuals with the high-risk AA genotype were more likely to benefit from cNRT. In contrast, varenicline increased abstinence, but its effect did not vary with CHRNA5. However, the genetic effects differed between the placebo control groups across two trials (wald = 3.94, df = 1, p = 0.047), this non-replication can alter the interpretation of pharmacogenetic findings. Conclusions Results from two complementary smoking cessation trials demonstrate inconsistent genetic results in the placebo arms. This evidence highlights the need to compare the most effective pharmacotherapies with the same placebo control to establish pharmacogenetic evidence to aid decisions on medication choice for patients trying to quit smoking.

To assess if the allelic variations of rs16969968/rs1051730 in the CHRNA5-CHRNA3-CHRNB4 gene cluster are associated with smoking cessation after nicotine replacement therapy (NRT).We searched for NRT studies published from 2000-2013 that reported counts for allelic variation of rs16969968/rs1051730 and measured abstinence rates at the end of NRT treatment. We identified four studies which met the criteria, giving us a test sample of 2036 participants.There was no effect of rs16969968/rs1051730 in influencing the success rate at the end of NRT (n = 6, effect size [ES]: 0.969, 95% CI: 0.77 to 1.23, z = 0.27, p = 0.791).There is no robust evidence that allelic variations of rs16969968 or rs1051730 are associated with smoking cessation after NRT. Original submitted 26 November 2014; Revision submitted 9 March 2015.

Rationale: The CHRNA5-CHRNA3-CHRNB4 locus is associated with self-reported smoking behavior and also harbors the strongest genetic associations with chronic obstructive pulmonary disease (COPD) and lung cancer. Because the associations with lung disease remain after adjustment for self-reported smoking behaviors, it has been asserted that CHRNA5-CHRNA3-CHRNB4 variants increase COPD and lung cancer susceptibility independently of their effects on smoking. Objectives: To compare the genetic associations of exhaled carbon monoxide (CO), a biomarker of current cigarette exposure, with self-reported smoking behaviors. Methods: A total of 1,521 European American and 247 African American current smokers recruited into smoking cessation studies were assessed for CO at intake before smoking cessation. DNA samples were genotyped using the Illumina Omni2.5 microarray. Genetic associations with CO and smoking behaviors (cigarettes smoked per day, Fagerstrom test for nicotine dependence) were studied. Measurements and Main Results: Variants in the CHRNA5-CHRNA3-CHRNB4 locus, including rs16969968, a nonsynonymous variant in CHRNA5, are genomewide association study–significantly associated with CO (β = 2.66; 95% confidence interval [CI], 1.74–3.58; P = 1.65 × 10−8), and this association remains strong after adjusting for smoking behavior (β = 2.18; 95% CI, 1.32–3.04; P = 7.47 × 10−7). The correlation between CO and cigarettes per day is statistically significantly lower (z = 3.43; P = 6.07 × 10−4) in African Americans (r = 0.14; 95% CI, 0.02–0.26; P = 0.003) than in European-Americans (r = 0.36; 95% CI, 0.31–0.40; P = 0.0001). Conclusions: Exhaled CO, a biomarker that is simple to measure, captures aspects of cigarette smoke exposure in current smokers beyond the number of cigarettes smoked per day. Behavioral measures of smoking are therefore insufficient indices of cigarette smoke exposure, suggesting that genetic associations with COPD or lung cancer that persist after adjusting for self-reported smoking behavior may still reflect genetic effects on smoking exposure.