The Genetic Architecture of Smoking and Smoking Cessation

This study includes samples from two projects: Collaborative Genetic Study of Nicotine Dependence (COGEND; PI: Laura Bierut) and University of Wisconsin Transdisciplinary Tobacco Use Research Center (UW-TTURC; PI: Timothy Baker).

Data are available for an additional 1420 COGEND subjects through the Study of Addiction: Genetics and Environment (SAGE), dbGaP study accession phs000092. The majority of these subjects are independent from the current study, but there is a small amount of overlap between the two samples (n=29 subjects) for quality control purposes. It should be noted that the case definition in the SAGE study is DSM-IV alcohol dependence. The case definition in the current study is nicotine dependence by a current score of 4 or greater on the Fagerström Test for Nicotine Dependence (FTND).

The overall goal of this project is to identify and characterize genetic variants that contribute to the development of nicotine dependence, related smoking behaviors, and smoking cessation. The COGEND sample includes unrelated cases and controls for a genetic association study of nicotine dependence. Cases are defined by a commonly used definition of nicotine dependence, a current score of 4 or more (maximum score of 10) on the Fagerström Test for Nicotine Dependence (FTND). Control status is defined as an individual who smoked at least 100 cigarettes during their lifetime, yet never became dependent (lifetime FTND=0). By selecting controls who smoked, those genetic effects that are specific to nicotine dependence can be examined.

The UW-TTURC sample includes nicotine dependent smokers from three smoking cessation studies. Subjects had to smoke at least 10 cigarettes per day (confirmed smoking by an alveolar carbon monoxide (CO) level greater than 9) and report being motivated to quit smoking. Participants were excluded based on evidence of psychosis history, clinically significant depression symptoms, other severe mental illness, or contraindications to smoking cessation medications.

COGEND: COGEND was initiated in 2001 as a three-part program project grant funded through the National Cancer Institute (NCI; PI: Laura Bierut). The three projects included a study of the familial transmission of nicotine dependence, a genetic study of nicotine dependence, and a study of the relationship of nicotine dependence with nicotine metabolism. The primary goal is to detect, localize, and characterize genes that predispose or protect an individual with respect to heavy tobacco consumption, nicotine dependence, and related phenotypes and to integrate these findings with the family transmission and nicotine metabolism findings. The primary design is a community based case-control family study. Nicotine dependent cases and non-dependent, smoking controls were identified and recruited from Detroit and St. Louis. In addition, one sibling for each case and control subject was recruited in a subset of the sample. More than 54,000 subjects aged 25-44 years were screened by telephone; more than 3,100 subjects were personally interviewed; and more than 2,900 subjects donated blood samples for genetic studies.

UW-TTURC: The UW-TTURC was initiated in 2001 as a study of nicotine dependence and smoking cessation treatment. The second round of UW-TTURC was initiated in 2005 as a study of efficacy of smoking cessation and long term outcomes. Nicotine dependent smokers seeking cessation treatment were identified and recruited from Madison and Milwaukee, WI. Over 9,000 adult smokers were screened by telephone; 2,575 individuals were enrolled and randomized to treatment conditions that involved use of different smoking cessation medications. Participants from the UW-TTURC smoking cessation clinical trials had the option of participating in a genetic substudy, and approximately 2,000 donated blood samples for genetic studies. The goal of the genetic studies of smokers seeking cessation treatment is to detect, localize, and characterize genes that predispose or protect an individual with respect to heavy tobacco consumption, nicotine dependence, and related phenotypes including cessation, withdrawal, and relapse.

Both studies (COGEND and UW-TTURC) include measures of basic socio-demographic variables, including age, sex, race/ethnicity, family income, and educational attainment. Information on nicotine dependence, as assessed by the Fagerström Test for Nicotine Dependence (FTND) is available for all subjects. In addition, participants also completed the Nicotine Dependence Syndrome Scale (NDSS; Shiffman et al., 2004) and the Wisconsin Inventory of Smoking Dependence Motives (WISDM-68; Piper et al, 2004). Coding for both individual variables and indices has been standardized across studies. All subjects were assessed in person by trained research assistants.

This study is part of the Gene Environment Association Studies initiative (GENEVA, http://www.genevastudy.org) funded by the trans-NIH Genes, Environment, and Health Initiative (GEI). The overarching goal is to identify novel genetic factors that contribute to the genetic architecture of smoking through large-scale genome-wide association studies of two well-characterized cohorts. Genotyping was performed at the Johns Hopkins University Center for Inherited Disease Research (CIDR). Data cleaning and harmonization were done at the GEI-funded GENEVA Coordinating Center at the University of Washington.

• Study Weblinks:
  • COGEND
  • UW-TTURC
• Study Design:
  • Case-Control
• Study Type:
  • Case-Control
  • Case Set
• dbGaP estimated ancestry using GRAF-pop
• Total number of consented subjects: 3499
• Subject Sample Telemetry Report (SSTR)

• BioProject
• PubMed
• BioSample
• MeSH
• PMC

COGEND

Existing data and samples were selected from the Collaborative Genetic Study of Nicotine Dependence. Cases are defined by a commonly used definition of nicotine dependence, a current FTND score of 4 or greater (maximum score of 10). Control status is defined as an individual who has smoked at least 100 cigarettes, but has never been dependent (lifetime FTND=0).

Permission to share data and samples was obtained from all subjects in the informed consent form. Informed consent was obtained from all subjects by trained research assistants. Prior to signing the consent form, a research assistant reviewed the form with the subject and answered any questions.

UW-TTURC

Existing data and samples were selected from three studies of nicotine dependence and smoking cessation treatment. Subjects were required to smoke at least 10 cigarettes per day (confirmed smoking by an alveolar carbon monoxide (CO) level greater than 9) and report being motivated to quit smoking. Subjects were included if they had phenotypic data and DNA, and provided consent to share data and samples.

COGEND

COGEND was initiated in 2001 as a three-part program project grant funded through the National Cancer Institute (PI: Laura Bierut). The three projects included a study of the familial transmission of nicotine dependence, a genetic study of nicotine dependence, and a study of the relationship of nicotine dependence with nicotine metabolism. The primary goal was to detect, localize, and characterize genes that predispose or protect an individual with respect to heavy tobacco consumption, nicotine dependence, and related phenotypes and to integrate these findings with the family transmission and nicotine metabolism findings. The primary design was a community based case-control family study.

Nicotine dependent and control probands were recruited from the community using the Missouri Family Registry in St. Louis, MO and Health Maintenance Organizations in Detroit, MI. Nicotine dependent cases were identified during telephone screening as current smokers with a Fagerström Test for Nicotine Dependence (FTND) score of 4 or greater (maximum score of 10). Control subjects were identified during telephone screening as smokers (individuals who smoked at least 100 cigarettes lifetime), who never had any symptoms of dependence (lifetime FTND=0). All subjects had to be between the ages of 25 to 44 years and speak English. Subjects could not have a condition that prevented them from providing informed consent or effectively participating in the protocol (e.g., language difficulty, CNS damage, or extremely poor health).

All subjects were assessed using the Semi-Structured Assessment of Nicotine Dependence (SSAND), which was developed specifically for COGEND and is modeled after the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) and Composite International Diagnostic Interview (CIDI).

Data collection ended in 2007; data analysis is ongoing. For more details, see http://zork.wustl.edu/cogend/.

UW-TTURC

The UW-TTURC was initiated in 2001 as a study of nicotine dependence and smoking cessation treatment. The second round of UW-TTURC was initiated in 2005 as a study of efficacy of smoking cessation and long term outcomes. Nicotine dependent smokers seeking cessation treatment were identified and recruited from Madison and Milwaukee, WI. Over 9,000 adult smokers were screened by telephone; 2,575 individuals were enrolled and randomized to treatment conditions that involved use of different smoking cessation medications. Inclusion criteria for the smoking cessation studies were smoking at least 10 cigarettes per day, confirmed smoking by an alveolar carbon monoxide (CO) level greater than 9, and being motivated to quit smoking. Participants were excluded based on evidence of psychosis history, clinically significant depression symptoms, other severe mental illness, and contraindications to smoking cessation medications.

Participants from the UW-TTURC smoking cessation clinical trials had the option of participating in a genetic substudy, and approximately 2,000 donated blood samples for genetic studies. The goal of the genetic studies of smokers seeking cessation treatment is to detect, localize, and characterize genes that predispose or protect an individual with respect to heavy tobacco consumption, nicotine dependence, and related phenotypes including cessation, withdrawal, and relapse. Institutional Review Boards at all sites approved the protocols.

All subjects were personally interviewed. Nicotine dependence was assessed using the FTND, multifactorial nicotine dependence scales, and DSM-IV criteria.

• Primary Phenotype: Smoking Cessation
• Nicotine Dependence
• Cigarette Smoking

• Principal Investigator
  • Laura J. Bierut, MD. Washington University School of Medicine, St. Louis, MO, USA.
• Co-Investigator
  • Timothy Baker, PhD. University of Wisconsin, Madison, WI, USA.
  • Naomi Breslau, PhD. Michigan State University, East Lansing, MI, USA.
  • Li-Shiun Chen, MD. Washington University School of Medicine, St. Louis, MO, USA.
  • Alison Goate, DPhil. Washington University School of Medicine, St. Louis, MO, USA.
  • Richard Grucza, PhD. Washington University School of Medicine, St. Louis, MO, USA.
  • Dorothy Hatsukami, PhD. University of Minnesota, Minneapolis, MN, USA.
  • Anthony Hinrichs, PhD. Washington University School of Medicine, St. Louis, MO, USA.
  • Eric O. Johnson, PhD. Research Triangle Institute International, Research Triangle Park, NC, USA.
  • Megan Piper, PhD. University of Wisconsin, Madison, WI, USA.
  • John Rice, PhD. Washington University School of Medicine, St. Louis, MO, USA.
  • Nancy Saccone, PhD. Washington University School of Medicine, St. Louis, MO, USA.
  • Scott Saccone, PhD. Washington University School of Medicine, St. Louis, MO, USA.
  • Stevens Smith, PhD. University of Wisconsin, Madison, WI, USA.
  • Jen-Chyong Wang, PhD. Washington University School of Medicine, St. Louis, MO, USA.
• Institute
  • National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD, USA.
• Funding Source
  • P01 CA089392. National Institutes of Health, Bethesda, MD, USA.
  • P50 DA019706. National Institutes of Health, Bethesda, MD, USA.
  • P50 CA084724. National Institutes of Health, Bethesda, MD, USA.
• Genotyping Center
  • Johns Hopkins University Center for Inherited Disease Research (CIDR), Baltimore, MD, USA.
• Funding Source for Genotyping
  • HHSN268200782096C. NIH contract High throughput genotyping for studying the genetic contributions to human disease. National Institutes of Health, Bethesda, MD, USA.
  • U01HG004438-01. NIH GEI grant JH/CIDR Genotyping for Genome-Wide Association Studies. National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.