Study 06 – The Genetics of Vulnerability to Nicotine

Investigator:  Pamela Madden

Release Date:  Available at NIDA and dbGaP

Abstract:  This study focuses on two primary smoking phenotypes: (i) a broader phenotype, lifetime heavy smoking, which is the phenotype being used to define affected sib pairs and hence which determines selection of families for genotyping; and (ii) a narrower phenotype of lifetime nicotine dependence, which requires that the respondent meet criteria for DSM-IV nicotine dependence, and scores at least 4 out of 6 on the two-item Fagerstrom Test of Nicotine Dependence (FTND).  Definitions are based on smoking history; i.e., current non-smokers who met criteria for heavy smoking (or nicotine dependence) when they were smokers are being classified as heavy or dependent smokers. Families are being ascertained through panels of adult Australian twins, and a sample of spouses of Australian twins, who have been identified as having a history of heavy smoking in earlier surveys.  Diagnostic telephone interviews are being conducted with index cases, and their full siblings and parents, to identify sibships with at least one affected sib pair (ASP) concordant for heavy smoking, and at least one living parent (target N=400 Australian families with approximately 600 ASPs; and 600 TDT trios comprised of a nicotine dependent index case and both biological parents). A 10cm genome-wide scan will be conducted using the 400 ASP families.  Affected sib-pair methods of linkage analysis will be used to identify candidate chromosomal regions suggestive of linkage, and a transmission disequilibrium test approach will be used to test for candidate gene effects on nicotine dependence, and for fine mapping of candidate regions.  An electronic database (without personal identifiers) is being established through the NIDA Genetics Consortium that includes genotype, diagnostic, and other pertinent information.  Lymphoblast cell lines will be stored in a repository established through the NIDA Genetics Consortium for distribution to qualified members of the scientific community.  The investigators responsible for this project are open to collaborations with qualified scientists whose research has been approved by NIDA, as well as open to collaborations with junior investigators or Post Doctoral fellows interested in training opportunities in the area of statistical genetics, genetic epidemiology (including behavioral genetics), or molecular genetics. 

Sampling Design:  An affected full sibling pair design, with the inclusion of any additional affected full siblings in the family, both biological parents (when available), and (if one or both parents are unavailable for study) unaffected full siblings who have been exposed to nicotine (i.e., have smoked at least once or twice), but never became regular smokers (i.e., smoked fewer than 100 cigarettes in their life).  This design will permit powerful affected sib pair linkage analyses and TDT (including sib-TDT) analyses. 

Australia has a large national twin panel in which smoking data have been collected prospectively over a period of many years (from 1980-82 onwards).  Heavy smoking cases are being identified from these panels.  In the case of MZ twin pairs concordant for heavy smoking, one twin, with preference given to a twin who also meets our criteria for nicotine dependence, will be selected as the index case, and the co-twin will be discarded from traditional ASP and TDT analyses.

Overview of Data Collection: Sample Ascertainment:  Families with at least one offspring who is a current or former smoker have been identified from previous surveys of families enrolled in the Australian twin registry.  Index cases are being administered a 15 minute screening interview by telephone to provide confirmation of a history of heavy cigarette smoking, and to obtain additional information on the history of cigarette use and the survival status of other family members.  Index cases are the affected spouse of a twin, or the affected twin from pairs discordant for history of heavy smoking, or a randomly chosen twin from pairs where both have a history of regular smoking (i.e., has smoked at least 100 cigarettes lifetime), and at least one live biological parent.  If permission is granted by the index case, eligible family members are contacted and invited to provide a blood sample and to complete a telephone diagnostic interview.  In families with just one available biological parent, an additional unaffected sibling who has never smoked on a regular basis (i.e., has smoked fewer than 100 cigarettes lifetime, but has experimented with cigarettes once or twice) is being included (when available) to help compensate for the loss of information due to missing parental phenotypes.

Assessment Battery:  The telephone interview assesses DSM-IV diagnoses and modified DSM-IIIR diagnoses (i.e., without time clustering) for nicotine dependence, alcohol and other drug dependence and abuse, major depression, and childhood conduct disorder.  Most diagnostic assessments are based on the SSAGA/SSAGA-II, developed for the multi-site gene-mapping alcoholism study (the Collaborative Study on the Genetics of Alcoholism:  COGA), which in turn are derived from the CIDI and the DIS.  However, the tobacco section was adapted directly from the CIDI and DIS (as the original SSAGA did not include a diagnostic section on nicotine dependence).  Age-of-onset of dependence and standard self-report assessments of quantity/frequency of peak use are being obtained for the use of tobacco, alcohol, and other drugs.


Tobacco and Alcohol Project

Instrument: Tobacco and Alcohol Project (Opening Screen)

Respondent Booklet: Tobacco and Alcohol Study Respondent Booklet; Version for Brothers and Sisters; Version 1.0