Study of Addiction: Genetics and Environment (SAGE)

This study is part of the Gene Environment Association Studies initiative (GENEVA) funded by the National Human Genome Research Institute. The overarching goal is to identify novel genetic factors that contribute to addiction through a large-scale genome-wide association study of DSM-IV alcohol dependent (and frequently illicit drug dependent) cases and non-dependent, unrelated control subjects of European and African American descent.

The focus of this proposal is a case-control design of unrelated individuals for a genetic association study of addiction. Cases are defined as individuals with DSM-IV alcohol dependence (lifetime) and potentially other illicit drug dependence. In addition to the categorical diagnosis, we have data on ordinal measurements of number of DSM-IV symptoms for alcohol, nicotine, marijuana, cocaine, opiates and other drugs so that we will able to construct quantitative measurements of addiction severity over a wide range of substances. Controls are defined as individuals who have been exposed to alcohol (and possibly to other drugs), but have never met lifetime diagnosis for alcohol dependence or dependence on other illicit substances. Analyses that include refinement of the phenotype and incorporation of important demographic and environmental factors into association studies will be pursued.

Cases and controls were selected from three large, complementary datasets: the Collaborative Study on the Genetics of Alcoholism (COGA), the Family Study of Cocaine Dependence (FSCD), and the Collaborative Genetic Study of Nicotine Dependence (COGEND).

COGA: COGA was initiated in 1989 and is a large-scale family study that has had as its primary aim the identification of genes that contribute to alcoholism susceptibility and related characteristics. COGA is funded through the National Institute on Alcohol Abuse and Alcoholism (NIAAA). Subjects were recruited from 7 sites across the U.S. Alcohol dependent probands were recruited from treatment facilities and assessed by personal interview. After securing permission, other family members were also assessed. A set of comparison families was drawn from the same communities as the families recruited through the alcohol dependent probands. Assessment involved a comprehensive personal interview developed for this project, the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA), which gathers detailed information on alcoholism related symptoms along with other drugs and psychiatric symptoms. Families with three or more first-degree relatives who were alcohol dependent were invited for more extensive testing, including neurophysiology evaluations (ERPs and EEGs) and a battery of neuropsychological assessments. Blood was obtained for genetic studies. Institutional Review Boards at all sites approved the protocols, including sharing in the NIAAA national repository.

COGA has four Co-Principal Investigators Bernice Porjesz, Victor Hesselbrock, Howard Edenberg, and Laura Bierut. COGA includes nine different centers where data collection, analysis, and storage take place. The nine sites and Principal Investigators and Co-investigators are: University of Connecticut (Victor Hesselbrock); Indiana University (Howard Edenberg, John Nurnberger, Jr., Tatiana Foroud); University of Iowa (Samuel Kuperman); SUNY Downstate (Bernice Porjesz); Washington University in St. Louis (Laura Bierut, Alison Goate, John Rice); University of California at San Diego (Marc Schuckit); Howard University (Robert Taylor); Rutgers University (Jay Tischfield); Southwest Foundation (Laura Almasy). Q. Max Guo serves as the NIAAA Staff Collaborator. This national collaborative study is supported by the NIH Grant U10AA008401 from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the National Institute on Drug Abuse (NIDA).

Family Study of Cocaine Dependence (FSCD): This project was initiated in 2000 as a case-control family study of cocaine dependence funded through the National Institute on Drug Abuse (NIDA; PI: Laura Bierut). The primary goal was to increase the understanding of the familial and non-familial antecedents and consequences of cocaine dependence. Cocaine dependent individuals were systematically recruited from chemical dependency treatment units (both public and private; residential and outpatient) in the greater St. Louis metropolitan area. Community based control subjects were identified through a Missouri Driver's License Registry (maintained at Washington University for research purposes) and matched by age, race, gender, and residential zip code. As a supplement to this project, blood samples were collected for future genetic analysis and were included in the NIDA Genetics Consortium. Phenotypic data, DNA, and cell lines are in the NIDA Center for Genetics Studies.

Collaborative Genetic Study of Nicotine Dependence (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. All subjects were recruited from Detroit and St. Louis. Nicotine dependent cases and non-dependent smoking controls were identified and recruited. In addition, one sibling for each case and control subject was recruited in a subset of the sample. Over 56,000 subjects aged 25-44 years were screened by telephone, over 3,100 subjects were personally interviewed, and over 2,900 donated blood samples for genetic studies.

All three studies (COGA, COGEND, FSCD) include measures of basic socio-demographic variables, including age, sex, race/ethnicity, family income, educational attainment, religious participation, and family structure. Other important covariates and/or potential moderators of genetic effects include comorbid addictions and age at initiation of use for cigarettes, alcohol and drugs. The assessments also include measures of various life stressors, such as physical and sexual abuse, which have been implicated in gene-environment interactions for several disorders. Coding for both individual variables and indices has been standardized across studies. All subjects were assessed in person by trained research assistants.

Funding support for genotyping, which was performed at the Johns Hopkins University Center for Inherited Disease Research (CIDR), was provided by the NIH GEI (U01HG004438), the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Drug Abuse, and the NIH contract "High throughput genotyping for studying the genetic contributions to human disease"(HHSN268200782096C).

Note for Publications Related to Study: The Study of Addiction: Genetics and Environment (SAGE) has not yet generated publications. Below is a listing of publications related to the three studies from which the SAGE sample was selected. COGA has over 228 publications listed at www.niaaagenetics.org

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 addiction through a large-scale genome-wide association study of DSM-IV alcohol dependent (and frequently illicit drug dependent) cases and non-dependent, unrelated control subjects of European and African American descent. 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:
  • GENEVA: Gene Environment Association Studies
  • Genes and Environment Initiative Study of Addiction: Genetics and Environment (SAGE)
• Study Design:
  • Case-Control
• Study Type:
  • Case-Control
• dbGaP estimated ancestry using GRAF-pop
• Total number of consented subjects: 4121
• Subject Sample Telemetry Report (SSTR)

• BioProject
• PubMed
• BioSample
• MeSH
• PMC

Collaborative Study on the Genetics of Alcoholism (COGA)
A case control series of unrelated individuals was selected from the over 8,000 subjects who participated in the genetic arm of COGA. Cases met criteria for DSM-IV alcohol dependence and were preferentially selected from the proband group. If interviewed more than once, the subject had to be alcohol dependent on all interviews. Control subjects are individuals who have consumed alcohol, but never experienced any significant alcohol related problems. In addition, the control subjects did not meet any criteria for any illicit drug dependence (on any interview, if interviewed more than once).

Family Study of Cocaine Dependence (FSCD)
The sample consists of poly-substance dependent cases and controls. For this project, all cases met criteria for DSM-IV alcohol dependence (and because of the study design, most case subjects also met criteria for DSM-IV cocaine dependence). Controls are individuals from the same communities who have consumed alcohol, but have no lifetime history of dependence on any substance. A third group of subjects was defined as "other" if they were not alcohol dependent, but met lifetime diagnosis for DSM-IV marijuana dependence or dependence on another illicit drug.

Collaborative Genetic Study of Nicotine Dependence (COGEND)
For this case control study of addiction, we selected cases as individuals who met criteria for DSM-IV alcohol dependence from either nicotine dependent cases or the non-dependent control subjects. Control subjects were selected from the non-dependent control population and had consumed alcohol, but did not meet criteria for alcohol, nicotine, or illicit drug dependence. A third group of subjects was defined as "other" if they were not alcohol dependent, but met lifetime diagnosis for DSM-IV marijuana dependence or dependence on another illicit drug.

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.

Collaborative Study on the Genetics of Alcoholism (COGA)
COGA was initiated in 1989, with Henri Begleiter as the Principal Investigator and Theodore Reich as the Co-Principal Investigator for 15 years. In 2004, while Henri Begleiter remained the PI, four Co-PIs were put into place: Howard Edenberg, Victor Hesselbrock, Bernice Porjesz and Laura Bierut. In 2006, the structure of the leadership changed again, with these four scientific Co-PIs leading the project, and Bernice Porjesz additionally serving as the Administrative PI. In addition to Henri Begleiter and Theodore Reich, several past key members of COGA were T.K. Li, Raymond Crowe, Wendy Reich, and C. Michael Conneally, who have moved on to new positions or have retired.

In 1990, Phase I of COGA began, systematically ascertaining probands in treatment within six catchment areas, located across the United States (Indiana, New York, St. Louis, Connecticut, Iowa, San Diego). Probands met criteria for alcohol dependence based upon personal interview using the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA), a polydiagnostic instrument developed by COGA. Probands also had to have at least two first-degree relatives available for evaluation. Over the next 5 years, affected probands and family members participated in the study. During this time, control families with the same family structure were also ascertained from the community, to be representative of the general population; controls did not have to be unaffected individuals. All families completed the same battery of tests. A subset of families underwent neurophysiological assessments.

In Phase II, between 1995 and 1999, some recruitment of new families continued, and the first follow-up protocol (5 year) was initiated. Affected families were extended. Adult clinical interviews conducted at this time used the SSAGA-II (a slight modification of the SSAGA to meet new diagnostic criteria).

Phase III began in 1999, and was primarily an extension of Phase II with an emphasis on recruiting high-risk families with young children. At this same time Howard University became an additional recruitment site.

In 2004, COGA began Phase IV, the prospective study of adolescents and young adults from pedigrees ascertained in Phases I-III, which is ongoing. Participants are reassessed every two years.

For more details see zork.wustl.edu/niaaa/coga_instruments/resources.

Family Study of Cocaine Dependence (FSCD)
FSCD was initiated in 2000 as a case-control family study of cocaine dependence. Laura Bierut was the Principal Investigator, and the study was funded by NIDA. The primary goal of this case-control study was to increase the understanding of the familial and non-familial antecedents and consequences of cocaine dependence. Subjects were systematically recruited from chemical dependency treatment units (both public and private; residential and outpatient) in the greater St. Louis metropolitan area to identify potential cocaine dependent individuals. Subjects were required to speak English and be over the age of 18 years. 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).

Community based control subjects were identified through a Missouri Driver's License Registry (maintained at Washington University for research purposes) and matched by age, race, gender, and residential zip code. Zip code matching was a proxy for socioeconomic and neighborhood matching. Control subjects were initially contacted with a recruitment letter briefly explaining the study and then screened by telephone call. During the phone call, the study was further described, and age, race, and gender were confirmed. If the community based comparison subject was dependent on any substance, a second comparison subject with no substance dependence was recruited. To screen for substance dependence, potential control subjects were asked about maximum number of drinks consumed in a 24-hour period, which correlates strongly with alcohol dependence. Control subjects were then recruited and thoroughly assessed to confirm a lifetime history of no dependence on any substance.

All subjects were assessed using the Semi-Structured Assessment for Cocaine Dependence (SSACD), a polydiagnostic instrument developed for this project and closely based on the SSAGA.

Data collection ended in 2005; data analysis is ongoing. For more details see http://fire.wustl.edu/FSCD/index.htm.

Collaborative Genetic Study of Nicotine Dependence (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 Driver's License Registry in St. Louis and Health Maintenance Organization in Detroit. Nicotine dependent cases were identified during telephone screening as current smokers with a Fagerström Test for Nicotine Dependence (FTND) score of 4 or more (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). In a subset of the sample, one sibling was also recruited for case and control subjects.

All subjects were assessed using the Semi-Structured Assessment of Nicotine Dependence (SSAND), which was developed specifically for COGEND and is modeled after the 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/.

• Primary Phenotype: Alcoholism
• Alcohol Dependence
• Nicotine Dependence
• Drug Dependence

• Principal Investigator
  • Laura J. Bierut, MD. Washington University School of Medicine, St. Louis, MO, USA.
• Co-Principal Investigator
  • John P. Rice, PhD. Washington University School of Medicine, St. Louis, MO, USA.
• Steering Committee
  • Naomi Breslau, PhD. Michigan State University, East Lansing, MI, USA.
  • Howard J. Edenberg, PhD. Indiana University, Indianapolis, IN, USA.
  • Alison Goate, DPhil. Washington University School of Medicine, St. Louis, MO, USA.
  • Victor Hesselbrock, PhD. University of Connecticut, Farmington, CT, USA.
  • Eric Johnson, PhD. Research Triangle Institute International, Research Triangle Park, NC, USA.
• Collaborators
  • Arpana Agrawal, PhD. Washington University School of Medicine, St. Louis, MO, USA.
  • Laura Almasy, PhD. Southwest Foundation, San Antonio, TX, USA.
  • Kathleen Bucholz, PhD. Washington University School of Medicine, St. Louis, MO, USA.
  • Li-Shiun Chen, MD. Washington University School of Medicine, St. Louis, MO, USA.
  • Robert Culverhouse, PhD. Washington University School of Medicine, St. Louis, MO, USA.
  • Danielle Dick, PhD. Virginia Commonwealth University, Richmond, VA, USA.
  • Tatiana Foroud, PhD. Indiana University, Indianapolis, IN, 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.
  • John Kramer, PhD. University of Iowa, Iowa City, IA, USA.
  • Robert Krueger, PhD. Washington University School of Medicine, St. Louis, MO, USA.
  • Samuel Kuperman, MD. University of Iowa, Iowa City, IA, USA.
  • Michael Lynskey, PhD. Washington University School of Medicine, St. Louis, MO, USA.
  • Rosalind Neuman, PhD. Washington University School of Medicine, St. Louis, MO, USA.
  • John I. Nurnberger, Jr., MD, PhD. Indiana University, Indianapolis, IN, USA.
  • Bernice Porjesz, PhD. SUNY Downstate Medical Center, Brooklyn NY, 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.
  • Marc A. Schuckit, MD. University of California, San Diego, CA, USA.
  • Robert Taylor, MD. Howard University, Washington, DC, USA.
  • Jay A. Tischfield, PhD. Rutgers University, Piscataway, NJ, USA.
  • Jen C. Wang, PhD. Washington University School of Medicine, St. Louis, MO, USA.
• Funding Source
  • U01 HG004422. National Human Genome Research Institute, Bethesda, MD, USA.
  • U10 AA008401. National Institute on Alcohol Abuse and Alcoholism and National Institute on Drug Abuse, Bethesda, MD, USA.
  • P01 CA089392. National Cancer Institute, Bethesda, MD, USA.
  • R01 DA013423. National Institute on Drug Abuse, Bethesda, MD, USA.
  • R01 DA019963. National Institute on Drug Abuse, Bethesda, MD, USA.