A Genome-Wide Association Study of Heroin Dependence

This collaboration of Australian and American investigators aims to identify genes associated with liability for heroin dependence. The project uses a case-control design in which cases met lifetime DSM-IV criteria for heroin dependence. Controls included assessed individuals who did not meet DSM-IV heroin dependence criteria and unassessed general population controls. Cases and controls were obtained from the several large investigations including: The Comorbidity and Trauma Study, Heroin Dependence in Western Australia, the OZ-ALC Study, a Twin Study of Mole Development in Adolescence, and ongoing genetic studies of substance dependence conducted by investigators at Yale and collaborating institutions. These projects are briefly described below.

The Comorbidity and Trauma Study (PI: Elliot Nelson), a retrospective case-control study examining genetic and environmental factors contributing to heroin dependence liability. The study was funded by the National Institute on Drug Abuse (NIDA), and was run in collaboration with Washington University, the Queensland Institute of Medical Research (QIMR), and the National Drug and Alcohol Research Centre (NDARC), University of New South Wales. Case participants were recruited from maintenance clinics in the greater Sydney area. Control participants were recruited from employment centres and community centres, open street malls, and local press servicing the same geographical area as the opioid maintenance treatment clinics and either denied recreational use of opioids or had used these drugs recreationally fewer than 11 times lifetime. The prevalence in these individuals of non-opioid licit drug dependence and illicit drug dependence as well as childhood trauma exposure and other psychiatric disorders is elevated considerably versus estimates of similar measures in Australian general population samples. Participants provided blood samples as a source of DNA and completed a comprehensive psychiatric diagnostic interview based on the Semi-Structured Assessment of the Genetics of Alcoholism - Australia (SSAGA-OZ) augmented with sections drawn from other instruments assessing childhood trauma exposure, family history, and screening for borderline personality disorder.

Heroin Dependence in Western Australia (PI: Sybille Schwab) is a study focusing both on genetic contributions to heroin dependence and response to naltrexone treatment of the disorder. Participants completed a clinical assessment and provided blood samples during their treatment at the Perth Naltrexone Clinic now name as the Fresh Start Recovery Programme. Funding for the project was provided by the Australia Government's National Health and Medical Research Council (Grant # 513862; PI: Sybille Schwab)

Affected subjects from ongoing genetic studies of substance dependence conducted by investigators at Yale (PI: Joel Gelernter) and collaborating institutions were collected in the course of several NIDA-funded studies. Those included in the current set were assessed by means of the SSADDA (Semi-Structured Assessment for Drug Dependence and Alcoholism). All are opioid dependent European-Americans, and all list heroin as the opioid must used. Most were collected at Yale University School of Medicine or University of CT School of Medicine under the supervision of Drs Joel Gelernter and Henry Kranzler. Control subjects were also collected in the course of several NIDA- and NIAAA-funded studies. Those included in the current set were assessed by means of the SSADDA (Semi-structured Assessment for Drug Dependence and Alcoholism). Most were collected at Yale University School of Medicine or University of Connecticut School of Medicine under the supervision of Drs Joel Gelernter and Henry Kranzler.

The OZ-ALC Study (PI: Andrew Heath) consists of a large group of twins and their family members ascertained from the general population Australian Twin Registry who have participated in ongoing research projects. For the control investigation, we have selected individuals who do meet criteria for illicit drug dependence who have had GWAS genotyping with the Illumina Human CNV370-Quad. Inclusion of individuals with alcohol dependence or nicotine dependence was minimized. For a more detailed description of the study, please see this link.

The Twin Study of Mole Development in Adolescence (PI: Nick Martin) is an ongoing investigation of melanocytic naevi funded by the Australian Government's National Health and Medical Research Council (Grant # 389891; PI: Nick Martin). For the current project, unassessed parents of these twins will serve as a control group. These individuals will either have been previously genotyped with the Illumina Human 610-Quad BeadChip or will be genotyped as part of the current project. Parents have largely survived the period of risk for heroin dependence, and by virtue of their participation in this research, are very likely to have a prevalence of heroin dependence lower than that in the general population (i.e., <0.7%).

• Study Design:
  • Case-Control
• Study Type:
  • Case-Control
• dbGaP estimated ancestry using GRAF-pop
• Total number of consented subjects: 6487
• Subject Sample Telemetry Report (SSTR)

• PubMed

Cases

1. The Comorbidity and Trauma Study - Inclusion criteria included participation in pharmacotherapy maintenance treatment for opioid dependence at some point in their lives, aged 18 years or over; and had an adequate understanding of English. Participants reporting recent suicidal intent or who were known to be currently experiencing psychosis were excluded from the study.
2. Heroin Dependence in Western Australia - Heroin dependent individuals treated at the Perth Naltrexone Clinic subsequently renamed the Fresh Start Recovery Programme for whom blood samples were available from a clinic trial or were collected prospectively for a genetic study.
3. Ongoing genetic studies of substance dependence conducted by investigators at Yale and collaborating institutions - Opioid dependent European-Americans who listed heroin as the opioid must used.

Neighborhood controls

1. The Comorbidity and Trauma Study - Individuals recruited from employment centres and community centres, open street malls, and local press servicing the same geographical area as the opioid maintenance treatment clinics who either denied recreational use of opioids or who had used these drugs recreationally fewer than 11 times.

Assessed controls

1. The OZ-ALC Study - Individuals for whom GWAS genotyping had been completed who did not meet criteria for illicit drug dependence. Inclusion of individuals with alcohol dependence or nicotine dependence was minimized.
2. Ongoing genetic studies of substance dependence conducted by investigators at Yale and collaborating institutions - Individuals assessed by means of the SSADDA (Semi-structured Assessment for Drug Dependence and Alcoholism as having no substance dependence or abuse diagnoses and no psychosis.

Unassessed controls

1. A Twin Study of Mole Development in Adolescence - Parents of adolescent twins participating in a genetic study of mole development for whom GWAS genotyping had been previously completed or for whom DNA samples were available for GWAS genotyping.

The Comorbidity and Trauma Study was funded in 2003 by NIDA as a collaboration of investigators at Washington University, the Queensland Institute of Medical Research, and the National Drug and Alcohol Research Centre, University of New South Wales. Data collection began in 2004 and candidate gene genotyping was completed in 2009. The investigation is a component of the NIDA Genetics Consortium which facilitated the collaborative relationships that led to the current investigation.

Heroin Dependence in Western Australia (PI: Sybille Schwab) is a collaboration of genetics and clinical investigators that utilizes the large population of individuals presenting for naltrexone treatment of heroin dependence in Perth, Western Australia. The project focuses both on genetic contributions to heroin dependence and response to naltrexone treatment of the disorder.

The affected and control subjects from ongoing genetic studies of substance dependence conducted by investigators at Yale (PI: Joel Gelernter) and collaborating institutions were collected in the course of several NIDA-funded and NIAAA-funded studies that have resulted from the longstanding collaboration of Drs. Joel Gelernter at Yale University School of Medicine and Henry Kranzler at the University of Connecticut School of Medicine and colleagues at their own and other institutions.

The OZ-ALC Study (PI: Andrew Heath) is the result of a longstanding collaboration of investigators at Washington University School of Medicine (led by Andrew Heath) and Queensland Institute of Medical Research (led by Nick Martin). For details on the project's history, please see the link.

The Twin Study of Mole Development in Adolescence (PI: Nick Martin) began in 1992 when all available monozygotic and dizygotic twin pairs aged 12-14 years were initially ascertained in 1992 via the Brisbane school system for a study of moles. A GWAS was subsequently funded by the Australia Government's National Health and Medical Research Council.

• Primary Phenotype: Heroin Dependence

• Principal Investigator
  • Elliot C. Nelson, MD. Washington University School of Medicine, St. Louis, MO, USA.
• Project Analyst
  • Nancy L. Saccone, PhD. Washington University School of Medicine, St. Louis, MO, USA.
• Co-investigators
  • Andrew C. Heath, DPhil. Washington University School of Medicine, St. Louis, MO, USA.
  • Nicholas G. Martin, PhD. Queensland Institute of Medical Research, Brisbane, Queensland, AU.
  • Joel Gelernter, MD. Yale School of Medicine, New Haven, CT, USA.
  • Sibylle G. Schwab, PhD. Western Australian Institute for Medical Research, Perth, Western Australia, AU.
  • Henry R. Kranzler, MD. University of Connecticut School of Medicine, Farmington, CT, USA.
  • Grant W. Montgomery, PhD. Queensland Institute of Medical Research, Brisbane, Queensland, AU.
  • John P. Rice, PhD. Washington University School of Medicine, St. Louis, MO, USA.
  • Pamela A.F. Madden, PhD. Washington University School of Medicine, St. Louis, MO, USA.
• Institute
  • National Institute on Drug Abuse, Bethesda, MD, USA.
• Genotyping Center
  • Johns Hopkins University Center for Inherited Disease Research (CIDR), Baltimore, MD, USA.
• Funding Source for CIDR Genotyping
  • HHSN268200782096C. NIH contract "High throughput genotyping for studying the genetic contributions to human disease". National Institutes of Health, Bethesda, MD, USA.
  • HHSN268201100011I. NIH contract "High throughput genotyping for studying the genetic contributions to human disease". National Institutes of Health, Bethesda, MD, USA.