REQUEST PROPOSALS FOR ACCESS TO A WHOLE GENOME ASSOCIATION SCANNING RESOURCE TO IDENTIFY DRUG ADDICTION LOCI

RELEASE DATE:

NOTICE: NOT-DA-04-006

National Institute on Drug Abuse
(http://www.nida.nih.gov)

NEW! - Frequently Asked Questions - updated 5/4/04

PURPOSE

The purpose of this announcement is to solicit applications from qualified investigators to use a NIDA-supported resource to conduct a genome wide association study for drug addiction vulnerability loci. NIDA anticipates contracting a resource to conduct whole genome SNP association scanning by September 2004. This resource will use 1.5 million SNP markers evenly distributed throughout the genome as surrogates to identify differences in genomic sequences of pooled individuals. The 1.5 million whole genome association study will identify the underlying genetic components involved in addiction by identifying those SNPs that have a significantly different frequency in drug addicted compared with the non-drug addicted individuals. Once individual SNPs are identified as being associated with addiction, a second screen of those particular SNPs will be performed by the resource on the individual DNA samples from the pools. Once confirmed, a completely different set of DNA samples (addicted and non-addicted) will be used by the resource to replicate the findings and validate the association of the SNPs to addiction. The successful applicant or group of collaborative investigators working together will be provided with a set of significantly associated SNPs following submission and analysis of DNA samples. Applications from a consortium of investigators working together are highly encouraged to maximize the usefulness of the resource and to obtain an appropriate sample set and sample size for the study.

NIDA requests that qualified applicants submit proposals by July 1, 2004 describing an appropriate study design for accessing this whole genome SNP association scanning resource. Highly dense genome-SNP association scanning is a powerful method to detect association of genetic loci with a complex phenotype such as addiction. Success of this project relies on two key factors: (1) a high-density SNP array to perform linkage disequilibrium analyses, and (2) a large number of well-characterized DNA samples and their associated phenotypic definitions from drug addicted and non-drug addicted individuals.

To qualify for this solicitation, applicants must be or previously have been NIDA Genetics Consortium (NGC) members, or become members of the NGC on or before July 1, 2004. To learn more about becoming a member of the NGC, please refer to: http://www.drugabuse.gov/about/organization/genetics/FAQ_GeneticStudies.html

For more information concerning this initiative including application procedures and review criteria, see below.

INQUIRIES

Inquiries concerning this notice are strongly encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome.

Direct programmatic inquiries to:

Joni Rutter, Ph.D.
Genetics and Molecular Neurobiology Research Branch
Division of Neuroscience and Behavioral
National Institute on Drug Abuse
6001 Executive Boulevard, Room 4S-4282, MSC 9555
Bethesda, MD 20892-9555
Telephone: (301) 443-1887
Email: jrutter@mail.nih.gov

The PI should submit an application packet, which includes the following:

• A cover page citing this NOTICE and requesting access to the resource to conduct a whole genome SNP association scan, the PI name or Co-PIs names, name(s) and title of the institutional official(s), phone number(s), email(s), address information for the PI or co-PIs and institutional official. The cover page should be signed by the PI or co-PIs and countersigned by an authorized institutional official(s). A proposal no more than 10 pages with margins not different than used in the PHS 398 form, describing the project, should include the following:
  • An abstract.
  • Applicant's history of NGC membership, or proposed plan to become an NGC member.
  • Background and significance.
    Evidence that a genome-wide SNP association scan is likely to identify genetic loci associated with substance abuse and addiction phenotypes based on factors such as heritability, relative risk, the heterogeneity of the genetic components of the phenotype, heterogeneity of the environmental components of the phenotype, sample size, and the size of the genetic locus effects, including possibilities of different disease allele frequencies and marker allele frequencies, and how the extent of the LD (between the marker and disease locus) that the contractor can offer will contribute to greater power of finding an association. This evidence may be based on preliminary data presented by the investigators requesting access or based on data published in peer-reviewed journals.
  • A detailed description of the type of design for the association scan to be conducted: e.g. case-control vs. affected/unaffected sibs, including a discussion on matching and familial structure if applicable. Applicants may wish to consult the following references to assist in the design of their study:
    
    Carlson, CS et al., Selecting a maximally informative set of single-nucleotide polymorphisms for association analyses using linkage disequilibrium Am.J.Hum.Genet. 74:106-120, 2004
    
    Carlson, CS et al., Additional SNPs and linkage-disequilibrium analyses are necessary for whole-genome association studies in humans Nat.Genet.33:518-521, 2003
    
    Hinds, DA et al., Matching strategies for genetic association studies in structured populations Am.J.Hum.Genet. 74:317-325, 2004
    
    Patil, N et al., Blocks of limited haplotype diversity revealed by high-resolution scanning of human chromosome 21. Science. 2001;294:1719-23
    
    Olivier, M et al., Complex high-resolution linkage disequilibrium and haplotype patterns of single-nucleotide polymorphisms in 2.5 Mb of sequence on human chromosome 21.Genomics. 2001 Nov;78(1-2):64-72
  • A detailed description of addiction phenotype and severity of the phenotype to be scanned that includes the history of how the subjects were ascertained and collected, exclusion criteria, and potential for re-consent.
  • The number and description of the case subjects and control subjects available. NIDA expects that a minimum of 500 cases and 500 controls should be proposed for the first pass association scan. Another 300-500 cases and 300-500 controls will be needed to independently replicate the results. A statement regarding the inclusion of women, minorities and children in the research study should be included.
  • Description of the amount of DNA available for the initial genome-wide scan and the amount of additional DNA available for future replication (At least 35 µg of DNA from each individual sample will be required to perform genotyping and submitted samples must be bar coded). Note that individual volunteers whose data is used in this study must have consented to have their anonymized DNA and clinical samples made available to qualified scientific investigators around the world.
  • Detailed plans for follow-up studies if association is or is not found.
  • A sharing plan to share data and research resources used and generated by the genome-wide SNP association scan. The sharing plan should be consistent with the sharing plan required for membership in the NIDA Genetics Consortium with the following inclusions addressed. NIDA expects investigators to submit a paper for publication within 12 months after receipt of data from the contractor. The data will be publicly available upon publication or 12 months after receipt of data, whichever comes first. The sharing plan should further address how research resources and intellectual property, if any is generated, will be managed, such that research resources like SNPs and other information stemming from the analysis will remain available to the broader scientific community consistent with NIH policies.
  • IRB approval to conduct the proposed study.

FUNDS ONLY AVAILABLE FOR GENOME-WIDE SCAN CONTRACT

Investigators are highly encouraged to submit a collaborative proposal that maximizes the utility of the resources and increases the chance of finding an association(s). Proposals must be received no later than July 1, 2004. If an application is received after that date, it will be returned to the applicant without review. Because of the expense of doing a whole genome SNP association scan, NIDA currently anticipates only approving one proposal from a qualified investigative team; SUCH APPLICANTS MAY BE A CONSORTIUM OF MULTIPLE APPLICANTS, which will have access to this resource. Furthermore, it is expected that with the exception of conducting the genome wide scan itself, the applicant will cover the cost associated with designing the study, selecting DNA samples and other costs not directly covered under the whole genome SNP association scan contract.

Send the original signed application and five photocopies in one package to:

Joni Rutter, Ph.D.
National Institute on Drug Abuse
6001 Executive Boulevard, Room 4S-4282, MSC 9555
Bethesda, MD 20892-9555
Phone: 301-443-1887
E-mail: jrutter@mail.nih.gov

For deliveries from non-US mail carriers, send the application to:

National Institute on Drug Abuse
6001 Executive Boulevard, Room 4S-4282,
Rockville, MD 20852

REVIEW CONSIDERATIONS

Proposals for access to the resource for genome wide SNP scanning will be peer reviewed by an access committee composed of at least 5 scientists with expertise in genetics, phenotypic analysis, and gene association studies.

The NIDA access committee for genome-wide SNP association scanning will evaluate proposals for genome-wide SNP association scanning based on the following criteria:

• The design of the proposed association study e.g. case control vs. affected-unaffected sib-pairs, the appropriateness of the controls, and how issues of stratification/matching are addressed
• The availability of adequate numbers of subjects to conduct the genome scan with sufficient power to detect association Note that individual volunteers whose data are used in this study must have consented to have their anonymized DNA and clinical samples made available to qualified scientific investigators around the world.
• The amount of DNA available for the initial genome-wide scan and the amount of additional DNA available for future replication (At least 35 µg of DNA from each individual sample will be required to perform genotyping).
• The quality and completeness of phenotyping and "extremity" of phenotypes selected for genotyping. Phenotypes must be highly detailed and clearly stated for both the cases (addicted) and controls (non-addicted).
• The likelihood that a genome-wide SNP association scan will identify genetic loci associated with substance abuse and addiction phenotypes based on factors such as heritability, relative risk, the heterogeneity of the genetic components of the phenotype, the size of the genetic locus effects, heterogeneity of the environmental components of the phenotype, and sample size.
• The ability of applicant to analyze and interpret the resulting data.
• The plans for follow-up studies if association is or is not found
• IRB Approval to conduct the proposed study.
• NIDA Genetic Consortium (NGC) membership status. Investigators must be or previously been members of the NGC Existing and previous members must have completed submission of their clinical data that is associated with blood samples already sent to the NIDA Center for Genetic Studies at the time of access. Both intramural and extramural investigators may join the NIDA Genetics Consortium. For membership information see:
  http://www.drugabuse.gov/about/organization/genetics/FAQ_GeneticStudies.html

Reviewers will comment, as appropriate, on the adequacy and feasibility of the plans for sharing data and research resources used and generated by the genome-wide SNP association scan, which would include addressing submission of a paper for publication within 12 months following receipt of the data. Comments on the plans and any concerns will be presented in an administrative note in the Summary Statement. These comments will not affect the evaluation of the proposal's scientific merit. NIH program staff will consider the adequacy of the plans in determining whether to recommend an application for award.