Expired PA-14-025: Discovering Novel Targets: The Molecular Genetics of Drug Addiction and Related Co-Morbidities (R01)

Part 1. Overview Information

Participating Organization(s)	National Institutes of Health (NIH)
Components of Participating Organizations	National Institute on Drug Abuse (NIDA)
Funding Opportunity Title	Discovering Novel Targets: The Molecular Genetics of Drug Addiction and Related Co-Morbidities (R01)
Activity Code	R01 Research Project Grant
Announcement Type	Reissue of PA-11-026
Related Notices	January 10, 2017 - This PA has been reissued as PA-17-120. December 5, 2016 - Notice of Intent to Publish a Funding Opportunity Announcement for Discovering Novel Targets: The Molecular Genetics of Drug Addiction and Related Co-Morbidities (R01). See Notice NOT-DA-17-005. NOT-OD-16-004 - NIH & AHRQ Announce Upcoming Changes to Policies, Instructions and Forms for 2016 Grant Applications (November 18, 2015) NOT-OD-16-006 - Simplification of the Vertebrate Animals Section of NIH Grant Applications and Contract Proposals (November 18, 2015) NOT-OD-16-011 - Implementing Rigor and Transparency in NIH & AHRQ Research Grant Applications (November 18, 2015) June 4, 2014 - Notice NOT-14-074 supersedes instructions in Section III.3 regarding applications that are essentially the same.
Funding Opportunity Announcement (FOA) Number	PA-14-025
Companion Funding Opportunity	None
Number of Applications	See Section III. 3. Additional Information on Eligibility.
Catalog of Federal Domestic Assistance (CFDA) Number(s)	93.279
Funding Opportunity Purpose	This FOA encourages applications for research projects that identify and/or validate chromosomal loci and variations in genes that are associated with vulnerability to addiction and that inform the likelihood of responsiveness to treatment. Applications that propose to examine intermediate phenotypes or endophenotypes to assess the molecular genetics of drug addiction, addiction vulnerability and/or their associated co-morbidities and how they are related to drug addiction are especially encouraged. Also encouraged are genetic as well as computational and large-scale genomic approaches, which may include but are not limited to linkage, linkage disequilibrium, case-control or family-based studies, and integration of data from other databases that may supplement substance abuse genetics and genomics data. Data may be collected from the general population, special populations, recent admixed populations, and/or animal models. Secondary data analysis of data collected from the general population, special populations, recent admixed populations, and/or animal models is also appropriate for this announcement. Investigators are encouraged to include, as a component of their project and as appropriate, gene x gene interactions, gene x environment interactions, gene x environment x development interactions, pharmacogenetics, and non-human models.

Key Dates

Posted Date	December 10, 2013
Open Date (Earliest Submission Date)	January 5, 2014
Letter of Intent Due Date(s)	Not Applicable
Application Due Date(s)	Standard dates apply, by 5:00 PM local time of applicant organization. Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.
AIDS Application Due Date(s)	Standard AIDS dates apply, by 5:00 PM local time of applicant organization. Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.
Scientific Merit Review	Standard dates apply
Advisory Council Review	Standard dates apply
Earliest Start Date	Standard dates apply
Expiration Date	January 8, 2017
Due Dates for E.O. 12372	Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

Table of Contents

Part 1. Overview Information
Part 2. Full Text of the Announcement
Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

This FOA seeks investigator-initiated applications for genetic and genomic research projects that identify chromosomal loci and/or genetic variation and haplotypes that are associated with either increased or decreased vulnerability to drug addiction, including stimulants (e.g., cocaine, amphetamine, caffeine), narcotics (e.g. opiates), nicotine/tobacco products, benzodiazepines, barbiturates, cannabis, hallucinogens, and/or multiple drugs of abuse and, as needed, accounting for associated co-morbidities (e.g., HIV/AIDS, major depression, schizophrenia, bipolar disorder, alcoholism) in human beings or animal models.

The state of the science on genetics of addiction may be quite different for a given drug. For example, the literature is robust with genome-wide association studies (GWAS) on nicotine dependence, but replicated genetic findings are limited for certain other drugs of abuse. Similarly, there is interest in chromosomal loci and/or genetic variation and haplotypes that are associated with differences in responses to treatment for addiction to these drugs of abuse and related disorders

Recent advances in statistical genetics, molecular biology, and genomic approaches have greatly accelerated the ability to identify the etiology of diseases that have a genetic basis. Animal models provide an alternative way for understanding the underlying biology of these complex diseases. In addition, many databases (e.g., 1000 Genomes, HapMap, dbGaP) are available to supplement existing studies, and/or mine directly. These and related approaches are likely to have applicability to the brain diseases of addiction. Thus, molecular and computational characterization of all types of genetic variation identified through genetic studies is also encouraged.

Identifying specific genes and gene variants that mediate addiction or other complex, multi-genic diseases is complicated by the fact that analytical methods developed for single-gene disorders do not necessarily incorporate the effects of gene interactions. Investigators are encouraged to consider using innovative genetic models, pedigree structure, haplotypes, and other methods of statistical analyses for the identification of genetic variations conferring vulnerability to complex genetic disorders such as drug addictions with or without co-morbid mental disorders, and response to pharmacotherapies for these disorders.

Phenotype definition of both case and control (both exposed and unexposed) individuals is a central issue in the analysis of complex traits such as addiction and is an essential component to applications responding to this FOA. Investigators are encouraged to use existing instruments that have been used by the NIDA Genetics Consortium, http://nidagenetics.org/ and browse through the study information links to access the instruments used.

In addition, NIDA has developed a series of core elements for assessing and harmonizing demographic information and substance use history for genetic studies. The core elements can be accessed through this link: http://www.drugabuse.gov/about/organization/Genetics/ngcdomains/. NIDA strongly encourages all applicants to discuss how these core elements are addressed in their data sharing plan by either assessing them directly or indirectly by proxy measures.

This FOA particularly seeks applications that propose to study intermediate phenotypes or endophenotypes. For these studies, emphasis should be placed on how these intermediate phenotypes and endophenotypes map onto the phenotypic outcome of drug addiction (e.g. DSMIIIR or DSMIV criteria or other validated and heritable outcome measures). Endophenotypic measures in some cases may afford greater reliability compared to an overt addiction diagnosis. Although genetic effect sizes associated with endophenotypes have not necessarily been larger than those reported for other phenotypes for many psychiatric disorders, their usefulness for identifying addiction loci remains to be determined.

Alternative phenotype definition may better describe the genetic aspects of addiction. Therefore, investigators may propose the use of other phenotypic information such as the presence or absence of biological markers or exhibition of unique individual traits, as well as combinations of these and/or co-morbid conditions. Justification for the use of proposed alternative phenotypes and how it relates to the addiction phenotype should be clearly stated and evidence for heritability provided.

Investigators including the exploration of environmental factors should include detailed explanations of how the environments were measured, and how they may impact outcome. Gender and ethnic specific analyses in the molecular genetics of addiction vulnerability is encouraged.

Examples of broad research topics include, but are not limited to:

Molecular genetics approaches:

Research on human sample populations examining family-based linkage studies, linkage disequilibrium, case-control and/or family-based association studies using candidate gene approaches, haplotype, high-density whole genome scanning, deep sequencing, or whole genome sequencing to identify chromosomal loci and/or genes, gene variants, and haplotypes associated with phenotypes and endophenotypes of addiction vulnerability with or without co-morbid mental disorders;
Deep sequencing to follow-up GWAS or other approaches that have identified SNPs to find all variants (common, rare, structural, copy number, etc) in the associated region;
Examine intermediate phenotypes or endophenotypes to assess the molecular genetics of drug addiction and addiction vulnerability;
Use advanced analytical methods such as principal-components analysis, discriminant analysis, artificial neural networks, spectral analysis of EEG, neuroimaging for drug activity/re-activity, and/or pharmacokinetic/ pharmacodynamic genetic profiling may help define groups of phenotypes with a higher heritability for complex traits such as drug response phenotypes and treatment response phenotypes;
Analyses of family studies to identify biomarkers, endophenotypes, and sub clinical phenotypes associated with addictive disorders with or without co-morbid conditions, and environmental factors and processes that may moderate or mediate individual risk and protection;
Research examining the pharmacogenetics of treatments used for addiction (including pharmacotherapies and/or behavioral therapies) with or without co-morbid mental disorders;
Construction and analysis of SNP haplotypes that predict therapeutic response or adverse reactions to drugs;
Correlation of drug response profiles with intermediate phenotypes (e.g., brain imaging, learning and memory, executive function);
Identification of biomarkers to resolve clinical heterogeneity and heterogeneity of therapeutic drug response; studies of genetically determined functional changes in nuclear and cell surface receptors to explain the adverse or paradoxical drug responses to therapeutic agents; studies of allelic variation occurring in individual transporter genes that are associated with a functional consequence. Studies on dose and safety and efficacy are not appropriate for this FOA;
Research on animal models, including non-human primates, to study the genetics of addiction vulnerability; approaches using knock-out, knock-in, non-coding RNAs, or other novel technologies;
Animal models with careful attention to phenotype definition are needed to refine QTLs and identify genes associated with addiction;
Research incorporating the evaluation of environmental exposures or psychosocial stressors with the molecular approaches;
Research involving molecular characterization, and/or functional genomic, and/or proteomic screens of genes or gene variants identified as being associated with addiction vulnerability, including cross-species comparisons to evaluate the effects of a particular allele across organisms;
Studies analyzing the combined effects of gene variants from a gene family or pathway shown to be involved in addiction and/or co-morbid mental disorders;
Studies examining gene expression, tissue specificity, and epigenetic mechanisms, and/or non-coding RNA approaches to better understand the effects of a particular SNP or group of SNPs on addiction vulnerability; especially encouraged are studies that examine these paradigms according to developmental stage or across tissue types;
Studies examining the genetic vulnerability to HIV acquisition and/or disease progression among drug using populations. HIV/AIDS questions must be fully integrated into the application.

Statistical genetics and computational approaches:

Computational approaches that incorporate other data resources, such as HapMap, 1000 Genomes, Epigenomics, dbGaP, etc are encouraged, especially as they relate to understanding relationships among genes and environment, genes and phenotype, and systems biology of addiction;
Analyzing 1000 Genomes data for genes known to be associated with drug addiction to understand their genetic architecture in various populations (what is the repertoire of genetic variation in the genomic regions of genes associated with addiction phenotypes, and is it any different from genes not associated with addiction phenotypes);
Studies that narrow the set of variants identified in an associated region to prioritize them for functional analysis;
Research on statistical analyses of large data sets examining the genetics of addiction with or without co-morbid mental disorders, as well as use of innovative analytical approaches such as admixture designs and Bayesian methods; secondary data analyses are also of interest;
Research examining gene x gene, gene x environment, gene x gender, gene x treatment, gene x development, or any combinations thereof;
Addiction vulnerability traits have been linked to multiple regions of the genome and research is needed to identify specific genes and polymorphisms within and around those genes that lie within these linkage regions;
Statistical methods for analyzing epistasis.

Applicants whose approaches are designed to initially detect genetic linkages with addiction or intermediate phenotypes are encouraged to apply instead for molecular genetics PA-14-013 and PA-14-014.

Applicants whose approaches are designed to clarify already established genetic linkages are encouraged to apply instead for the NIDA Functional Genetics PA-14-013 and PA-14-014.

For additional NIDA funding opportunities in genetics, refer to the NIDA genetics workgroup homepage: http://www.drugabuse.gov/researchers/research-resources/genetics-research-resources .

It is highly recommended that applicants contact NIDA program staff during the early planning stages of project development to gauge interest in the genetics of the particular phenotype proposed, as well as the genetic approach being taken.

The NIDA Genetics Consortium (NGC)

The NIDA Genetics Consortium (NGC) consists of investigators who have modified their projects to conform to the guidelines listed in a previous FOA to use the resources provided by the NIDA Center for Genetics Studies. The NIDA Center for Genetics Studies is funded by a contract awarded to Rutgers University with a subcontract to Washington University at St. Louis for the purpose of creating databases, cryopreserved lymphocytes, and DNA samples, and for wide distribution of the data and DNA to the scientific community. After a proprietary period, the NIDA Center for Genetics Studies will, upon proper application and approval, distribute both the data and DNA samples to qualified researchers.

NIDA Genetics Consortium Membership and Meetings

Members of the NGC meet two times a year to discuss issues related to the molecular genetics of addiction vulnerability. Plans for membership in the NGC for all human genetics applications collecting blood samples are encouraged, but not required. Due to budget limitations on the contract, not all applicants requesting membership can be accepted into the consortium. For further information, seehttp://www.drugabuse.gov/frequently-asked-questions-about-nida-genetics-consortium-all-human-genetics-studies-nida .

Available Genotyping and Expression Array Resources

Investigators should note that there are several existing resources available to investigators for genotyping and expression array studies. One is the Center for Inherited Disease Research (CIDR), which is supported by a contract to Johns Hopkins University by eight NIH institutes including NIDA. CIDR was established in 1996 to provide high-throughput genotyping and statistical services for complex genetic diseases to the scientific community at large. Introductory no cost access to CIDR resources is available to investigators who have been approved by the CIDR Access Committee (CAC) and who are supported by one of the eight supporting NIH institutes (including NIDA). Thus, projects supported by this FOA are eligible for no cost access to CIDR resources following CAC approval.

Investigators should request access to CIDR resources, if needed, and obtain NIDA and CIDR approval before the requested start date of the grant. CIDR applications are accepted via continuous receipt https://grants.nih.gov/grants/guide/pa-files/PAR-11-210.html or contact Camilla Day at 301-402-0838 or at [email protected].

Special Considerations

HIV/AIDS Counseling and Testing Policy for the National Institute on Drug Abuse: In light of recent significant advances in rapid testing for HIV and in effective treatments for HIV, NIDA has revised its 2001 policy on HIV counseling and testing. NIDA-funded researchers are strongly encouraged to provide and/or refer research subjects to HIV risk reduction education and education about the benefits of HIV treatment, counseling and testing, referral to treatment, and other appropriate interventions to prevent acquisition and transmission of HIV. This policy applies to all NIDA funded research conducted domestically or internationally. For more information see https://grants.nih.gov/grants/guide/notice-files/NOT-DA-07-013.html.

National Advisory Council on Drug Abuse Recommended Guidelines for the Administration of Drugs to Human Subjects: The National Advisory Council on Drug Abuse (NACDA) recognizes the importance of research involving the administration of drugs with abuse potential, and dependence or addiction liability, to human subjects. Potential applicants are encouraged to obtain and review these recommendations of Council before submitting an application that will administer compounds to human subjects. The guidelines are available on NIDA's Web site at http://www.drugabuse.gov/funding/clinical-research/nacda-guidelines-administration-drugs-to-human-subjects.

Points to Consider Regarding Tobacco Industry Funding of NIDA Applicants: The National Advisory Council on Drug Abuse (NACDA) encourages NIDA and its grantees to consider the points it has set forth with regard to existing or prospective sponsored research agreements with tobacco companies or their related entities and the impact of acceptance of tobacco industry funding on NIDA's credibility and reputation within the scientific community. Please see http://www.drugabuse.gov/about-nida/advisory-boards-groups/national-advisory-council-drug-abuse-nacda/council-statements/points-to-consider-regarding for details.

Data Harmonization for Substance Abuse and Addiction via the PhenX Toolkit: NIDA strongly encourages investigators involved in human-subjects studies to employ a common set of tools and resources that will promote the collection of comparable data across studies and to do so by incorporating the measures from the Core and Specialty collections, which are available in the Substance Abuse and Addiction Collection of the PhenX Toolkit (www.phenxtoolkit.org). Please see NOT-DA-12-008 (https://grants.nih.gov/grants/guide/notice-files/NOT-DA-12-008.html) for further details.

Section II. Award Information

Funding Instrument	Grant: A support mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity.
Application Types Allowed	New Renewal Resubmission Revision The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.
Funds Available and Anticipated Number of Awards	The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications.
Award Budget	Application budgets are not limited but need to reflect the actual needs of the proposed project.
Award Project Period	The scope of the proposed project should determine the project period. The maximum project period is 5 years.

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made in response to this FOA.

Section III. Eligibility Information

1. Eligible Applicants

Eligible Organizations

Higher Education Institutions

Public/State Controlled Institutions of Higher Education
Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

Hispanic-serving Institutions
Historically Black Colleges and Universities (HBCUs)
Tribally Controlled Colleges and Universities (TCCUs)
Alaska Native and Native Hawaiian Serving Institutions
Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

Small Businesses
For-Profit Organizations (Other than Small Businesses)

Governments

State Governments
County Governments
City or Township Governments
Special District Governments
Indian/Native American Tribal Governments (Federally Recognized)
Indian/Native American Tribal Governments (Other than Federally Recognized)
Eligible Agencies of the Federal Government
U.S. Territory or Possession

Other

Independent School Districts
Public Housing Authorities/Indian Housing Authorities
Native American Tribal Organizations (other than Federally recognized tribal governments)
Faith-based or Community-based Organizations
Regional Organizations
Non-domestic (non-U.S.) Entities (Foreign Institutions)

Foreign Institutions

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Required Registrations

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
System for Award Management (SAM) (formerly CCR) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
eRA Commons - Applicants must have an active DUNS number and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account and should work with their organizational officials to either create a new account or to affiliate an existing account with the applicant organization’s eRA Commons account. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Eligible Individuals (Program Director/Principal Investigator)

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

2. Cost Sharing

This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.

3. Additional Information on Eligibility

Number of Applications

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

NIH will not accept any application that is essentially the same as one already reviewed within the past thirty-seven months (as described in the NIH Grants Policy Statement), except for submission:

To an RFA of an application that was submitted previously as an investigator-initiated application but not paid;
Of an investigator-initiated application that was originally submitted to an RFA but not paid; or
Of an application with a changed grant activity code.

Section IV. Application and Submission Information

1. Requesting an Application Package

Applicants must download the SF424 (R&R) application package associated with this funding opportunity using the Apply for Grant Electronically button in this FOA or following the directions provided at Grants.gov.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

Page Limitations

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.

Required and Optional Components

The forms package associated with this FOA includes all applicable components, required and optional. Please note that some components marked optional in the application package are required for submission of applications for this FOA. Follow all instructions in the SF424 (R&R) Application Guide to ensure you complete all appropriate optional components.

Instructions for Application Submission

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.

SF424(R&R) Cover