GENETIC EPIDEMIOLOGY OF SUBSTANCE USE DISORDERS

PA NUMBER: PA-02-112

July 24, 2007 - This PA has been replaced by PA-07-413 (R01), PA-07-415 (R21) and PA-07-414 (R03)

RELEASE DATE:  May 30, 2002

EXPIRATION DATE:  June 30, 2005, unless reissued. 

PARTICIPATING INSTITUTES AND CENTERS (ICs): 
National Institute on Drug Abuse
 (www.nida.nih.gov)

THIS PROGRAM ANNOUNCEMENT (PA) CONTAINS THE FOLLOWING INFORMATION

o Purpose of the PA
o Research Objectives
o Mechanism(s) of Support 
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Where to Send Inquiries
o Submitting an Application
o Peer Review Process
o Review Criteria
o Award Criteria
o Required Federal Citations

PURPOSE OF THIS PA  

The National Institute on Drug Abuse seeks to stimulate genetic epidemiologic 
studies of substance use disorders (SUDs, drug abuse and dependence).  
Previous studies using twin, adoption, and family approaches indicate that 
genetic factors substantially influence the risk for SUDs.  Building on these 
findings, new studies are needed to refine SUD phenotypes for future 
molecular genetic studies, clarify gene-environment interactions for fine-
tuning preventive interventions with high-risk populations, refine nosology 
and thus improve treatment matching, and expand findings to understudied 
populations.  Also needed are longitudinal and developmental studies, more 
advanced statistical and analytic approaches to complex disorders and traits, 
and new methodological approaches to address challenges such as the equal 
environment assumption, the definition of affected and unaffected status, and 
changes in adoption patterns and family configurations.

RESEARCH OBJECTIVES

Background

A variety of research approaches have established that SUDs are heritable 
complex disorders, and that family history of SUD is probably the most potent 
risk factor for these disorders.  Twin studies of general, clinical, and 
special populations have found high heritability estimates for SUD.  The 
adoption paradigm has highlighted the significance of gene-environment 
interactions in moderating the risk associated with biologic propensity, 
particularly the role of family environmental variables, and the significance 
of mediating factors such as aggression and dysregulation in the various 
pathways to abuse and dependence.  Familial aggregation studies have begun to 
elucidate areas of specificity as well as generality in the transmission of 
drug abuse liability, and highlight the significance of comorbid psychiatric 
conditions in the phenotypic picture.  

More refined genetic epidemiologic studies are now needed to guide future 
work on molecular genetics, prevention, and treatment of SUDs.  Genetic 
epidemiologic studies can contribute significantly to NIDA"s research efforts 
in these areas in several ways.  Genetic epidemiologic studies can further 
refine meaningful phenotypes for candidate gene studies, and guide 
appropriate measurement variables once populations are selected.  Phenotypes 
may include those with subclinical features, such as aggression or executive 
cognitive dysfunction, and comorbid subtypes.  Genetic epidemiologic studies 
can also highlight mechanisms of progression from drug use initiation to 
abuse and dependence, since prior studies have suggested that genes operate 
differently at different stages, and that expression of some genes may be 
accelerated or suppressed ("turned on" and "turned off") by drug use.  
Treatment studies can be enhanced by genetic epidemiologic contributions to 
improve nosology and by pharmacogenetic studies of genetically-determined 
individual responses to both drugs of abuse and treatment medications.  By 
clarifying meaningful environmental variables, studies of gene by environment 
interaction and gene-environment correlation can help target vulnerable 
populations and pinpoint fruitful areas for preventive interventions.  
Studies are also needed to test hypotheses in broader and multilevel 
contexts, and to test and develop appropriate genetic epidemiologic and 
behavior genetic models in previously under-studied populations such as 
minorities and women.  With regard to gender in particular, investigators are 
encouraged to incorporate sex difference into their research design and 
analyses when appropriate.

Numerous methodological challenges affect studies of the genetic epidemiology 
of SUDs.  Some of the most critical challenges include the definition of 
"affected" and "unaffected" status of subjects, measurement of drug access 
and exposure, the equal environment assumption and the possible impact when 
it is violated, recent changes in the openness of adoption and of selection 
biases that affect placement of children.  Creative approaches may be needed 
to address these challenges, and applicants are welcomed to consult with 
program staff on these and other methodological issues.

Applicants are encouraged to consider cost-effective approaches, including 
the addition of appropriate measures and data analysis to ongoing studies, 
secondary data analysis using established genetic epidemiologic databases, 
and alternative designs such as sequential cohort approaches that can 
accelerate findings.

Proposals responding to this Program Announcement are expected to focus on 
genetic epidemiologic techniques and designs.  Applicants seeking support for 
studies of the molecular genetics of drug abuse vulnerability are referred to 
the NIDA Program Announcement: Molecular Genetics Of Drug Addiction 
Vulnerability (http://grants.nih.gov/grants/guide/pa-files/PA-00-115.html).  Any 
molecular genetic component included in applications under this Genetic 
Epidemiology Program Announcement needs to be fully developed, with 
appropriate hypotheses and gene-identifying techniques.  Applicants proposing 
significant molecular genetic components are strongly encouraged to consult 
with program staff.  Further guidance can also be found at 
http://www.drugabuse.gov/Genetics/GeneticsHome.html.

Areas of interest

The following represents areas and issues of interest to NIDA, applicants are 
not limited to these ideas.  

o  Developmental and longitudinal approaches that can illuminate drug use 
stages, comorbidity sequencing, and progression from use to SUD.

o  Genetic epidemiologic studies of gene-environment interaction, integrating 
multilevel factors (e.g., intra-individual, interpersonal, ecological) that 
may mediate or moderate genetic vulnerability to SUDs.

o  Studies that bear on SUD nosology and typology.  Genetically-informed 
meaningful clinical subtypes have implications for guiding other SUD 
research, including studies of treatment matching, treatment development, 
etiology, and prevention.

o  Studies distinguishing between drug specificity and factors contributing 
to general liability to drug abuse and dependence (poly-drug abuse).

o  Genetic epidemiologic studies of subclinical phenotypes and of 
etiologically homogeneous groups, based on characteristics such as 
personality traits or temperament (e.g. novelty-seeking, behavioral 
disinhibition, stress reactivity) or pre-existing psychiatric disorder (e.g. 
conduct disorder).

o  Studies of individuals and family members whose drug exposure, use 
patterns, and related deficits do not meet full criteria for drug dependence, 
that may shed further light on vulnerability characteristics.

o  Studies that identify biomarkers or endophenotypes associated with 
addiction, including electrocortical activity, reactivity to initial drug 
exposure, physiological responsiveness to stress/startle, neurophysiological 
activity, and differences in sleep architecture.

o  New and replication studies in diverse ethnic groups, and cross-cultural 
studies, to clarify the generalizability of previous heritability findings.

o  Examination of gender differences as they relate to the behavioral 
genetics of SUDs.

o  Research on study design (e.g., sampling strategies, ascertainment, 
pooling or subdividing samples) that will enhance understanding of complex 
phenotypes.

o  Development of statistical tools and analytic methods that will enhance 
understanding of complex phenotypes, phenotypic relationships among 
disorders, and genotypic variation in relation to phenotypic expression. 

o  Studies on the ethical, legal, and social implications of genetic 
epidemiologic research on drug abuse and dependence (also see 
http://www.nhgri.nih.gov/ELSI/).

MECHANISMS OF SUPPORT 

This PA will use the NIH research project (R01), small grant (R03), and 
exploratory/developmental grant (R21) award mechanisms.  As an applicant, you 
will be solely responsible for planning, directing, and executing the 
proposed project.  Refer to the guidelines for the specific eligibility 
requirements for the small grant program (R03) at 
http://grants.nih.gov/grants/guide/pa-files/PAR-00-059.html, and the 
exploratory/developmental grant program (R21) at 
http://grants.nih.gov/grants/guide/pa-files/PA-01-012.html.  

This PA uses just-in-time concepts.  It also uses the modular as well as the 
non-modular budgeting formats (see 
http://grants.nih.gov/grants/funding/modular/modular.htm).  Specifically, if 
you are submitting an application with direct costs in each year of $250,000 
or less, use the modular format.  Otherwise follow the instructions for non-
modular research grant applications.

Those interested in applying for support for career development in genetic 
epidemiology of drug vulnerability are referred for further information to 
http://www.nida.nih.gov/researchtraining/traininghome.html.

ELIGIBLE INSTITUTIONS 

You may submit (an) application(s) if your institution has any of the 
following characteristics: 

o For-profit or non-profit organizations 
o Public or private institutions, such as universities, colleges, hospitals, 
and laboratories 
o Units of State and local governments
o Eligible agencies of the Federal government  
o Domestic or foreign

INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS

Any individual with the skills, knowledge, and resources necessary to carry 
out the proposed research is invited to work with their institution 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 programs. 

WHERE TO SEND INQUIRIES

We encourage your inquiries concerning this PA and welcome the opportunity to 
answer questions from potential applicants.  Inquiries may fall into two 
areas:  scientific/research and financial or grants management issues:

o Direct your questions about scientific/research issues to:

Naimah Z. Weinberg, M.D.
Medical Officer
Division of Epidemiology, Services, and Prevention Research
National Institute on Drug Abuse
6001 Executive Blvd., Rm. 5153, MSC 9589
Bethesda, MD 20892-9589
Rockville, MD 20852 (for express/courier)
Telephone:  (301) 402-1908
Fax:  (301) 480-2543
Email:  [email protected]

o Direct your questions about financial or grants management matters to:

Gary Fleming, J.D., M.A.
Grants Management Branch
National Institute on Drug Abuse
6001 Executive Boulevard, Room 3131   MSC 9541
Bethesda, MD  20892-9541
Telephone: (301) 443-6710
Fax:  (301) 594-6849
Email: [email protected]

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001).  The PHS 398 is available at 
http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive 
format.  For further assistance contact GrantsInfo, Telephone (301) 710-0267, 
Email: [email protected].

APPLICATION RECEIPT DATES: Applications submitted in response to this program 
announcement will be accepted at the standard application deadlines, which 
are available at http://grants.nih.gov/grants/dates.htm.  Application 
deadlines are also indicated in the PHS 398 application kit.

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications requesting 
up to $250,000 per year in direct costs must be submitted in a modular grant 
format.  The modular grant format simplifies the preparation of the budget in 
these applications by limiting the level of budgetary detail.  Applicants 
request direct costs in $25,000 modules.  Section C of the research grant 
application instructions for the PHS 398 (rev. 5/2001) at 
http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-by-step 
guidance for preparing modular grants.  Additional information on modular 
grants is available at http://grants.nih.gov/grants/funding/modular/modular.htm.

SPECIFIC INSTRUCTIONS FOR APPLICATIONS REQUESTING $500,000 OR MORE PER YEAR: 
Applications requesting $500,000 or more in direct costs for any year must 
include a cover letter identifying the NIH staff member within one of NIH 
institutes or centers who has agreed to accept assignment of the application.   

Applicants requesting more than $500,000 must carry out the following steps:

1) Contact NIDA program staff at least 6 weeks before submitting the 
application, i.e., as you are developing plans for the study, 

2) Obtain agreement from NIDA staff that NIDA will accept your application 
for consideration for award, and,
  
3) Identify, in a cover letter sent with the application, the staff member 
and Institute who agreed to accept assignment of the application.  

This policy applies to all investigator-initiated new (type 1), competing 
continuation (type 2), competing supplement, or any amended or revised 
version of these grant application types. Additional information on this 
policy is available in the NIH Guide for Grants and Contracts, October 19, 
2001 at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-004.html. 

SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of 
the application, including the checklist, and five signed photocopies in one 
package to:

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD  20892-7710
Bethesda, MD  20817 (for express/courier service)

APPLICATION PROCESSING: Applications must be received by or mailed on or 
before the receipt dates described at 
http://grants.nih.gov/grants/funding/submissionschedule.htm.  The CSR will 
not accept any application in response to this PA that is essentially the 
same as one currently pending initial review unless the applicant withdraws 
the pending application.  The CSR will not accept any application that is 
essentially the same as one already reviewed.  This does not preclude the 
submission of a substantial revision of an application already reviewed, but 
such application must include an Introduction addressing the previous 
critique.

PEER REVIEW PROCESS

Applications submitted for this PA will be assigned on the basis of 
established PHS referral guidelines.  An appropriate scientific review group 
convened in accordance with the standard NIH peer review procedures 
(http://www.csr.nih.gov/refrev.htm) will evaluate applications for scientific 
and technical merit.  

As part of the initial merit review, all applications will:

o Receive a written critique
o Undergo a selection process in which only those applications deemed to have 
the highest scientific merit, generally the top half of applications under 
review, will be discussed and assigned a priority score
o Receive a second level review by the appropriate national advisory council

REVIEW CRITERIA

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  In 
the written comments, reviewers will be asked to discuss the following 
aspects of your application in order to judge the likelihood that the 
proposed research will have a substantial impact on the pursuit of these 
goals: 

o Significance 
o Approach 
o Innovation
o Investigator
o Environment
  
The scientific review group will address and consider each of these criteria 
in assigning your application"s overall score, weighting them as appropriate 
for each application.  Your application does not need to be strong in all 
categories to be judged likely to have major scientific impact and thus 
deserve a high priority score.  For example, you may propose to carry out 
important work that by its nature is not innovative but is essential to move 
a field forward.

(1) SIGNIFICANCE:  Does your study address an important problem? If the aims 
of your application are achieved, how do they advance scientific knowledge?  
What will be the effect of these studies on the concepts or methods that 
drive this field?

(2) APPROACH:  Are the conceptual framework, design, methods, and analyses 
adequately developed, well integrated, and appropriate to the aims of the 
project?  Do you acknowledge potential problem areas and consider alternative 
tactics?

(3) INNOVATION:  Does your project employ novel concepts, approaches or 
methods? Are the aims original and innovative?  Does your project challenge 
existing paradigms or develop new methodologies or technologies?

(4) INVESTIGATOR: Are you appropriately trained and well suited to carry out 
this work?  Is the work proposed appropriate to your experience level as the 
principal investigator and to that of other researchers (if any)?

(5) ENVIRONMENT:  Does the scientific environment in which your work will be 
done contribute to the probability of success?  Do the proposed experiments 
take advantage of unique features of the scientific environment or employ 
useful collaborative arrangements?  Is there evidence of institutional 
support?

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your 
application will also be reviewed with respect to the following:

DATA: The adequacy of planned sample collection and data management. 

PROTECTIONS:  The adequacy of the proposed protection for humans, animals, or 
the environment, to the extent they may be adversely affected by the project 
proposed in the application.

INCLUSION:  The adequacy of plans to include subjects from both genders, all 
racial and ethnic groups (and subgroups), and children as appropriate for the 
scientific goals of the research.  Plans for the recruitment and retention of 
subjects will also be evaluated. (See Inclusion Criteria included in the 
section on Federal Citations, below)

BUDGET:  The reasonableness of the proposed budget and the requested period 
of support in relation to the proposed research.

AWARD CRITERIA

Applications submitted in response to a PA will compete for available funds 
with all other recommended applications.  The following will be considered in 
making funding decisions:  

o Scientific merit of the proposed project as determined by peer review
o Availability of funds 
o Relevance to program priorities

REQUIRED FEDERAL CITATIONS 

MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components 
involving Phases I and II clinical trials must include provisions for 
assessment of patient eligibility and status, rigorous data management, 
quality assurance, and auditing procedures.  In addition, it is NIH policy 
that all clinical trials require data and safety monitoring, with the method 
and degree of monitoring being commensurate with the risks (NIH Policy for 
Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 
1998: http://grants.nih.gov/grants/guide/notice-files/not98-084.html).  

INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of 
the NIH that women and members of minority groups and their sub-populations 
must be included in all NIH-supported clinical research projects unless a 
clear and compelling justification is provided indicating that inclusion is 
inappropriate with respect to the health of the subjects or the purpose of 
the research. This policy results from the NIH Revitalization Act of 1993 
(Section 492B of Public Law 103-43).

All investigators proposing clinical research should read the AMENDMENT "NIH 
Guidelines for Inclusion of Women and Minorities as Subjects in Clinical 
Research - Amended, October, 2001," published in the NIH Guide for Grants and 
Contracts on October 9, 2001 (http://grants.nih.gov/grants/guide/notice-
files/NOT-OD-02-001.html), a complete copy of the updated Guidelines are 
available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm.  
The amended policy incorporates: the use of an NIH definition of clinical 
research, updated racial and ethnic categories in compliance with the new OMB 
standards, clarification of language governing NIH-defined Phase III clinical 
trials consistent with the new PHS Form 398, and updated roles and 
responsibilities of NIH staff and the extramural community.  The policy 
continues to require for all NIH-defined Phase III clinical trials that: a) 
all applications or proposals and/or protocols must provide a description of 
plans to conduct analyses, as appropriate, to address differences by 
sex/gender and/or racial/ethnic groups, including subgroups if applicable, and 
b) investigators must report annual accrual and progress in conducting 
analyses, as appropriate, by sex/gender and/or racial/ethnic group 
differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: 
The NIH maintains a policy that children (i.e., individuals under the age of 
21) must be included in all human subjects research, conducted or supported 
by the NIH, unless there are scientific and ethical reasons not to include 
them. This policy applies to all initial (Type 1) applications submitted for 
receipt dates after October 1, 1998.

All investigators proposing research involving human subjects should read the 
"NIH Policy and Guidelines" on the inclusion of children as participants in 
research involving human subjects that is available at 
http://grants.nih.gov/grants/funding/children/children.htm. 

REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH 
policy requires education on the protection of human subject participants for 
all investigators submitting NIH proposals for research involving human 
subjects.  You will find this policy announcement in the NIH Guide for Grants 
and Contracts Announcement, dated June 5, 2000, at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research 
on hESCs can be found at http://grants.nih.gov/grants/stem_cells.htm and at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html.  Only 
research using hESC lines that are registered in the NIH Human Embryonic Stem 
Cell Registry will be eligible for Federal funding (see http://escr.nih.gov).   
It is the responsibility of the applicant to provide the official NIH 
identifier(s)for the hESC line(s)to be used in the proposed research.  
Applications that do not provide this information will be returned without 
review. 

PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The 
Office of Management and Budget (OMB) Circular A-110 has been revised to 
provide public access to research data through the Freedom of Information Act 
(FOIA) under some circumstances.  Data that are (1) first produced in a 
project that is supported in whole or in part with Federal funds and (2) 
cited publicly and officially by a Federal agency in support of an action 
that has the force and effect of law (i.e., a regulation) may be accessed 
through FOIA.  It is important for applicants to understand the basic scope 
of this amendment.  NIH has provided guidance at 
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.

Applicants may wish to place data collected under this PA in a public 
archive, which can provide protections for the data and manage the 
distribution for an indefinite period of time.  If so, the application should 
include a description of the archiving plan in the study design and include 
information about this in the budget justification section of the 
application. In addition, applicants should think about how to structure 
informed consent statements and other human subjects procedures given the 
potential for wider use of data collected under this award.

URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals 
for NIH funding must be self-contained within specified page limitations. 
Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) 
should not be used to provide information necessary to the review because 
reviewers are under no obligation to view the Internet sites.   Furthermore, 
we caution reviewers that their anonymity may be compromised when they 
directly access an Internet site.

HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to 
achieving the health promotion and disease prevention objectives of "Healthy 
People 2010," a PHS-led national activity for setting priority areas. This PA 
is related to one or more of the priority areas. Potential applicants may 
obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople.

AUTHORITY AND REGULATIONS: This program is described in the Catalog of 
Federal Domestic Assistance No. 93.279, and is not subject to the 
intergovernmental review requirements of Executive Order 12372 or Health 
Systems Agency review.  Awards are made under authorization of Sections 301 
and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and 
administered under NIH grants policies described at 
http://grants.nih.gov/grants/policy/policy.htm and under Federal Regulations 
42 CFR 52 and 45 CFR Parts 74 and 92. 

The PHS strongly encourages all grant recipients to provide a smoke-free 
workplace and discourage the use of all tobacco products.  In addition, 
Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in 
certain facilities (or in some cases, any portion of a facility) in which 
regular or routine education, library, day care, health care, or early 
childhood development services are provided to children.  This is consistent 
with the PHS mission to protect and advance the physical and mental health of 
the American people.

Weekly TOC for this Announcement
NIH Funding Opportunities and Notices

			Department of Health and Human Services (HHS)
NIH... Turning Discovery Into Health®