GENE-ENVIRONMENT EFFECTS AND EPIGENESIS IN DEPRESSION
 
RELEASE DATE:  April 9, 2004
 
RFA Number:  RFA-MH-05-006

EXPIRATION DATE:  July 17, 2004

Department of Health and Human Services (DHHS)

PARTICIPATING ORGANIZATION:
National Institutes of Health (NIH)
 (http://www.nih.gov)

COMPONENTS OF PARTICIPATING ORGANIZATION:
National Institute of Mental Health (NIMH)
 (http://www.nimh.nih.gov)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
 (http://www.niaaa.nih.gov/)
National Institute on Drug Abuse (NIDA)
 (http://www.nida.nih.gov/)

CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S): 93.242, 93.859, 93.273, 93.279
 
LETTER OF INTENT RECEIPT DATE:  June 16, 2004
APPLICATION RECEIPT DATE:  July 16, 2004
 
THIS RFA CONTAINS THE FOLLOWING INFORMATION

o Purpose of this RFA
o Research Objectives
o Mechanism of Support 
o Funds Available
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Special Requirements 
o Where to Send Inquiries
o Letter of Intent
o Submitting an Application
o Supplementary Instructions
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations

PURPOSE OF THIS RFA 

The goal of this Request for Applications (RFA) is to solicit applications to 
identify epigenetic mechanisms and characterize gene-environment interactions that 
produce vulnerability to depression.  Novel approaches to gene discovery, the 
identification of epigenetic mechanisms, elucidation of environmental risk factors, 
characterization of the genetic aspects of response to environmental change, and 
the use of biomarkers and other intermediate phenotypes correlated with the 
clinical disorder are encouraged.  Data and biomaterials collected in projects 
supported under this RFA will be included in the NIMH Human Genetics Initiative and 
broadly distributed to the scientific community.

RESEARCH OBJECTIVES

Depression is among the top five leading causes of disability and disease burden 
throughout the world. Its etiology is complex, with disease vulnerability 
influenced by multiple genes interacting with one another and with the physical and 
social environment.  Many of the genes involved likely require specific 
environmental circumstances in order to be expressed in a diagnosis of depression.  
Deciphering the genetic blueprint for depression is complicated by the fact that 
complex interactions between genes and the environment are not adequately assessed 
or understood. Likewise, alcohol use, abuse, dependence, and alcohol problems are 
influenced by multiple host susceptibility factors (e.g., metabolism, genetic 
variations in responses to alcohol, personality); by multiple environmental factors 
that promote or deter excessive alcohol consumption (e.g.,peer relationships, 
alcohol availability); and by gene-environment interactions. Both depression and 
alcohol abuse/dependence have genetic and environmental components that may 
interact. They are often diagnosed as co-occurring disorders and longitudinal 
studies have identified depressive affect among children as a risk factor for 
subsequent alcohol abuse and dependence. Neurogenetic studies have suggested that 
common serotonergic mechanisms may be shared by both disorders.

To date, the search for new genes affecting the risk for developing depression has 
produced many inconsistent results.  One reason is that the influence of 
environmental factors can vary by genotype (e.g. Blood pressure response to a low 
sodium diet has been shown to vary by polymorphisms of renin-angiotensin system 
genes). Failure to carefully consider gene-environment factors often results in the 
inability to detect or accurately quantify the underlying genetic contribution to 
phenotypic variability in the timing and appearance of depressive disorders.  
Recent research has shown that a functional polymorphism in the promoter region of 
the serotonin transporter gene was found to moderate the influence of stressful 
life events on depression.  Such findings implicate indirect paths from gene to 
disease, and suggest that vulnerability to depression may result from variations in 
a small number of genes whose effects are conditional on exposure to specific 
environmental risk factors.  

Environmental factors of interest for study in projects supported under this RFA 
are not limited to stressful life events.  A strong area of interest in this RFA 
includes the study of alcohol and substances of abuse as environmental risk factors 
for depression. Population-based longitudinal and retrospective studies of 
comorbidity have found that drug use precedes depression in many cases, perhaps 
precipitating depression in vulnerable individuals and even conferring a lifelong 
vulnerability.  Studies are needed to investigate the gene-environment interactions 
between substance exposure and genetic vulnerability to depression, including 
possible intermediate phenotypes or factors such as sleep disturbances.  Such 
studies should take into account genetic predisposition to both depressive and 
substance use disorders, due to assortative mating that has been identified between 
drug abusing men and depressed women.  Given the frequency with which substances 
including alcohol, tobacco products, and caffeine as well as illicit drugs are used 
in adolescence, these investigations hold important potential for understanding the 
diathesis of depression in adolescence and adulthood.

Alternatively, depression itself could be an environmental risk factor that affects 
an individual’s behavior leading to alcohol use disorders. For example, a 
depressive individual who uses alcohol for self-medication may ultimately develop 
alcohol abuse and alcoholism. The study of environmental factors affecting 
susceptibility to depression and alcohol use disorders may point to underlying 
mechanisms of co-occurrence (comorbidity) of these two disorders. 
     
Another fruitful line of scientific inquiry is the genetic characterization of 
individuals who respond favorably to short-term pharmacologic or other 
environmental treatment interventions for depression.  This would entail exposing 
subjects (in either human or animal research) to environmental perturbations or 
challenges that effect intermediate phenotypes or depression per se.  Animal 
studies supported under this RFA are expected to focus primarily on the 
identification and characterization of underlying molecular genetic mechanisms that 
mediate effects of environment on depressive pheontypes. Such research ultimately 
may enable the development of targeted therapeutic interventions to reduce risk 
factors and identify the most effective treatments in clinical practice. 

From a public health standpoint, individuals with modifiable genetic risk of 
depression could be identified prior to disease development.  Effective appropriate 
interventions tailored to the unique genotypic characteristics of an individual 
could then be initiated to reduce the likelihood of developing depression or modify 
its outcome.  For example, the identification of genotypes that predispose 
individuals to cortisol hypersecretion in stress-prone individuals might lead to 
recommendations for individuals with that gentotype to maintain a strict stress 
reduction program.

Projects that propose short-term interventions in human or animal studies must 
include careful baseline measurements of multiple risk factors prior to 
intervention. Applicants should carefully assess risk factors and environmental 
exposures that may impact the outcome of the intervention. It is expected that such 
studies in humans will focus on families, which include individuals at augmented 
genetic risk for depression and for which existing methodologies exist (e.g., 
linkage analysis) for gene localization. In addition, identification of novel genes 
related to environmental change will be facilitated by study on a more homogeneous 
genetic and environmental background than typically found in clinical or 
population-based studies. Interventions adopted by family units may be more 
successful than when applied to unrelated individuals.

Another major potential complication in genetic studies on depression is the 
potential role of epigenetic mechanisms that influence gene-environment 
interactions.  Epigenetic mechanisms regulate gene expression but do not involve 
alterations in the genetic code itself.  Epigenetic modifications can abolish gene 
function, even without a DNA sequence change.  Important epigenetic mechanisms 
include:  DNA methylation – pathogenic loss of gene function by methylation of 
adjacent control sequences; changes in chromatin configuration – chromosomal 
rearrangements can up-regulate or silence expression of an intact gene; imprinting 
– gene expression is controlled by methylation patterns that differ according to 
the parental origin of the gene; and changes in protein conformation – such changes 
propagate through a population of protein molecules, converting them from a stable 
conformation into a new form with different properties. 

Given that more of the genome that is conserved represents noncoding vs. coding 
sequence, and much of this appears susceptible to epigenetic modification, 
epigenetic abnormalities have important biological and clinical impact for genetic 
studies on human disease.  An increasing body of research provides evidence that 
aberrant epigenetic mechanisms affect the transcription of genes involved in the 
regulation of neural development and differentiation and in the etiology of several 
disorders of the nervous system, e.g., Prader-Willi and Angelman syndromes.  

Most of the studies on the role of epigenesis in human disease have focused on 
monogenic disorders, particularly those involving imprinted genes. A very exciting 
area of human molecular genetics is to extend this work and develop tools, 
technologies and methodologies by which epigenetic mechanisms may be identified and 
characterized for common human diseases caused by multiple genes in interaction 
with each other and the environment.  Consideration of epigenetic mechanisms may 
help resolve complexities that heretofore have stymied gene discovery efforts in 
depression.  Exciting new avenues of inquiry into the genetic basis of depression 
may be opened through careful consideration of epigenetic mechanisms in both human 
and animal studies.  Elucidation of the genetic architecture of depressive 
disorders and their risk factors will require meticulous assessment of 
environmental exposures and their influences on gene expression and epigenetic 
mechanisms, including DNA methylation and histone modification. 

Another major focus of this RFA is on the identification of environmental risk 
factors that interact with epigenetic mechanisms to produce vulnerability to 
depressive disorders.  This includes clinical studies that explore the 
effectiveness of therapeutic agents targeting DNA methylation and acetylation of 
histones.  Molecular pathways regulating epigenetic events that occur during 
development may be exploited as new targets for therapeutic intervention.

Research topics of interest include, but are not limited to, the following:

o  Localization of genes in which functional polymorphisms moderate the influence 
of environmental factors in families or in studies of rodent or other model 
organisms.

o  Localization of candidate genes that appear to confer “either/or” susceptibility 
to alcohol use problems and depression in families, and exploration of potential 
epigenetic and/or environmental factors that affect which disorder manifests.

o  Development of biomarkers for susceptibility to co-morbid alcohol dependence and 
depression.

o  Localization and characterization of genes influencing change on biomarkers or 
intermediate phenotypes (e.g., brain imaging, neurophysiology, learning and memory) 
in response to therapeutic drugs used to treat depression or in response to other 
environmental risk factors like stressful life events or exposure to alcohol, 
nicotine, caffeine, or illicit drugs.

o  The search for genes contributing to changes in intermediate phenotypes, e.g., 
cortisol secretion or functional changes in brain metabolism, in response to an 
intensive stress reduction program.

o  Analysis of methylation patterns in CpG dinucleotides located in regulatory 
regions of genes where there appears to be epigenetic effects on gene expression.

o  Identification and analysis in families of maternally expressed genes that are 
likely candidates for depression vulnerability genes. 

o  Analysis in experimental systems of the methylation patterns of genes whose 
expression is influenced by environmental risk factors of relevance to depression.

o  Analysis in experimental systems of the effects of therapeutic compounds and 
other environmental factors like stress, alcohol or drugs of abuse on changes in 
the methylation status of genes relevant to depression or intermediate phenotypes. 

MECHANISM OF SUPPORT
 
This RFA will use the NIH Research Project Grant (R01) award mechanism.  As an 
applicant you will be solely responsible for planning, directing, and executing the 
proposed project.  This RFA is a one-time solicitation.  Future unsolicited, 
competing-continuation applications based on this project will compete with all 
investigator-initiated applications and will be reviewed according to the customary 
peer review procedures. The anticipated award date is April 1, 2005. Applications 
that are not funded in the competition described in this RFA may be resubmitted as 
NEW investigator-initiated applications using the standard receipt dates for NEW 
applications described in the instructions to the PHS 398 application.  

This RFA uses just-in-time concepts.  It also uses the modular budgeting 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 budget format.  Otherwise follow the instructions for non-modular 
budget research grant applications.  This program does not require cost sharing as 
defined in the current NIH Grants Policy Statement at 
http://grants.nih.gov/archive/grants/policy/nihgps_2001/part_i_1.htm.  

FUNDS AVAILABLE 
 
NIH intends to commit $1,750,000 in FY 2005 to fund up to 4 new and/or competitive 
continuation grants in response to this RFA. An applicant may request a project 
period of up to 5 years.  Because the nature and scope of the proposed research 
will vary from application to application, it is anticipated that the size and 
duration of each award will also vary.  Although the financial plans of NIH provide 
support for this program, awards pursuant to this RFA are contingent upon the 
availability of funds and the receipt of a sufficient number of meritorious 
applications.  
 
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 institutions/organizations
 
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.   

SPECIAL REQUIREMENTS 
 
Sharing of Research Resources in the NIMH Human Genetics Initiative

As described below, applications must include a data sharing plan.  Data and 
biomaterials from subjects included in projects funded under this RFA will be made 
available and distributed to the broader scientific community, in accordance with 
existing procedures and protocols for the NIMH Human Genetics Initiative 
(http://nimhgenetics.org/). 

The sharing of biomaterials, data, and software in a timely manner has been an 
essential element in the rapid progress that has been made in the genetic analysis 
of human diseases.  To address the joint interests of the government in the 
availability of, and access to, the results of publicly funded research and in the 
opportunity for economic development based on these results, NIH requires 
applicants who respond to this RFA to develop and propose detailed plans for 
sharing specific data and biomaterials generated through the grant.  It is expected 
that the information to be shared includes all clinical and diagnostic information, 
in addition to cell lines and DNA. 

For this purpose, it is the opinion of NIMH that dissemination of such data and 
materials via individual laboratories and Web sites is not sufficient, as it would 
force interested investigators to have to search several different data collections 
to make use of the results of this initiative.  In addition, differences in 
protocols across projects for creating databases, establishing cell lines, and 
extracting DNA may make it impossible for researchers to combine information for 
integrated genetic analyses.  It is preferable that data and materials generated in 
grants funded under this RFA should be placed in common, public cell repositories 
and databases that are widely accessible by investigators in the scientific 
community.  An NIMH-supported data management facility and cell repository – the 
NIMH Center for Collaborative Genetic Studies on Mental Disorders 
(http://nimhgenetics.org) - is such a community resource.  Access to the Center is 
granted by NIMH when an applicant agrees to follow existing access procedures and 
policies utilized in the NIMH Human Genetics Initiative (http://nimhgenetics.org).  
Further information is available from the staff contact for scientific/research 
issues listed below.

It is expected that the investigator’s data sharing plan will specify the following 
elements:  (1) the creation of comprehensive and verified databases that contain 
all clinical, diagnostic, and genetic information collected and produced in the 
project; (2) the establishment of high-quality cell lines, from which DNA will be 
extracted and stored, for all subjects studied from whom blood samples have been 
obtained; (3) mechanisms by which all databases and biomaterials (DNA samples, cell 
lines) are widely distributed to qualified investigators in the scientific 
community; (4) a protocol for wide dissemination of these data and biomaterials; 
(5) a timetable for distribution; and (6) an assurance that data and biomaterials 
are disseminated in a manner comparable to pre-existing protocols and procedures 
for distributing such data and biomaterials in the NIMH Human Genetics Initiative 
(see http://nimhgenetics.org).

After extensive discussion with mental health and human genetics researchers and 
advocacy members, the Genetics Workgroup of the National Advisory Mental Health 
Council (NAMHC) recommended that NIMH should draft a policy that provides for the 
sharing of genetic materials after a 12- to 18-month proprietary period (see 
http://www.nimh.nih.gov/research/genetics.htm).  Adherence with the time frame 
recommended by the NAMHC’s Genetics Workgroup is highly desirable.  This is 
expected to result in all data being released to the scientific community by the 
end of the award period, even if a competing renewal application is submitted.  
More rapid sharing is encouraged.  Requests for exemptions or extensions will 
require compelling justification and will be fully evaluated through peer review 
and by program staff.

NIMH, in consultation with NIH’s Office of the General Counsel, the National Human 
Genome Research Institute's Ethical, Legal, and Social Implications Research 
Program and the Department of Health and Human Services' Office for Human Research 
Protections, has developed a model consent form for use in human genetic research 
at http://zork.wustl.edu/nimh/NIMH_initiative/NIMH_initiative_link.html.  This may 
then serve as a template that is subject to modification and/or approval by local 
institutional review boards.  It is expected that the applicant’s approved consent 
form address the following:  (1) disclosure that biomaterials (DNA and cell lines) 
and clinical data will be stored at a central data management/laboratory facility 
as part of a national resource of data and biomaterials distributed for the genetic 
analysis of the disease under investigation; (2) assurance that such data will be 
provided to a central facility without personal identifiers; (3) disclosure that 
analyses of these data will be conducted by other scientists currently not included 
within the current research team; and (4) disclosure that there is no plan to 
provide subjects with any financial benefits from commercial products derived from 
the data.  NIMH will review consent forms and IRB approvals for all projects prior 
to funding under this RFA.

High-Throughput Genotyping

All applications that plan to conduct high-throughput genotyping are expected to 
utilize a single laboratory.  One such resource available to applicants is the 
Center for Inherited Disease Research (CIDR), a centralized facility established to 
provide high-throughput microsatellite genotyping and statistical genetics 
services.  CIDR was established in 1996 as a joint effort of eight NIH Institutes, 
and is supported through a contract to Johns Hopkins University.  CIDR is available 
to all investigators through competitive peer review by a chartered CIDR Access 
Committee (CAC).  Projects are evaluated on the need for high throughput genotyping 
and the likelihood that genotyping will lead to successful gene mapping.  Given 
that NIMH is a supporting NIH Institute, research projects funded under this RFA 
and granted access to CIDR will be genotyped at no cost.  Further information about 
CIDR may be found at http://www.cidr.jhmi.edu.  Submission deadlines for 
applications requesting CIDR access are November 1, March 1 and July 1.

Applicants who plan to utilize CIDR are expected to request access to CIDR and to 
obtain the results of the CAC evaluation prior to submission of an application in 
response to this RFA.  Applicants with a pending CAC evaluation may also submit an 
application in response to this RFA.  An approval letter from the CAC may then be 
included in the application.  Regardless of the CAC evaluation, investigators may 
include in their application a scientific plan to accomplish a high throughput 
genome-wide scan at a single, centralized laboratory and statistical analyses, as 
well as budgeted genotyping and analysis costs.  For applicants who do not propose 
to use CIDR, it is expected that the time frame and costs for genomic scan and 
statistical analyses will be generally comparable to what could be achieved at CIDR 
or at comparable academic or commercial facilities.  A time frame for completion of 
a genome wide scan within one year, at a cost of less than $1 per genotype, appears 
reasonable.  It is anticipated that technologies will improve and the rate of work 
and associated cost will change.

WHERE TO SEND INQUIRIES

We encourage inquiries concerning this RFA and welcome the opportunity to answer 
questions from potential applicants.  Inquiries may fall into three areas:  
scientific/research, peer review, and financial or grants management issues:

o  Direct your questions about scientific/research issues to:

Steven O. Moldin, Ph.D.
Division of Neuroscience & Basic Behavioral Science
National Institute of Mental Health
6001 Executive Boulevard, Room 7191, MSC 9643
Bethesda, MD  20892-9643
Telephone:  (301) 443-2037
Fax:  (301) 443-2037
Email:  smoldin@mail.nih.gov

Zhaoxia Ren, M.D., Ph.D.
Division of Neuroscience and Behavior
National Institute on Alcohol Abuse and Alcoholism
5635 Fishers Lane, Room 2052, MSC 9304 
Bethesda, MD 20892-9304
Telephone: (301) 443-5733
Fax: (301) 443-1650
Email: zren@mail.nih.gov

Joni L. Rutter, Ph.D. 
Division of Neuroscience and Behavioral Research 
National Institute on Drug Abuse
6001 Executive Blvd. Room 5227, MSC 9555 
Bethesda, MD  20892-9555 
Telephone:  (301) 435-0298 
Fax: (301) 594-6043 
Email: jrutter@mail.nih.gov

o Direct your questions about peer review issues to:

Michael Kozak, Ph.D.
Division of Extramural Activities
National Institute of Mental Health
6001 Executive Boulevard, Room 6138, MSC 9609
Bethesda, MD  20892-9608
Telephone:  (301) 443-1340
Fax:  (301) 443-4720
Email:  kozakm@mail.nih.gov

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

Carol J. Robinson
Grants Management Branch
National Institute of Mental Health
6001 Executive Boulevard, Room 6118, MSC 9605
Bethesda, MD 20892-9605
Telephone:  (301) 443-3858
Fax:  (301) 443-6885
Email:  crobinso@mail.nih.gov

Gary Fleming, J.D., M.A.
Grants Management Branch
National Institute on Drug Abuse
6101 Executive Boulevard, Suite 242, MSC 8403
Bethesda, MD  20892-8403
Telephone:  (301) 443-6710
Fax:  (301) 594-6849
Email: gf6s@nih.gov
 
LETTER OF INTENT
 
Prospective applicants are asked to submit a letter of intent that includes the 
following information:

o  Descriptive title of the proposed research
o  Name, address, and telephone number of the Principal Investigator
o  Names of other key personnel 
o  Participating institutions
o  Number and title of this RFA 

Although a letter of intent is not required, is not binding, and does not enter 
into the review of a subsequent application, the information that it contains 
allows IC staff to estimate the potential review workload and plan the review.
 
The letter of intent is to be sent by the date listed at the beginning of this 
document.  The letter of intent should be sent to:

Steven O. Moldin, Ph.D.
Division of Neuroscience & Basic Behavioral Science
National Institute of Mental Health
6001 Executive Boulevard, Room 7191, MSC 9643
Bethesda, MD  20892-9643
Telephone:  (301) 443-2037
Fax:  (301) 443-2037
Email:  smoldin@mail.nih.gov

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001). Applications must have a DUN and Bradstreet 
(D&B) Data Universal Numbering System (DUNS) number as the Universal Identifier 
when applying for Federal grants or cooperative agreements. The DUNS number can be 
obtained by calling (866) 705-5711 or through the web site at 
http://www.dunandbradstreet.com/. The DUNS number should be entered on line 11 of 
the face page of the PHS 398 form. The PHS 398 document is available at 
http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format.  
For further assistance contact GrantsInfo, Telephone (301) 435-0714, Email: 
GrantsInfo@nih.gov.
 
SUPPLEMENTARY INSTRUCTIONS
 
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.

USING THE RFA LABEL:  The RFA label available in the PHS 398 (rev. 5/2001) 
application form must be affixed to the bottom of the face page of the application.  
Type the RFA number on the label.  Failure to use this label could result in 
delayed processing of the application such that it may not reach the review 
committee in time for review.  In addition, the RFA title and number must be typed 
on line 2 of the face page of the application form and the YES box must be marked. 
The RFA label is also available at: 
http://grants.nih.gov/grants/funding/phs398/labels.pdf.
 
SENDING AN APPLICATION TO THE NIH:  Submit a signed, typewritten original of the 
application, including the Checklist, and three 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)
 
At the time of submission, two additional copies of the application and all copies 
of the appendix material must be sent to:

Jean Noronha, Ph.D.
Division of Extramural Activities
National Institute of Mental Health
6001 Executive Boulevard, Room 6154, MSC 9609
Bethesda, MD  20892-9609
Telephone:  (301) 443-3367
Fax:  (301) 443-4720
Email: jnoronha@mail.nih.gov

APPLICATION PROCESSING:  Applications must be received on or before the application 
receipt date listed in the heading of this RFA.  If an application is received 
after that date, it will be returned to the applicant without review. 

Although there is no immediate acknowledgement of the receipt of an application, 
applicants are generally notified of the review and funding assignment within 8 
weeks.
 
The Center for Scientific Review (CSR) will not accept any application in response 
to this RFA that is essentially the same as one currently pending initial review, 
unless the applicant withdraws the pending application.  However, when a previously 
unfunded application, originally submitted as an investigator-initiated 
application, is to be submitted in response to an RFA, it is to be prepared as a 
NEW application.  That is, the application for the RFA must not include an 
Introduction describing the changes and improvements made, and the text must not be 
marked to indicate the changes from the previous unfunded version of the 
application.  

PEER REVIEW PROCESS  
 
Upon receipt, applications will be reviewed for completeness by the CSR and 
responsiveness by the NIMH. Incomplete applications will not be reviewed.  If the 
application is not responsive to the RFA, NIH staff may contact the applicant to 
determine whether to return the application to the applicant or submit it for 
review in competition with unsolicited applications at the next appropriate NIH 
review cycle.

Applications that are complete and responsive to the RFA will be evaluated for 
scientific and technical merit by an appropriate peer review group convened by the 
NIMH in accordance with the review criteria stated below.  As part of the initial 
merit review, all applications will:

o  Undergo a process in which only those applications deemed to have the highest 
scientific merit, generally the top half of the applications under review, will be 
discussed and assigned a priority score
o  Receive a written critique
o  Receive a second level review by an appropriate national advisory council or 
board. 
 
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 evaluate the application in order to judge the 
likelihood that the proposed research will have a substantial impact on the pursuit 
of these goals. The scientific review group will address and consider each of the 
following criteria in assigning the application’s overall score, weighting them as 
appropriate for each application. 

o  Significance 
o  Approach 
o  Innovation
o  Investigator
o  Environment

The 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, 
an investigator may propose to carry out important work that by its nature is not 
innovative but is essential to move a field forward.

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

APPROACH:  Are the conceptual framework, design, methods, and analyses adequately 
developed, well-integrated, and appropriate to the aims of the project? Does the 
applicant acknowledge potential problem areas and consider alternative tactics?

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

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

ENVIRONMENT:  Does the scientific environment in which the 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, the following items 
will be considered in the determination of scientific merit and the priority score:

o Likelihood of success for gene discovery in depression
o Likelihood of success for characterizing epigenetic mechanisms in depression
o Likelihood of success for delineating environmental risk factors that interact 
with genes and contribute to vulnerability to depression

PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK:  The involvement of human subjects 
and protections from research risk relating to their participation in the proposed 
research will be assessed. (See criteria included in the section on Federal 
Citations, below).
 
INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH:  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 in the sections on Federal Citations, below).

CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH:  If vertebrate animals are to be 
used in the project, the five items described under Section f of the PHS 398 
research grant application instructions (rev. 5/2001) will be assessed.  

ADDITIONAL REVIEW CONSIDERATIONS

SHARING RESEARCH DATA:  Applicants requesting more than $500,000 in direct costs in 
any year of the proposed research must include a data sharing plan in their 
application. The reasonableness of the data sharing plan or the rationale for not 
sharing research data will be assessed by the reviewers. However, reviewers will 
not factor the proposed data sharing plan into the determination of scientific 
merit or priority score (see http://grants.nih.gov/grants/policy/data_sharing).

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

RECEIPT AND REVIEW SCHEDULE

Letter of Intent Receipt Date:    June 16, 2004
Application Receipt Date:         July 16, 2004
Peer Review Date:                 November 2004
Council Review:                   January 2005
Earliest Anticipated Start Date:  April 1, 2005

AWARD CRITERIA

Award criteria that will be used to make award decisions include:

o  Scientific merit (as determined by peer review)
o  Availability of funds
o  Adequacy of plans to make data and biomaterials widely accessible in a timely 
manner to the research community
o  Potential of the results for environmental risk factor modification and 
enhancement of clinical care
o  Adequacy of plans to integrate data and biomaterials with comparable resources 
in the NIMH Human Genetics Initiative
o  Programmatic priorities
 
REQUIRED FEDERAL CITATIONS 

HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that applications 
and proposals involving human subjects must be evaluated with reference to the 
risks to the subjects, the adequacy of protection against these risks, the 
potential benefits of the research to the subjects and others, and the importance 
of the knowledge gained or to be gained.
http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm 

SHARING RESEARCH DATA:  Starting with the October 1, 2003 receipt date, 
investigators submitting an NIH application seeking $500,000 or more in direct 
costs in any single year are expected to include a plan for data sharing or state 
why this is not possible (see http://grants.nih.gov/grants/policy/data_sharing).  
Investigators should seek guidance from their institutions, on issues related to 
institutional policies, local IRB rules, as well as local, state and Federal laws 
and regulations, including the Privacy Rule.  Reviewers will consider the data 
sharing plan but will not factor the plan into the determination of the scientific 
merit or the priority score.  As discussed above under SPECIAL REQUIRMENTS, it is 
expected that all clinical data, DNA and cell lines produced from projects 
supported under this RFA will be broadly distributed to the scientific community 
through the NIMH Human Genetics Initiative (http://nimhgenetics.org).

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 "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: (if applicable) 
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.

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.

STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION:  The 
Department of Health and Human Services (DHHS) issued final modification to the 
“Standards for Privacy of Individually Identifiable Health Information”, the 
“Privacy Rule,” on August 14, 2002.  The Privacy Rule is a federal regulation under 
the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that 
governs the protection of individually identifiable health information, and is 
administered and enforced by the DHHS Office for Civil Rights (OCR). Those who must 
comply with the Privacy Rule (classified under the Rule as “covered entities”) must 
do so by April 14, 2003 (with the exception of small health plans which have an 
extra year to comply).  

Decisions about applicability and implementation of the Privacy Rule reside with 
the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) 
provides information on the Privacy Rule, including a complete Regulation Text and 
a set of decision tools on “Am I a covered entity?”  Information on the impact of 
the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress 
monitoring of grants, cooperative agreements, and research contracts can be found 
at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

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 RFA is related to one or 
more of the priority areas. Potential applicants may obtain a copy of "Healthy 
People 2010" at http://www.healthypeople.gov/.

AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal 
Domestic Assistance at http://www.cfda.gov/ and is not subject to the 
intergovernmental review requirements of Executive Order 12372 or Health Systems 
Agency review.  Awards are made under the authorization of Sections 301 and 405 of 
the Public Health Service Act as amended (42 USC 241 and 284) and under Federal 
Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the 
terms and conditions, cost principles, and other considerations described in the 
NIH Grants Policy Statement.  The NIH Grants Policy Statement can be found at 
http://grants.nih.gov/grants/policy/policy.htm.

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.


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