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/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) 710-0267, 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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