RFA-HG-27-009-Full-Announcement.html

Department of Health and Human Services

Part 1. Overview Information

Participating Organization(s)

National Institutes of Health (NIH)

Components of Participating Organizations

National Human Genome Research Institute (NHGRI)

Note: Not all NIH Institutes, Centers, and Offices (ICOs) participate in Announcements. Applicants should carefully note which ICOs participate in this announcement and view their respective areas of research interest at the ICO-Specific Scientific Interests website. ICOs that do not participate in this announcement will not consider applications for funding.

Funding Opportunity Title

Genomic Variant Interactions With Other Variants Or The Environment (UM1 Clinical Trials Not Allowed)

Activity Code

UM1 Research Project with Complex Structure Cooperative Agreement

Announcement Type

New

Related Notices

Check for any recent Notices of NIH Policy Changes that may impact application requirements.

Funding Opportunity Number (FON)

RFA-HG-27-009

Companion Funding Opportunity

RFA-HG-27-007

, UM1

Research Project with Complex Structure Cooperative Agreement

RFA-HG-27-008

, U24 Resource-Related Research Project (Cooperative Agreements)

RFA-HG-27-010

, UM1

Research Project with Complex Structure Cooperative Agreement

Number of Applications

See Part 2, Section III. 3. Additional Information on Eligibility.

Assistance Listing Number(s)

93.172

Funding Opportunity Purpose

The purpose of this Notice of Funding Opportunity (NOFO) is to solicit applications to study the effects of genetic or environmental interactions on genomic variant impact. To accomplish this, interaction centers will first propose a research framework to investigate whether interactions with effects beyond additive are important modifiers of the impact of variants. Centers will apply their framework to experimentally test combinations for interactions and share their data as well as analyses through the Impact of Genomic Variation on Function (IGVF) portal and catalog. Centers will share their method for predicting the most important combinations for future testing. The rationale for this combination of research and resource work is the identification of a structure within the interaction landscape might result in better predictions of the most important interactions to test, leading to more effective variant testing, better understanding of genome-wide association studies (GWAS), and improved polygenic scores. As IGVF Consortium members, centers will work together to ensure all consortium resources are accessible to a wide variety of potential users. Centers are also expected to collaborate with other consortium components to coordinate assays, variants, and cell types, and to develop shared analysis strategies to meet consortium goals.

Funding Opportunity Goal(s)

As a leading authority in the field of genomics, the mission of the National Human Genome Research Institute (NHGRI) is to accelerate scientific and medical breakthroughs that improve human health by driving cutting-edge research, developing new technologies, and studying the impact of genomics on society. Congress initially established NHGRI to characterize the structure and function of the human genome, including the mapping and sequencing of individual genes. This also includes reviewing and funding research proposals, developing training programs, coordinating international genome research, communicating advances in genome science to the public, and reviewing and funding proposals to address the ethical and legal issues associated with this research. NHGRI supports the development of methods, resources and technologies to improve the health of all humans through advances in genomics research. NHGRI supports research that accelerates foundational resources, technology development, and experimental and computational approaches for basic genomics and functional genomics research; for the application of genomics to medical science and clinical care; and to support ethical, legal and social implications (ELSI) research concerning societal issues that need to be addressed, especially as genomic science advances. For years, NHGRI has participated in the NIH effort to turn discovery into health by helping small businesses develop innovative genomics technologies that improve health and save lives. NHGRI also develops and supports initiatives that expand opportunities for genomics education and careers, cultivating genomics training programs and workforce development initiatives.

Key Dates

Posted Date

October 09, 2026

Open Date (Earliest Submission Date)

November 14, 2026

December 14, 2026

Not Applicable

Not Applicable

September 2027

All applications are due by 5:00 PM local time of applicant organization.

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

No late applications will be accepted for this Notice of Funding Opportunity (NOFO).

Expiration Date

December 15, 2026

Due Dates for E.O. 12372

Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide, except where instructed to do otherwise (in this NOFO or in a Notice from NIH Guide for Grants and Contracts).

Conformance to all requirements (both in the How to Apply - Application Guide and the NOFO) is required and strictly enforced. Applicants must read and follow all application instructions in the How to Apply - Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the How to Apply - Application Guide, follow the program-specific instructions.

Applications that do not comply with these instructions may be delayed or not accepted for review.

Table of Contents

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

Part 2. Full Text of Announcement

Section I. Notice of Funding Opportunity Description

Background A major challenge in genomics is defining the role of genomic variation in influencing phenotypes in human biology and diseases. As outlined in NHGRI's 2020 Strategic Vision, studies characterizing the functional consequences of variants have not kept pace with studies of variant discovery or association, and this lack of functional genomic information remains a barrier that impedes progress in genomics.

The Impact of Genomic Variation on Function Consortium (IGVF) was established in 2021 to address the challenge of understanding how genomic variation affects genome function to influence phenotypes using a coordinated team-science approach. The program utilizes emerging experimental and computational genomic approaches to build a catalog of the impact of genomic variants on genome function and phenotypes and to share data and other resources with the scientific community.

Program Goals and Notices of Funding Opportunity (NOFOs) NHGRI is issuing an open call for applications to participate in a second phase of IGVF, based on recent community recommendations on functional variant interpretation and input from the National Advisory Council for Human Genome Research. The goals of the second phase of IGVF are to:

To achieve these goals the following NOFOs are issued:

NHGRI encourages all investigators with ideas aligned with the goals of this NOFO to submit applications.

Research Scope and Objectives Current understanding of the interactions of genetic variants with other variants, or with the environment, is limited. In molecular studies (e.g. genetics using model organisms, functional genomics, and protein engineering) interactions beyond additive effects such as epistasis or synergy are sometimes detected. However, investigation of human diseases and traits using statistical methods such as GWAS find a minimal contribution from effects beyond additive. At least superficially, there is tension between these sets of findings. Do interactions beyond additive contribute to human traits and human disease, and if so, how prevalent is that contribution, and what are specific examples of such interactions? Using perturbations to test all by all (or higher orders of variant interaction) is not possible with current technologies. However, if interactions beyond additive are important for human traits and diseases, and if there is structure within the interaction landscape where non-additive interactions are enriched, these centers might identify the subspace of interactions that are most informative to test using perturbations, leading to more effective variant testing, better understanding of GWAS, and improved polygenic scores.

The objectives for this NOFO are to:

The scope of this NOFO also includes the following:

A theoretical and quantitative framework for assessing interactions: Interaction centers should be grounded in a framework to test phenotypic joint variant effects or joint effects of variants with environments. Frameworks should be theoretically grounded (e.g. quantitative or evolutionary genetics) categorize interactions (examples include additive, superadditive, epistatic/hypostatic), and be compatible with high-throughput variant testing.

Characterizing Interactions: Interaction centers should implement at least one system high-throughput testing of interactions. There should be a systematic and efficient strategy for subsampling the space of all possible combinations taking into account evidence from human genetics and biological function. Examples of joint variant tests include combinations of variants within and between loci (e.g., cis and trans effects), combinations of variant types (e.g., coding and non-coding variants, rare and common alleles), testing variants across genetic backgrounds (e.g., testing variants across a range of local or global genetic ancestry). Examples of joint variant and exposure tests include the impact of inflammation, stress, or altered metabolism on variant penetrance. (Note, for this RFA, testing a set of variants across cell types is not responsive.) Combinations could be pairwise or higher order. Interactions may be tested at the level of genes, regulatory elements, or variants. Interaction centers may propose to detect phenotypic changes at one or more scales, such as molecular (e.g., RNA abundance or kinase activity), cellular (e.g., morphology), multi-cellular (phenotypes that require interaction of more than one cell type, which need not be cell autonomous phenotypes), or organismal phenotypes (e.g., behavior or development). Interaction centers may test one or more classes of variants (examples include common, rare, disease associated, synthetic), using at least one high-throughput assay for testing (examples include reporters, epigenome editing, genome editing), and at least one phenotype for detecting responses (examples include RNA-seq, survival, a cellular response). Interaction center assays and data processing pipelines should be in production by the end of the first year of funding.

Contribute results of tested variant combinations as well as models for predicting the most important combinations to test as part of the IGVF catalog: The primary goal of the consortium is to collaboratively produce a variant/element/phenotype catalog for use by the community. Interaction centers will contribute data and results for variants and interactions that were tested. Interaction centers will submit raw data, processed data, metadata, and integrative analysis to the resource. This catalog will report the perturbation and phenotype assay(s), the biological system(s), results and interpretation. Recipients will collaborate with the IGVF Data and Coordinating Center (DACC) about representations of their data and analyses and specify use cases that should be supported by the catalog.

Enable others to perform related studies using these approaches: Interaction centers will fully share data and analyses; in addition, they will share with the community the algorithms, software, protocols, models and technologies used to create the data and analyses. The consortium will assess the experimental and computational approaches used. This may include the specificity, sensitivity, accuracy and generalizability of approaches. It may also include determining the systematic limitations and biases as well as strengths of the approaches. The consortium may identify what is needed to improve future assessments of the role of genetic variation in genome function. This could be a joint effort across interaction centers, if scientifically appropriate.

Improve generalizable approaches or technologies for high-throughput assays (optional): This NOFO is NOT a technology development opportunity; Interaction centers must perform their their major data collection based on methods that are ready at the time of funding. However, Interaction centers may use a small portion of their resources (not to exceed 5%) to develop or refine experimental and computational approaches. Refinement of existing assays or development of new orthogonal assays for validation are examples. Technology development under this NOFO is limited to approaches for characterization of functional genomic elements that are high-throughput, generalizable across experimental systems and disease, with the potential to implement during the current project period.

Consortium Formation and Coordination This NOFO uses the cooperative agreement award instrument. Interaction centers will become members of the IGVF Consortium. Consortium members are expected to work collaboratively with NHGRI and all members of the consortium towards meeting consortium goals, in addition to the specific research goals outlined in their individual applications.

Members of the IGVF Consortium will work together to:

Consortium members are expected to coordinate assays, variants, and cell types and to develop shared analysis strategies and uniform computational workflows, when applicable, to meet consortium goals, rather than function as independent projects with independent goals. When appropriate, selection of variants and cell types in this second program phase should be done in consideration of variants and cell types characterized in the first phase of IGVF (see: https://data.igvf.org/resources/). IGVF research is limited to mammalian systems, with a preference for human studies including samples derived from individuals across a breadth of genetic ancestries and the consideration of sex as a biological variable. Variants selected for testing should account for allele frequencies and disease associations within and across human populations. Proposed cell types and states should be derived from tissues important in development, differentiation, or human diseases.

A central goal of IGVF is the development of data, tools, and other resources that can be used by researchers not funded by this program. Consortium members will be expected to generate pipelines, tools, and educational materials that facilitate community uptake of IGVF data and methods, and to work together to ensure all consortium resources are accessible to a wide variety of potential users. Data, predictions, and models should be shared early and organized in ways that enable a variety of uses by the broader scientific community, from searches of individual variant impacts to large scale integrative or machine learning approaches.

Consortium memberswill also be expected to continue to collaborate with other projects and consortia with interests in variant interpretation and coordination across resources, especially in efforts to develop shared data processing and analysis pipelines to enable data sharing and comparisons. This includes work with the Atlas of Variant Effects (AVE) Alliance, The Molecular Phenotypes of Null Alleles in Cells (MorPhiC), the Clinical Genome (ClinGen) Resource, the Genomics Research to Elucidate the Genetics of Rare Diseases (GREGoR), the Human Pangenome Reference Consortium (HPRC), and other consortia, as relevant .

Consents and Data Sharing in IGVF A key deliverable of IGVF is the development of two public data resources, the IGVF Catalog and Data Portal. To facilitate user access to these resources, NHGRI expects that centers will prioritize the use of samples derived from research participants that have been consented for the broadest possible sharing of genomic data, such as consent for unrestricted access, or for general research use and broad sharing through controlled access. Consent language should also avoid restrictions on the types of users who may access these data for genomics research.

To Learn More A webinar will be held where NIH staff will present overviews of IGVF NOFOs and answer NOFO-related questions from prospective applicants. Time, date, and webinar links will be made available through a Notice in the NIH Guide. The webinar is open to all prospective applicants, but participation is not required to apply.

Prospective applicants are strongly encouraged to contact the email address listed as the Scientific/Research Contact(s) below to discuss the responsiveness and alignment of their proposed work with program goals.

Applications Not Responsive to this NOFO The following types of applications are not responsive to this NOFO and will not be reviewed:

See Section VIII. Other Information for award authorities and regulations.

Section II. Award Information

Funding Instrument

Cooperative Agreement: A financial assistance mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH scientific or program staff will assist, guide, coordinate, or participate in project activities. See Section VI.2 for additional information about the substantial involvement for this NOFO.

Application Types Allowed

New

The OER Glossary and the How to Apply - Application Guide provide details on these application types. Only those application types listed here are allowed for this NOFO.

Clinical Trial?

Not Allowed: Only accepting applications that do not propose clinical trials. Note: Applications may propose activities involving human subjects that are not deemed clinical trials.

Need help determining whether you are doing a clinical trial?

Funds Available and Anticipated Number of Awards

NHGRI intends to commit $10M total costs in FY 2027 to fund 5 awards.

Award Budget

Application budgets must not exceed $1.5M direct costs per year. Application costs must reflect the actual needs of the proposed project.

Award Project Period

The maximum project period is five years.

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

Section III. Eligibility Information

1. Eligible Applicants

Eligible Organizations

Nonprofits Other Than Institutions of Higher Education

For-Profit Organizations

Local Governments

Federal Governments

Eligible Agencies of the Federal Government

U.S. Territory or Possession

Other

Independent School Districts

Public Housing Authorities/Indian Housing Authorities

Native American Tribal Organizations (other than Federally recognized tribal governments)

Faith-based or Community-based Organizations

Regional Organizations

Non-domestic (non-U.S.) Entities (Foreign Organizations)

Foreign Organizations/Foreign Collaborations

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

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

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

NIH will no longer issue awards (i.e., new, renewal, or non-competing continuation) to domestic or foreign entities that involve foreign subawards/subcontracts. All NIH-funded research involving foreign subawards/subcontracts must be submitted in response to a NOFO that is specifically designated for funded international collaborations. See NIH Grants Policy Statement 16.8 Collaborative International Research Awards.

Applications involving foreign subawards/subcontracts submitted in response to this NOFO will be deemed noncompliant and will not be considered for funding. This policy applies to all monetary international collaborations resulting in foreign subawards/subcontracts, however, it does not preclude unfunded international collaborations or foreign components, funding for foreign consultants, or procurement of unique equipment or supplies from foreign vendors.

Required Registrations

Applicant Organizations Applicant organizations must complete and maintain the following registrations as described in the How to Apply - Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. Failure to complete registrations in advance of a due date is not a valid reason for a late submission, please reference NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications for additional information System for Award Management (SAM) – Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code. Foreign organizations must obtain a NATO Commercial and Government Entity (NCAGE) Code (in lieu of a CAGE code) in order to register in SAM. Unique Entity Identifier (UEI)- A UEI is issued as part of the SAM.gov registration process. The same UEI must be used for all registrations, as well as on the grant application.

Program Directors/Principal Investigators (PD(s)/PI(s)) All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. Obtaining an eRA Commons account can take up to 2 weeks.

All PD(s)/PI(s) must be registered with ORCID. The personal profile associated with the PD(s)/PI(s) eRA Commons account must be linked to a valid ORCID ID. For more information on linking an ORCID ID to an eRA Commons personal profile see the ORCID topic in our eRA Commons online help.

Eligible Individuals (Program Director/Principal Investigator)

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with their organization to develop an application for support.

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

2. Cost Sharing This NOFO does not require cost sharing as defined in the NIH Grants Policy Statement NIH Grants Policy Statement Section 1.2 Definition of Terms.

3. Additional Information on Eligibility Number of Applications

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

The NIH will not accept duplicate or highly overlapping applications under review at the same time, per NIH Grants Policy Statement Section 2.3.7.4 Submission of Resubmission Application. This means that the NIH will not accept:

Section IV. Application and Submission Information

1. Requesting an Application Package The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are available in Part 1 of this NOFO. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide except where instructed in this notice of funding opportunity to do otherwise (in this NOFO, in a policy notice, or other notice from NIH Guide for Grants and Contracts). Conformance to the requirements in the How to Apply - Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

Page Limitations All page limitations described in the How to Apply – Application Guide and the Table of Page Limits must be followed.

For this specific NOFO, the Research Strategy is limited to 30 pages (exclusive of the Specific Aims page).

Instructions for Application Submission

The following section supplements the instructions found in the How to Apply – Application Guide and should be used for preparing an application to this NOFO.

SF424(R&R) Cover All instructions in the How to Apply - Application Guide must be followed.

SF424(R&R) Project/Performance Site Locations

SF424(R&R) Other Project Information

SF424(R&R) Senior/Key Person Profile

The PD(s)/PI(s) must designate a dedicated Project Manager to direct the day-to-day operations of the Coordinating Center. A PD/PI may serve as the Project Manager.

R&R Budget

R&R Subaward Budget

PHS 398 Cover Page Supplement

PHS 398 Research Plan All instructions in the How to Apply - Application Guide must be followed, with the following additional instructions:

Specific Aims:

Describe the specific goals of the Interaction Center and its role in achieving the overall objectives of the IGVF Consortium.

Research Strategy:

In the Research Strategy, applicants should propose plans, approaches, and potential alternative strategies for carrying out the goals of the Interaction Center. The Research Strategy must be uploaded as a single PDF attachment, and should include the following subsections. (Overview may be included as part of Significance; Management plan may be included as part of Investigator; Framework, Selection, Perturbation methods, Model, Contributing, Enable, and Improvement may be included as part of the approach.)

Overview Applicants must provide a high-level view of the proposed project including:

Management plan

Theoretical and quantitative framework for assessing interactions Applicants must propose a theoretically grounded, quantitative framework for detecting and interpreting the joint effects of variants or joint effects of variants and exposures.

This plan should:

Selection of interactions for systematic testing Applicants must propose a plan to select genomic variants and/or elements for systematic testing of interactions. These projects are intended to be hypotheses generating/discovery science rather than testing specific hypotheses or mechanisms.

This plan should:

Application of genomic perturbation methods to assay the impact of interactions on phenotypes Applicants must propose a plan to apply genomic perturbation methods to collect high quality phenotypic data using one or more robust assays, and to analyze that data.

This plan should:

Model for prioritizing interaction testing (optional) Applicants may propose a plan to generate a model for prioritizing future interaction combinations that are likely to be enriched in effects beyond additive. However, this may not be possible for some experimental approaches.

This plan should:

Contribute results of tested variant combinations as well as models for predicting the most important combinations to test as part of the IGVF catalog.

Applicants must present a plan to incorporate results, including data and models, into a consortium-wide catalog relating variants/elements to phenotypes. This proposed plan must indicate how the catalog would allow the community to interpret the results obtained. Ultimately the consortium will generate a single catalog, rather than each project developing their own catalog. This catalog will be developed collaboratively by the consortium and hosted by the DACC. The implemented plan will be selected by the consortium during the first year, and thus may not match the plan proposed by any applicant.

This plan should:

Enable others to perform related studies using these approaches Applicants must describe their plan to enable others in the field to adopt the approaches used by this project and the consortium.

This plan should:

Improvements in generalizable approaches or technologies for high-throughput interaction assays (optional).

Applicants have the option to propose to use a small portion of their resources to develop and/or refine experimental and/or computational approaches. However, this is NOT a technology development funding opportunity, and the center CANNOT be dependent upon the success of this activity.

If included, this plan should:

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the How to Apply - Application Guide.

The following instructions also apply:

The Resource Sharing Plan should summarize whether and how resources (e.g., educational materials; methods; models; physical products, materials, and reagents; protocols; research findings and products; and software) will be made available. Applicants should include a description of the format, an indication of who will be responsible for implementation and plans for long-term maintenance, whether there will be opportunities for community input and feedback, platform(s) or mechanism(s) that will be used to make resources publicly accessible, and proposed timeline for implementing the Resource Sharing Plan. Resource Sharing Plans should not duplicate other sections of the main Research Plan but should refer to them when appropriate. After initial review, NHGRI program staff may negotiate revisions of this plan with the prospective awardee. The final negotiated version of this plan will become a term and condition of the award.

In addition to the above expectations, NHGRI expects that plans for sharing software generated under this funding opportunity will meet the following expectations:

For more guidance on writing a Resource Sharing Plan, see https://www.genome.gov/about-nhgri/Policies-Guidance/Writing-a-Resource-Sharing-Plan.

Other Plan(s):

All instructions in the How to Apply - Application Guide must be followed, with the following additional instructions:

Appendix: Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the How to Apply - Application Guide.

No publications or other material, with the exception of blank questionnaires or blank surveys, may be included in the Appendix.

PHS Human Subjects and Clinical Trials Information When involving human subjects research, clinical research, and/or NIH-defined clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the How to Apply - Application Guide, with the following additional instructions:

If you answered "Yes" to the question "Are Human Subjects Involved?" on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials…