Key Dates

NOT-MH-22-016 - Notice of Intent to Publish a Funding Opportunity Announcement for Scalable and Systematic Neurobiology of Psychiatric and Neurodevelopmental Disorder Risk Genes: Assay and Data Generation Centers (RM1 Clinical Trial Not Allowed)

National Institute of Mental Health (NIMH)

The National Institute of Mental Health (NIMH) intends to promote a new initiative by publishing a Funding Opportunity Announcement (FOA) to solicit applications to establish a Data Resource and Administrative Coordination Center (DRACC) as a component of the Scalable and Systematic Neurobiology of Psychiatric and Neurodevelopmental Disorder Risk Genes (SSPsyGene) Consortium. The long-term goal of SSPsyGene is to systematically characterize phenotypes, across biological scales of organization (molecular, cellular, circuit, systems/organismal), for neurodevelopmental and psychiatric disorder (NPD) risk genes. The DRACC will be responsible for (1) establishing a rigorous approach to prioritize NPD risk genes for functional characterization across the consortium, (2) providing administrative and logistical coordination among all funded groups in the consortium, (3) establishing a data processing pipeline, and (4) building and maintaining a neural phenotype knowledge base. To achieve the goals of the SSPsyGene Consortium, the DRACC will work in collaboration with the Assay and Data Generation Centers (ADGCs) that will carry out high-throughput assays to characterize the function of selected risk genes in the central nervous system (see NOT-MH-22-016). The DRACC will develop methods and standards to harmonize the data generated by the ADGCs and create a cross-modality and cross-species phenotypic data set to systematically characterize the function of NPD risk genes. This resource will be made available for broad use by the biomedical community.

This Notice is being provided to allow potential applicants sufficient time to develop meaningful collaborations and responsive projects.

The FOA is expected to be published in Winter 2022 with an expected application due date in Summer 2022.

This FOA will utilize the U24 activity code. Details of the planned FOA are provided below.

Current prioritization of genes for biological characterization does not necessarily reflect the physiological importance nor relevance of the genes to human disease. Instead, 90% of research focuses on 10% of genes in the human genome. This limited knowledge base impedes our ability to understand basic gene function and disease mechanisms despite accelerated discovery of disease genes over the past decade. One of the main bottlenecks in translating disease-associated genes into biological insight lies in the lack of scalable experimental platforms that can extend the unbiased nature of gene discovery to the discovery of biological function. Emerging technologies addressing these limitations now offer the opportunity to functionally characterize the contribution of genetic variation to complex common diseases, such as neurodevelopmental and psychiatric disorders (NPDs; e.g., autism and schizophrenia). This can be achieved with systematic and coordinated assays that capture the genetic and phenotypic space at a greater scale and expanded breadth. Such an approach would provide a collaborative and efficient framework for delineating biology in order to generate a standardized, experimentally derived, functional catalog of NPD risk genes. This basic neurobiology resource would provide a fertile foundation for future studies into disease mechanisms. The NIMH is thus initiating a new program, the Scalable and Systematic Neurobiology of Psychiatric and Neurodevelopmental Disorder Risk Genes (SSPsyGene) Consortium, with the goal of developing a comprehensive phenotypic catalog across biological scales for genes associated with NPDs. The SSPsyGene Consortium will support multidisciplinary research centers to optimize and implement systematic and scalable approaches for characterizing the developmental, molecular, cellular, systems, and organismal CNS function of NPD risk genes. The resulting phenotypic data will be integrated across modalities, levels of organization, and genes, to create a harmonized, integrated knowledge base that forms a solid foundation of data needed for future efforts into potential shared and unique disease mechanisms.

The SSPsyGene Consortium will be made up of two highly interactive components with complementary roles as follows:

• Assay and Data Generation Centers (ADGC) (Companion, see NOT-MH-22-016) to engineer comparable null alleles across experimental systems, to assess and catalog the resulting molecular and cellular phenotypes, pilot these assays for a select allelic series of patient variants, and support optimization of innovative assays of CNS function.
• Data Resource and Administrative Coordinating Center (DRACC) to develop a rigorous data-driven framework for prioritizing NPDs risk genes; receive, integrate, annotate, harmonize, and present data for the consortium and public use; and provide logistical support for the consortium.

Assays will include informative, CNS-relevant phenotypes across scales of biological organization from molecular and cellular to physiological and organismal, using experimental systems (e.g., human cell-based models, model organisms, ex vivo preparations) that are reproducible and scalable for hundreds of genes, are informative of human neurobiology, and align with NIMH priorities. While the long-term goal of SSPsyGene is to reach biological saturation with respect to NPD risk genes, the target for the initial phase of the initiative is at least 100-250 protein-coding genes. Development of a scientifically rigorous gene prioritization schema will be led by the DRACC with input from all members of the SSPsyGene Consortium, the NIMH, and external advisors. The main focus of this phase of SSPsyGene will be on assaying null alleles to gain insights into basic gene function, however to address the ultimate goal of understanding the functional impact of disease-associated genetic variation, the consortium will also pilot established SSPsyGene assays against an allelic series from a small subset of NPD risk genes.

Research Objectives

The DRACC will coordinate and collaborate with all ADGCs as the core of SSPsyGene. The DRACC will be responsible for developing a rigorous formal framework for prioritizing risk genes and establishing a repository of consortium-generated data and metadata, analyses and annotations, and related information that will enable future efforts to understand the function of protein-coding genes and disease-associated variants. The DRACC is anticipated to work closely with other consortium components to develop standardized data submission, quality metrics, and processing. It will also disseminate primary, processed, and annotated data to the research community via a web portal. In addition, the DRACC will develop methods to integrate with similar or complementary resources. Additionally, the DRACC will serve as an administrative coordination center for the consortium.

Anticipated research objectives include:

1. Establish a rigorous approach to prioritize NPD risk genes for functional characterization across the consortium. The DRACC will work with consortium members, NIMH, and external scientific consultants to prioritize a set of ~100-250 or more NPD risk genes for assessment within the SSPsyGene Consortium.
2. Develop a comprehensive, formal neural phenotype knowledge base that includes data-driven phenotypic taxonomies and ontology across data modalities, biological scales, and experimental systems.
3. Receive, process, track, and quality control (QC) primary data, develop a database for storage, and make data available for consortium and community use. This would include developing specifications for data and metadata and providing data management of multiple potential data types including, but not limited to sequencing data; other omic-scale data types (e.g., proteomics, metabolomics); high-content imaging data (e.g., immunohistochemistry, spatial transcriptomics, morphology); neural activity data (e.g., optical physiology, multi-electrode array, calcium imaging); and other data types (e.g., molecular interactions and pathways; activity-based or perturbation-based assays).
4. Serve as an administrative and coordinating center for the consortium, including organizing consortium meetings, facilitating interactions and joint projects, and the development of standard operating procedures and policies.

Applications are not being solicited at this time.

Please direct all inquiries to:

Alexander Arguello, PhD
National Institute of Mental Health (NIMH)
301-827-3547
alexander.arguello@nih.gov

Rebecca Beer, PhD
National Institute of Mental Health (NIMH)
301-402-3969
rebecca.beer@nih.gov