Purpose:
This Funding Opportunity Announcement (FOA) is one of two to establish 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 (NPDs) risk genes. This resource will be made available for broad use by the biomedical community.
The program will leverage scalable technologies to functionally characterize ~100-250 null alleles from genes with an increased burden of loss-of-function mutations in NPDs. It will also optimize novel assays for cellular and physiological phenotypes, assess the scale limitations of such methods for allelic series of patient variants across large numbers of risk genes, and develop common data formats.
This specific FOA seeks applications for a Data Resource and Administrative Coordination Center (DRACC) that 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 knowledge base that adheres to Findability, Accessibility, Interoperability, and Reuse (FAIR) principles. The DRACC will work in a hub and spoke model in collaboration with the Assay and Data Generation Centers (ADGCs), as described in the companion funding announcement RFA-MH-22-111 to achieve the goals of the SSPsyGene Consortium.
Background:
Current prioritization of genes for biological characterization does not necessarily reflect their physiological importance nor relevance 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.
Most attempts to evaluate the impact of disease-associated genes or variants have been limited in scale to one or a few genes against a relatively narrow range of biological functions. Systematic efforts are constrained by our ability to fully capture the spectrum of potential disease relevant biological phenotypes across a sufficiently large number of genes or variants in a cost-efficient and comprehensive way. New scalable technologies are emerging that address these limitations and offer the opportunity to probe the role of genetic variation in 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 more thoroughly capture the genetic and phenotypic space at a scale and breadth not covered by existing efforts. Such an approach would provide a collaborative and efficient framework for identifying biological function beyond current small-scale and often ad hoc single gene efforts 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 long-term goal of developing a comprehensive phenotypic catalog across biological scales (molecular, cellular, circuit, systems) for genes and gene variants associated with NPDs.
Consortium Structure and Objectives
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 neurobiological function of genes associated with risk for NPDs. 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 to make robust inferences into potential shared and unique disease mechanisms. To accomplish this objective, NIMH intends to establish a consortium of investigators at multiple sites and with broad expertise in the areas of genomics, high throughput technology, and neurobiology, linked together through a central Data Resource and Administrative Coordination Center that serves to promote collaboration and communication and to provide data integration across the consortium.
The SSPsyGene Consortium will be comprised of:
- Assay and Data Generation Centers (ADGC) RFA-MH-22-111 to engineer a selected set of 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 clinically significant variants, and support optimization of innovative assays of central nervous system (CNS) function.
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Data Resource and Administrative Coordinating Center (DRACC) RFA-MH-22-110 (this FOA) will coordinate with the ADGCs to develop a rigorous data-driven strategy for selecting a set of 100-250 NPD risk genes; receive, integrate, annotate, harmonize, and present data for consortium and public use; and provide leadership and logistical support for the consortium.
Assays will include CNS-relevant phenotypes across scales of biological organization from molecular and cellular to physiological and organismal that are amenable for scalable and systematic investigations. The initial focus for the SSPsyGene Consortium will be on implementation of high-throughput molecular and cellular assays. Ultimately, the goal of the initiative is to broadly characterize genes across a variety of fundamental CNS functions including developmental processes, cell morphology, neurite motility, intrinsic membrane properties, synaptic physiology, inter- and intra-cellular signaling, circuit dynamics, natural behaviors, or other neural phenotypes. To support this goal, the initiative will also support optimization and implementation of pilot assays using scalable screening platforms/technologies.
This initative supports the use of experimental systems – in vitro or in vivo, cellular or organismal – that are reproducible and scalable for hundreds of genes, are informative of human neurobiology, and align with NIMH priorities. Examples of potential scalable experimental systems include:
- Human cell-based assays (e.g., induced pluripotent stem cells [iPSCs])
- Model organism paradigms (e.g., Xenopus tropicalis, Danio rerio, C. elegans)
- Others w/ high-throughput capabilities (e.g., ex vivo, non-human cell-based assays)
While the long-term goal of the SSPsyGene Consortium is to build a comprehensively annotated resource describing the CNS function of all NPD risk genes, the target for the initial phase of the initiative is 100-250 protein coding genes. These will be selected from genes with a genome-wide significant increased burden of mutations identified in large-scale sequencing studies of NPDs such as intellectual disability/developmental delay, autism spectrum disorder, and schizophrenia. Genes that have a demonstrated pathogenic role in rare forms of NPDs, for which penetrant rare variants have been identified and rigorous statistically significant evidence of causal roles has been established, may also be selected. The DRACC will coordinate with the ADGCs to develop a strategy to select and prioritize the set of 100-250 genes through the SSPsyGene Consortium Coordinating Committee (CCC), in accordance with the guidance provided in the Report of the National Advisory Mental Health Council Workgroup on Genomics. The number of genes selected will be sufficient to allow for a diverse set to be targeted to begin to sample the space of genetic risk and reveal potential points of biological convergence, while also permitting overlap to test the same gene in multiple assays and enable the assessment of reproducibility and robustness.It is anticipated that all assays will be conducted against the core, common set of genes, with the potential for inclusion of additional genes when warranted.
Key Dates:
URL for more information:
https://grants.nih.gov/grants/guide/rfa-files/RFA-MH-22-110.html
Filed Under: Funding Opportunities