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Scalable and Systematic Neurobiology of Psychiatric and Neurodevelopmental Disorder Risk Genes (SSPsyGene) Consortium – Frequently Asked Questions (FAQs)

This page provides answers to frequently asked questions about the Notice of Funding Opportunity: The Scalable and Systematic Neurobiology of Psychiatric and Neurodevelopmental Disorder Risk Genes (SSPsyGene) Consortium: Assay and Data Generation Centers  (RM1) (RFA-MH-24-145).

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Question: What is the anticipated or ideal deliverable for the SSPsyGene Consortium?

Response: The SSPsyGene Consortium aims to produce a systematic annotation of basic neurobiological function of genes associated with risk for neurodevelopmental and psychiatric disorders (NPDs). The resulting phenotypic data will be integrated across modalities, levels of organization, and genes to create a harmonized, integrated knowledge base needed to substantively advance our understanding of basic gene function and, ultimately, make robust inferences into potential shared and unique disease mechanisms.

Gene selection

Question: What are the target number of genes to be investigated over the 5-year project period?

Response: While it is anticipated that assays should aim to characterize 100-250 genes, some phenotypes and assay formats may be more amenable to moderate scale screening against a subset (50-100) of the gene set. In the latter case, any limitation in scalability should be balanced by more sophisticated or detailed phenotypic characterization to yield mechanistic insight.

Question: Is the list of genes available? Will each applicant need to come up with a separate plan for gene list selection?

Response: While the long-term goal of the SSPsyGene Consortium is to build a comprehensively annotated resource describing the CNS function of all neurodevelopmental and psychiatric disorder risk genes, the current target for the initiative is 100-250 protein coding genes. A Gene Selection Task Group within the SSPsyGene Consortium has initiated efforts to prioritize a set of ~100-250 genes associated with NPDs to be interrogated by all Assay and Data Generation Centers (ADGCs), the list of which can be found on the “Resources” tab of the SSPsyGene Consortium website  operated by the UC Santa Cruz Data Resource and Administrative Coordinating Center (DRACC). ADGCs supported in Phase 2 of the initiative will be involved in continued efforts to refine and expand the list, as well as developing a rigorous, data-informed approach for selecting patient variants in allelic series from a subset of NPD risk genes. As noted in the application instructions, applicants for the ADGCs should describe a proposed approach for risk gene prioritization from this list. Particularly for moderate throughput assays, strategies for selecting a subset of genes from the list should be discussed in the context of the chosen assay(s) or readout(s). To maximize the potential disease relevance, genes with a genome-wide significant excess burden of loss-of-function mutations in NPDs such as intellectual disability/developmental delay, autism spectrum disorder, and schizophrenia are the focus. Additional factors to consider are expression within the experimental systems, conservation across species, developmental specificity, balanced representation across disorders, existing knowledge of gene function (with less studied genes to be prioritized), and alignment with the recommendations from the Report of the National Advisory Mental Health Council Workgroup on Genomics.

Question: When selecting the genes, is it necessary to avoid the genes studied by the funded groups?

Response: No, all ADGCs are expected to screen the same set of genes selected by the SSPsyGene Consortium, as described in the list that can be found on the “Resources” tab of the SSPsyGene Consortium website  operated by the UC Santa Cruz DRACC.

Question: Can I do unbiased genome-wide screening? Can I include analysis of copy number variants (CNVs) associated with disease risk?

Response: The goal of this initiative is to fill a very specific knowledge gap area, which is that many protein-coding genes are now associated with NPD risk, but their basic neurobiology remains poorly understood. SSPsyGene is designed to 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 NPD disease mechanisms. Because of this, broader genome-wide screens and analysis of larger multi-genic intervals associated with disease risk are beyond the scope of this initiative.

Question: Are null alleles the focus for the initiative? Many of these genes may be essential genes, making analysis of null alleles difficult in some contexts. What about heterozygous versus homozygous null?

Response: Initial characterization has focused primarily on null alleles. The Consortium will also determine the need to assess heterozygous versus homozygous states. It is understood that some targeting approaches may not be appropriate for all genes or all assays (e.g., a constitutive homozygous null for one gene may be lethal in a model organism). It is also understood that some targeting approaches are more costly, time- and labor-intensive than others. Additionally, proposed approaches need not be strictly limited to actual genetic knockouts, as long as the alleles can be functionally equivalent to a null (i.e., do not produce functional protein) and otherwise aid in attaining the RFA goals. As an initial first pass into gene function, applicants can propose highly scalable genetic perturbation approaches that do not involve individual stable mutants (e.g., CRISPR interference). Applications should describe how alleles will be ascertained/QC'd to ensure they are stable enough to work in assays and how they will assess dosage sensitivity. The Consortium may also develop a rigorous, data-informed approach for selecting patient variants to assay an allelic series in subset of NPD risk genes. For investigators who want to propose this approach, the details for generating and validating an allelic series of patient variants from a subset of genes should also be provided. Please note that patient variants should not be the sole focus of the application but rather should balance breadth (number of risk genes) and depth (number of patient variants per gene) with a focus on the overall goal of SSPsygene, to advance understanding of basic gene function using scalable approaches. Applications should also include a discussion of potential artifacts or confounders (e.g., genetic compensation for certain alleles; cases in which the homozygous null is cell lethal in their assays; cases where heterozygous null effects are not detected in selected assays; degree of cross-species conservation) and how they will be addressed.

Experimental systems and assays

Question: Are applicants expected to develop their own null alleles, or should they propose assays that will be performed on null alleles supplied by other centers? Would currently funded applicants share their genetically modified human induced pluripotent stem cell (iPSC) lines with new consortium members?

Response: As noted in the Application Instructions for the ADGCs, applicants are required to describe how alleles will be produced along with the rationale for this choice. Applications may propose to generate new alleles, or may use existing resources (e.g., available libraries of CRISPR/Cas9 alleles in iPSCs that can be differentiated into systems for assays; knock-out animal resources such as the Knockout Mouse Project or Zebrafish International Resource Center). The SSPsyGene Consortium is expected to be collaborative and this may include the sharing of resources and reagents where feasible. However, access at this time to specific resources should not be assumed and ultimately each ADGC will be responsible for targeting the common set of genes in their chosen system(s). Applicants may reach out to funded ADGCs to discuss the potential for a collaboration involving access to specific resources. Any proposed collaborations with existing ADGCs should be documented and budgeted in the application, including Letter(s) of Support, effort commitment (as needed) and any costs for preparing and distributing resources among teams, to establish feasibility of the proposed approach.

Question: For iPSC work, will the set of induced pluripotent stem cell (iPSC) lines for engineering be predetermined for applicants? 

Response: A Common Cell Line Task Group within the SSPsyGene Consortium has identified a small number of “workhorse” iPSC lines using selection criteria listed on the “Resources” tab of the SSPsyGene Consortium website operated by the UC Santa Cruz DRACC. Investigators proposing to use human iPSC-based assays are strongly encouraged to utilize one or more of these lines in their assays to anchor their studies with the other ADGCs, although they may include additional lines of their choosing with justification.

Question: Is any particular experimental system required as a component of an ADGC application? Or is the RFA agnostic to the model organism/experimental system?

Response: The intention of the SSPsyGene initiative is to leave the types of assays and models open to encourage a diversity of approaches and technologies. Applications are only constrained by the throughput capabilities of the proposed system to rigorously and systematically characterize 50-250 genes within the possible budget. Different experimental systems may be more or less amenable to a specific functional/phenotypic readout. It is possible that applications proposing to utilize pluripotent cell-based paradigms or model organisms with a short generation time will be most feasible within such budget and throughput constraints. However, applicants are welcome to propose projects using other model systems and encouraged to carefully justify project feasibility in such applications.

Question: Can the assay system be different from the systems supported by the initial set of SSPsyGene ADGCs? Can assays be proposed that are supported by the initial ADGCs, but for which we have additional expertise, such as improved biosensors and readouts that would go beyond existing capabilities?

Response: As the first group of ADGCs have been funded for the SSPsyGene Consortium in response to RFA-MH-22-111 , potential applicants in response to RFA-MH-25-145  are encouraged to propose experimental systems and assays not currently represented within the consortium. Applicants are encouraged to review the currently funded awards in NIH RePORTER  and also discuss plans with the scientific contacts listed in the RFA, to ensure that their application is not duplicative of current efforts but rather complements and enhances the existing research. This may include alternative approaches for similar assays that extend existing capabilities.

Question: Should an applicant discuss the inherent limitation of proposed assays for interrogating all of the genes proposed by the SSPsyGene Consortium? Each assay will have limitations that may make it technically challenging and, in some cases, impossible to interrogate every gene and it will not be possible to know all of the potential issues in advance, as the full gene list has not been selected?

Response: It is understood that some genes may not be appropriate for all assays (e.g., null allele cannot successfully be generated in a particular experimental system, or the gene is not expressed in a particular cell type). Furthermore, it may not be possible to know all of the potential issues until the Consortium has selected the genes to be interrogated. As with any application, it is important to consider potential pitfalls and alternatives in the proposed experimental plan. For each assay, applicants are encouraged to discuss technical limitations of the approach that may limit success for certain gene targets and discuss potential alternatives approaches that could be employed. Applicants proposing moderate throughput assays should discuss the proposed approach for selecting the subset of the gene list that will be assayed.

Question: Will the RFA support characterization of gene function across various neuronal and non-neuronal cell types or are experimental systems/assays limited to neurons?

Response: Assays to assess gene function in any CNS cell type are allowable under the SSPsyGene RFAs.

Question: Is the focus on molecular/cellular levels of analysis? Are assays targeting neuronal communication or neural circuit function within the scope of the RFA?

Response: The initial focus for the SSPsyGene Consortium will be on the 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. While the primary focus at this time is at the molecular/cellular scale, assays may include CNS-relevant phenotypes across scales of biological organization from molecular and cellular to physiological and organismal, if they are amenable for scalable and systematic investigations.

Question: Should applications propose initial validation of results from the high throughput assays? Do these need to be done at the same scale/throughput?

Response: While highly scalable measures to support systematic characterization of gene function are the primary focus of the initiative, applications should incorporate plans for validating key results to ensure rigor. While maintaining scalability/throughput throughout the validation process is encouraged, applicants may propose lower throughput approaches at later stages of validation with appropriate justification as to the need and selective use. Pilot studies, committing no more than 10 percent of the budget (and not starting in year 1), can also be proposed to optimize and implement novel assays that validate or extend on initial findings.

Question: Is it preferred that applications focus on a single level of analysis or should applicants propose assays across multiple levels? Can one propose a single assay across multiple model organisms?

Response: Each application must propose projects that address at least one of the high priority assay areas listed described in the ADGC RFA (Molecular Assays; Cellular, Circuit, or Systems/Organismal Assays). Applicants have the flexibility to select any assay category or may opt to propose assays in multiple areas or across multiple experimental systems/species. Assays should be considered based on their throughput and the utility of information they provide to advance understanding of the neurobiological function of NPD risk genes. Proposals to carry out multiple complementary assays within each priority area or across areas are of interest.

Question: Are behavioral assays of interest? How about behavioral assays in conjunction with a priority assay listed in the RFA?

Response: The primary focus of the SSPsyGene Consortium is on high-throughput with selected moderate-throughput analyses. Robust, reproducible and quantitative behavioral phenotyping may be proposed, although this may be more feasible with model organisms with short generation times and a size suitable for scalable assays. Successful RM1 applications will likely also have a strong focus on molecular and/or cellular assays. Further, with the goal of achieving a systematic characterization at scale, each of the RM1 awardees will be expected to complete rigorous functional characterization all of the 50-250 genes that the Consortium appoints to the common core gene set within the project period.

Question: Would looking at conditional effects of the genes (such as drug treatment or joint perturbation with other genes) be considered responsive? What about gene by environment interactions or assessing the impact of genetic background?

Response: Perturbation-based approaches and assessment of polygenic or environmental effects are permitted, provided they meet the criteria of scalability and address the fundamental goal of the SSPsyGene initiative – understanding the basic brain function of selected NPD risk genes. Assessing the impact of genetic background on phenotypes is not a primary goal of SSPsyGene, though considering elements of diversity and variation in experimental systems is encouraged to the extent feasible, while maintaining the focus on scalability.

Data analysis

Question: How much data analysis is expected to be performed by the ADGC as opposed to being performed by the DRACC?

Response: As instructed in the RFA, ADGC applicants are expected to collaborate with the central Data Resource and Administrative Coordination Center (DRACC) to develop and implement data processing pipelines for submission of data. ADGC applicants are expected to propose and budget for staff expertise and general resources for bioinformatic analysis and to work closely with the current DRACC on metadata/data standards, data processing and data submission/ingestion. This may include adoption of common data processing pipelines if already established within the Consortium. Applicants are strongly encouraged to utilize a cloud-based Terra workspace developed by the current DRACC to fully process raw, quality control-verified, and modality-specific feature data levels for storage. Applicants should prioritize analyses that are designed to characterize the quality and utility of their data for downstream applications (e.g., consistency, biological and technical variability).

Application instructions

Question: What is a PEDP and is it required?

Response: A requirement of this RFA is the inclusion of a “Plan for Enhancing Diverse Perspectives” (PEDP). This is a summary of strategies to advance the scientific and technical merit of the proposed project through inclusivity. Applicants must include a 1 page PEDP summary as an ‘Other Attachment’ and are expected to show how enhancing diverse perspectives is supported throughout the application. PEDP considerations are included in each of the scored review criteria. Applications must include a PEDP, or they will be administratively withdrawn prior to review. More information on the PEDP can be found here .

Question: What is the maximum budget allowed for a project?

Response: Application budgets are not limited but need to reflect the actual needs of the proposed project. NIMH intends to commit $5,000,000 per year in total costs to fund 2-4 awards.