Mission Statement

The SSPsyGene consortium implements systematic and coordinated assays that generate an accessible catalog of genotypes and phenotypes of neurodevelopmental and psychiatric disorder risk gene deletion models.

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. 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. The SSPsyGene approach provides a collaborative and efficient framework for delineating biology 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 is comprised of highly interactive components with complementary roles:

• Five Assay and Data Generation Centers (ADGC): The goal of the ADGCs is to optimize and implement scalable and systematic assays to interrogate the neurobiological functions of NPD risk genes. ADGCs will engineer comparable null alleles across experimental systems, 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. The ADGCs will form a collaborative network, working with the SSPsyGene DRACC to perform complementary assays on a common set of genes, to develop data, metadata, and methods standards to ensure results are comparable, reproducible, and to enable data integration.
• Data Resource and Administrative Coordinating Center (DRACC): The DRACC will coordinate and collaborate with all Assay and Data Generation Centers (ADGCs) as the core of SSPsyGene. The goal of the DRACC is to develop a rigorous data-driven framework for prioritizing NPDs risk genes; receive, integrate, annotate, harmonize, and present data for 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 (human cell-based models and model organisms) 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.