From Genomic Association to Causation: A Convergent Neuroscience Approach to Linking Levels of Analysis for Understanding Neuropsychiatric Disorders (U19 Clinical Trial Optional) | RFA MH 21 165

Opportunity Information: Apply for RFA MH 21 165

The NIH funding opportunity "From Genomic Association to Causation: A Convergent Neuroscience Approach to Linking Levels of Analysis for Understanding Neuropsychiatric Disorders" (RFA-MH-21-165) is a cooperative agreement (U19; clinical trial optional) aimed at pushing psychiatric genetics and neuroscience beyond correlation and toward clear, testable causal explanations. The central purpose is to connect evidence across multiple biological and clinical scales such as genes and molecular pathways, cells, neural circuits, behavior, and clinical phenotypes in ways that can explain how neuropsychiatric disorders arise and persist. Rather than treating each scale as a separate silo, the program is built around the idea of "convergent neuroscience," where teams integrate data and theory to show how measurable features at one level produce quantifiable changes at another level, either directly or through emergent effects that only appear when systems are viewed at a higher scale.

A defining emphasis of the FOA is that proposed projects must be organized around causal linkages between at least two contiguous levels of analysis that are plausibly disease-relevant and objectively measurable. "Contiguous" here means adjacent or closely connected levels in a hierarchy, such as genetic variation to gene expression, gene expression to cellular physiology, cellular physiology to circuit function, circuit function to behavior, or behavior to clinical dimensions. Genetic variation can serve as one of the linked levels, or it can serve as the context for connecting other higher-level measurements (for example, using genetic risk to stratify individuals or models while testing mechanistic links between circuit activity and behavioral readouts). The expectation is not simply to map associations, but to identify relationships that can be interrogated in humans and/or in experimentally tractable in vivo or in vitro systems, including animal models or cellular models where manipulation and controlled testing are possible.

The FOA lays out four required features that shape what a competitive application looks like. First, the project needs a strong premise focused on identifying causal, disease-relevant relationships between objective criteria measured at two or more contiguous levels, using human studies and/or experimental models that can realistically probe causality. Second, applicants are expected to leverage large and diverse datasets that already exist or will be generated by the project, and to use those data to develop theoretical models that are explicitly testable within three years of the award. This is a key point: the modeling is not meant to be open-ended or purely descriptive, but instead needs to produce concrete hypotheses on a defined timeline. Third, those model-derived predictions must then be experimentally tested, with an explicit commitment to outcomes that could confirm or reject the model rather than only producing supportive evidence. Fourth, the program encourages scalable approaches that increase throughput and reliability while improving what can be measured, including sensitivity, selectivity, spatial and temporal resolution, and robustness. In practical terms, the FOA is signaling strong interest in platforms and pipelines that can be applied broadly and reproducibly, rather than one-off measurements that are difficult to generalize.

The intended deliverable is a mechanistic explanation of key functional dimensions relevant to mental illness pathophysiology, supported by causal evidence that bridges levels of analysis. That means the end result should look like an integrated account that starts with specific measurable constituents (for example, a genetic perturbation, molecular signature, or cellular phenotype), passes through intermediate mechanisms (such as synaptic function or circuit dynamics), and arrives at quantifiable outcomes (behavioral readouts, cognitive processes, or clinically meaningful dimensions). The FOA is essentially asking teams to build and stress-test explanatory models that can translate from genomic association signals into causal biological narratives that clarify how neuropsychiatric dysfunction is instantiated.

Because of the "convergent" framing, team composition is also a core element. The FOA expects leadership that combines deep experimental expertise (experimental neurobiology and/or clinical research) with "orthogonal" theoretical disciplines such as mathematics, computational modeling, or physics. The idea is that theory is not an add-on used after data collection, but a central driver that shapes what data are collected, how they are integrated, and how causal hypotheses are formulated and tested. This is also why the award mechanism is a U19 cooperative agreement: NIH intends to have substantial programmatic involvement and to coordinate activities across funded groups to create a broader, aligned scientific effort rather than isolated projects.

A major structural component of the opportunity is participation in the Convergent Neuroscience (CN) Consortium. Awardees are expected to work in a community-driven way, aligning their practices with other U19 groups. Data and analysis methods must be managed using a harmonized framework through a CN Consortium Data Commons. This implies shared standards, compatible data structures, and coordinated approaches to data sharing and analytic transparency, with the goal of making results comparable, integrable, and reusable across projects. The consortium model also signals that collaboration, interoperability, and openness are not optional extras; they are part of how the program intends to accelerate progress and improve reproducibility.

Eligibility is broad and includes many types of U.S.-based organizations: state, county, and local governments; special districts; independent school districts; public housing authorities; public and private institutions of higher education; federally recognized tribal governments; other tribal organizations; nonprofits with or without 501(c)(3) status; for-profit organizations (excluding small-business-only limits); and small businesses. The FOA also highlights inclusion of institutions serving underrepresented communities, including Historically Black Colleges and Universities, Hispanic-serving institutions, Tribally Controlled Colleges and Universities, Alaska Native and Native Hawaiian Serving Institutions, and Asian American Native American Pacific Islander Serving Institutions, as well as faith-based and community-based organizations and U.S. territories or possessions. Foreign institutions (non-U.S. entities) are not eligible to apply, and non-U.S. components of U.S. organizations are not eligible. However, foreign components as defined under the NIH Grants Policy Statement are allowed, meaning a U.S. applicant may include certain international elements when justified and compliant with NIH policy.

Administratively, the opportunity is offered by the National Institutes of Health under CFDA 93.242, with the original closing date listed as March 17, 2021, and a creation date of October 15, 2020. The clinical trial designation is "optional," meaning applicants can propose studies that include clinical trials if appropriate to their causal model testing, but they are not required to do so. Overall, the FOA is designed for ambitious, tightly integrated, multi-project research programs that can move from genomic and multi-scale data to predictive theory, and then to decisive experimental tests that clarify causal mechanisms underlying neuropsychiatric disorders.

• The National Institutes of Health in the health sector is offering a public funding opportunity titled "From Genomic Association to Causation: A Convergent Neuroscience Approach to Linking Levels of Analysis for Understanding Neuropsychiatric Disorders (U19 Clinical Trial Optional)" and is now available to receive applicants.
• Interested and eligible applicants and submit their applications by referencing the CFDA number(s): 93.242.
• This funding opportunity was created on 2020-10-15.
• Applicants must submit their applications by 2021-03-17. (Agency may still review applications by suitable applicants for the remaining/unused allocated funding in 2026.)
• Eligible applicants include: State governments, County governments, City or township governments, Special district governments, Independent school districts, Public and State controlled institutions of higher education, Native American tribal governments (Federally recognized), Public housing authorities/Indian housing authorities, Native American tribal organizations (other than Federally recognized tribal governments), Nonprofits having a 501 (c) (3) status with the IRS, other than institutions of higher education, Nonprofits that do not have a 501 (c) (3) status with the IRS, other than institutions of higher education, Private institutions of higher education, For-profit organizations other than small businesses, Small businesses, Others.

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