The Department of Health and Human Services, through the National Institutes of Health (NIH), has announced a funding opportunity titled "Developing Novel Theory and Methods for Understanding the Genetic Architecture of Complex Human Traits (R01 Clinical Trial Not Allowed)." This initiative, reissued under announcement PAR-25-255, aims to support interdisciplinary research that develops innovative theories and methods to elucidate the interplay between genetic and non-genetic factors influencing complex traits. Participating NIH institutes include the National Human Genome Research Institute (NHGRI), the National Institute of Mental Health (NIMH), and the National Cancer Institute (NCI). The opportunity is open to applications focusing on robust modeling and analysis of large-scale datasets that integrate biological, social, and ecological factors, with an emphasis on diverse team collaboration.

The primary goal is to advance understanding of the genetic architecture of human traits through methods that surpass traditional allele frequency and effect size analyses. Researchers are encouraged to explore multi-scale interdependencies, non-linear interactions, and innovative computational approaches. Proposed frameworks should incorporate mechanistic models, simulations, and validations using public datasets. Special focus areas include genetic determinants of mental health (NIMH), cancer risk factors and disparities (NCI), and broadly applicable genomic models (NHGRI). Notably, applications must include a Plan for Enhancing Diverse Perspectives (PEDP), aligning research activities with principles of inclusivity and equity.

Funding for awarded projects is contingent on the NIH budget, with no specific upper limit for most projects, although NCI-related applications have a maximum budget of $350,000 per year in direct costs. The project period can extend up to five years. Eligible applicants include higher education institutions, nonprofits, small businesses, local governments, and foreign entities, among others. All applicants must be registered with the System for Award Management (SAM), Grants.gov, and eRA Commons prior to submission.

Applications will be evaluated based on significance, innovation, approach, and the strength of the interdisciplinary team. Proposals must demonstrate the scientific merit of their methods, particularly in addressing covariances across organizational levels and validating theories against empirical datasets. Plans must also ensure the ethical use and communication of findings, especially for socially sensitive traits. Proposals lacking a PEDP or focusing solely on specific traits without broader applicability will be deemed non-responsive.

Key dates include an open submission window starting January 5, 2025, with the first application due on February 5, 2025. Subsequent deadlines follow standard NIH cycles through October 5, 2026. Applicants are strongly encouraged to submit letters of intent by the earliest submission date to facilitate planning. For assistance, NIH provides contacts for programmatic, peer review, and administrative inquiries.

This initiative represents a significant opportunity for researchers to develop transformative methods that integrate natural and social sciences in the study of human genetic variation. Successful applicants will contribute to a deeper understanding of health and disease mechanisms, with potential benefits for precision medicine and public health. Interested parties should consult the NIH Grants Policy Statement and the specific NOFO instructions to ensure compliance and maximize the competitiveness of their submissions.