Abstract
Genome-wide association studies (GWAS) identify genetic variants underlying complex traits but are limited by stringent genome-wide significance thresholds. We present GRIN (Gene set Refinement through Interacting Networks), which increases confidence in the expanded gene set by retaining genes strongly connected by biological networks when GWAS thresholds are relaxed. GRIN was validated on both simulated interrelated gene sets as well as multiple GWAS traits. From multiple GWAS summary statistics of suicide attempt, a complex phenotype, GRIN identified additional genes that replicated across independent cohorts and retained biologically interrelated genes despite a relaxed significance threshold. We present a conceptual model of how these retained genes interact through neurobiological pathways that may influence suicidal behavior, and identify existing drugs associated with these pathways that would not have been identified under traditional GWAS thresholds. We demonstrate GRIN’s utility in boosting GWAS results by increasing the number of true positive genes identified from GWAS results.
| Original language | English |
|---|---|
| Article number | 1360 |
| Journal | Communications Biology |
| Volume | 7 |
| Issue number | 1 |
| DOIs | |
| State | Published - Dec 2024 |
Funding
This research used resources of the Oak Ridge Leadership Computing Facility at the Oak Ridge National Laboratory, which is supported by the Office of Science of the U.S. Department of Energy under Contract No. DE-AC05-00OR22725. This work was sponsored by MVP CHAMPION (DAJ), NIH grants DA041913 (DAJ), DA051908 (DAJ), MH116269 (DMR), MH121455 (DMR), Brain & Behavior Research Foundation (NARSAD Young Investigator Award No. 29551 [NM]), Department of Veterans Affairs (VA) Clinical Science Research and Development (CSR&D) grants lK6BX003777 (JCB, NAK, DWO), and the VA Million Veteran Program (MVP), and the Australian Research Council Center of Excellence for Plant Success in Nature & Agriculture (project number CE200100015) (DK). This publication does not represent the views of the VA or the United States Government. We also thank and acknowledge MVP (Office of Research and Development, Veterans Health Administration), the MVP Suicide Exemplar Workgroup, and the ISGC for their contributions to this manuscript. A complete listing of contributors from the MVP, MVP Suicide Exemplar Workgroup, and ISGC is provided in the Supplemental Information. This manuscript has been authored by UT-Battelle, LLC under Contract No. DE-AC05-00OR22725 with the U.S. Department of Energy. The United States Government retains and the publisher, by accepting the article for publication, acknowledges that the United States Government retains a non-exclusive, paid-up, irrevocable, world-wide license to publish or reproduce the published form of this manuscript, or allow others to do so, for United States Government purposes. The Department of Energy will provide public access to these results of federally sponsored research in accordance with the DOE Public Access Plan (http://energy.gov/downloads/doe-public-access-plan).
| Funders | Funder number |
|---|---|
| Health Services Research and Development | |
| United States Government | |
| VA Million Veteran Program | |
| DOE Public Access Plan | |
| Marathi Vidnyan Parishad | |
| Idaho Space Grant Consortium | |
| Office of Research and Development | |
| Brain and Behavior Research Foundation | |
| Office of Science | |
| U.S. Department of Veterans Affairs | |
| CSR&D | lK6BX003777 |
| Australian Research Council Centre of Excellence for Plant Success in Nature and Agriculture | CE200100015 |
| U.S. Department of Energy | DE-AC05-00OR22725 |
| National Institutes of Health | DA041913, DA051908, MH116269, MH121455 |
| NARSAD | 29551 |
