Analyses of GWAS signal using GRIN identify additional genes contributing to suicidal behavior

Sullivan, Kyle A.; Lane, Matthew; Cashman, Mikaela; Miller, J. Izaak; Pavicic, Mirko; Walker, Angelica M.; Cliff, Ashley; Romero, Jonathon; Qin, Xuejun; Mullins, Niamh; Docherty, Anna; Coon, Hilary; Ruderfer, Douglas M.; Garvin, Michael R.; Pestian, John P.; Ashley-Koch, Allison E.; Beckham, Jean C.; McMahon, Benjamin; Oslin, David W.; Kimbrel, Nathan A.; Jacobson, Daniel A.; Kainer, David

doi:10.1038/s42003-024-06943-7

Title: Analyses of GWAS signal using GRIN identify additional genes contributing to suicidal behavior

Journal Article · 21 October 2024 · Communications Biology

DOI: https://doi.org/10.1038/s42003-024-06943-7 · OSTI ID:2474785

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^[2]; Cashman, Mikaela ^[3]; Miller, J. Izaak ^[1];

^[1]; Walker, Angelica M. ^[2]; Cliff, Ashley ^[2]; Romero, Jonathon ^[2];

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^[1]; Pestian, John P. ^[8];

^[9]; Beckham, Jean C. ^[4]; McMahon, Benjamin ^[10]; Oslin, David W. ^[11];

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Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)
Univ. of Tennessee, Knoxville, TN (United States). Bredesen Center for Interdisciplinary Research and Graduate Education
Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States); Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Durham Veterans Affairs Health Care System, NC (United States); Duke Univ., Durham, NC (United States)
Icahn School of Medicine at Mount Sinai, New York, NY (United States)
Univ. of Utah, Salt Lake City, UT (United States)
Vanderbilt Univ., Nashville, TN (United States)
Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States); Univ. of Cincinnati, OH (United States)
Duke Univ., Durham, NC (United States)
Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
VISN 4 Mental Illness Research, Education, and Clinical Center, Center of Excellence, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA (United States); Univ. of Pennsylvania, Philadelphia, PA (United States)
Durham Veterans Affairs Health Care System, NC (United States); Duke Univ., Durham, NC (United States); VA Health Services Research and Development Center of Innovation to Accelerate Discovery and Practice Transformation, Durham, NC (United States)
Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States); Univ. of Queensland, Brisbane, QLD (Australia)

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.

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Research Organization:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)

Sponsoring Organization:: Brain & Behavior Research Foundation (BBRF); National Institutes of Health (NIH); USDOE Office of Science (SC), Biological and Environmental Research (BER); United States Department of Veterans Affairs (VA)

Grant/Contract Number:: AC05-00OR22725

OSTI ID:: 2474785

Journal Information:: Communications Biology, Journal Name: Communications Biology Journal Issue: 1 Vol. 7; ISSN 2399-3642

Publisher:: Springer NatureCopyright Statement

Country of Publication:: United States

Language:: English

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