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Research / Funded grants

2021 Young Investigator

Understanding Suicide through Postmortem Targeted Brain Multi-omics

2 research findings from this AFSP-funded study.

Research finding · June 2025

We are deepening our understanding of biological research through genetic studies

Understanding why some individuals are more vulnerable to suicide than others is a key challenge in prevention efforts — particularly in groups with higher rates like military service members. While research shows that suicidal behavior can run in families, much of the genetic work to date has focused on common genetic variants (genetic differences that are widespread) with small effects. Far less is known about the impact of rare, protein-altering mutations — especially in individuals from diverse backgrounds. Identifying these genetic signals (patterns in our DNA that may contribute to suicide risk) could offer new insights into the biology of suicide and inform future tools for prevention and care.

With the funds from his AFSP grant, Dr. Matthew Girgenti used whole-genome sequencing (a method that analyzes nearly every letter of a person’s DNA) in over 13,000 active-duty U.S. Army soldiers, including nearly 1,000 with a history of suicide attempt. They discovered 19 genes with rare, protein-altering changes that appeared more often in those who had attempted suicide. Several of these genes — such as RGS7BP, CIB2, and ACTR6 — have shown altered expression in brain tissue from individuals who died by suicide. These associations were observed across racial and ethnic groups. The findings deepen our understanding of the biological roots of suicide risk and point to new areas for study.

Citation: Wilkerson, M. D., Hupalo, D., Gray, J. C., Zhang, X., Wang, J., Girgenti, M. J., Alba, C., Sukumar, G., Lott, N. M., Naifeh, J. A., Aliaga, P., Kessler, R. C., Turner, C., Pollard, H. B., Dalgard, C. L., Ursano, R. J., & Stein, M. B. (2024). Uncommon Protein-Coding Variants Associated With Suicide Attempt in a Diverse Sample of U.S. Army Soldiers. Biological psychiatry, 96(1), 15–25. https://doi.org/10.1016/j.biopsych.2023.12.008

This finding comes from an AFSP-funded study — see the grant below ↓

Research finding · January 2024

Trauma exposure in Veterans can moderate genetic risk for suicidal thoughts and behaviors

Genetic researchers in the field of suicide prevention research have shown that risk for suicidal behaviors is partly hereditary. Previous studies have identified specific genes that are associated with an individual’s genetic predisposition for suicide. Researchers use statistical modeling to combine these identified genes to estimate a level of genetic risk, which is known as a polygenic (i.e., influenced by two or more genes) risk score. Keeping in mind that genetics are not a sole contributor to suicide, factors related to an individual’s environment, such as exposure to traumatic events, likely also affects the development of suicidal behavior.

To explore this further in the context of Veterans and trauma exposure, Dr. Matthew Girgenti and his team analyzed genetic and environmental data from the National Health and Resilience in Veterans Study (NHRVS). Data were drawn from 1,664 Veterans, of which 555 had seen combat and 85 had made a suicide attempt. The Veterans submitted saliva samples for genotyping and completed a web-based survey that assessed suicide attempt history and trauma exposure. Using a suicide attempt-specific statistical model, Dr. Girgenti calculated a polygenic risk score for each person, which was significantly associated with individuals who made a suicide attempt. After adding trauma exposure to his model, he found that a combination of a high polygenic risk score and high exposure to trauma together was best at identifying who had made a suicide attempt. Further research is needed to learn more and clarify the contributions of genetic liability and trauma to suicide behavior.

Citation: Nichter B et al (2023). Genetic liability to suicidal thoughts and behaviors and risk of suicide attempt in US military veterans: moderating effects of cumulative trauma burden. Psychological Medicine 53,6325–6333. https://doi.org/10.1017/S0033291722003646

This finding comes from an AFSP-funded study — see the grant below ↓

The grant behind this work · 2021 Young Investigator

Understanding Suicide through Postmortem Targeted Brain Multi-omics

Matthew Girgenti, PhD

Matthew Girgenti, Ph.D.

Yale School of Medicine

Mentor: John Krystal, M.D.

Amount awarded
$90,000 Focus area
Genetic

Inside the Research

The majority of epidemiologic studies have shown PTSD is associated with an increased risk of suicide. However, the molecular determinants of both traits are not well understood and predictive biomarker discovery as well as therapeutic development in this area is still in its infancy. The goal of this project is to elucidate the molecular determinants that contribute to the development of PTSD and suicidal behavior using single cell genomics in postmortem brain tissue.

Full scientific abstract

Suicide is among the most prevalent causes of death in developed countries and the leading or second leading cause of death among young people. Psychiatric disorders are strongly linked to suicidal behavior. To date there are have been several genome-wide association studies (GWASs) on suicide attempt. These studies have examined individuals with comorbid psychiatric disorders (e.g. MDD) and have compared attempters with nonattempters to test for genetic variants that might contribute independently to suicide attempt. These studies have revealed inconsistent genetic findings and infrequent replication across studies, raising the possibility of different molecular changes in suicides with different psychiatric comorbidities. It is critical to identify the underlying neurobiology of suicide particular to specific psychiatric disorders because of the very significant medical and psychiatric morbidity and mortality, and the promise of new therapeutics based on its biological underpinnings. Despite its clinical importance, there have yet to be human biology-focused postmortem studies of well-matched cases and controls for suicide between major psychiatric disorders.

This proposal seeks to perform a postmortem, multi-omic study of brains from 75 total subjects: PTSD (n=15), MDD (n=15), PTSD-S (PTSD + suicide, n=15), MDD-S (MDD + suicide, n=15) and normal controls (n=15). We will focus on targeted brain regions with known differential association with suicide risk as a function of identified intermediate phenotypes (comorbid PTSD and MDD) including the amygdala and the prefrontal cortex. We will determine differential mRNA expression and chromatin assembly accessibility in single nuclei isolated across brain areas. We hypothesize that single cell-type, multi-modal genomic analysis across brain regions will reveal 1.) that pathways in MDD and PTSD will be differentially identified in specific cell types in suicide subjects with comorbid MDD and PTSD and 2.) that genome-wide exploratory approaches will identify novel epigenomically regulated gene pathways. Our main outcome will be a model of cell type-specific genetic, epigenomic, and transcriptomic profiles of brain regions from cases vs. controls. These data will allow an understanding of the cell type-specific and psychobiological subtypes of suicide transcriptional and epigenomic profiles, and findings will be integrated with detailed multi-omic data from other studies and genome wide-association studies of suicide.

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