# Bidirectional validation of loci associated with suicide risk using the Million Veteran Data and postmortem human brain

> **NIH VA I01** · JAMES J PETERS VA  MEDICAL CENTER · 2024 · —

## Abstract

PROJECT SUMMARY:
 Veterans are at disproportionately higher risk of suicide than civilians. Novel approaches towards development
and improvement in delivery of personalized medicine using genomic approaches for our Veterans at-risk is
mission critical. There is no sensitive and specific method to determine who is at risk for suicide, although such a
test would help clinicians to save lives. This research team have contributed to the accumulating evidence of altered
immune response in suicide. We have detected elevated levels of pro-inflammatory cytokines and altered
epigenetic and gene transcript patterns of genes related to inflammation in blood and brain samples of at-risk
suicidal patients and in brains from individuals who died by suicide. We also found altered distributions of activated
microglia and elevated densities of vessel-associated phagocytes in prefrontal cortex white matter after suicide.
The presence of these abnormalities at autopsy strongly points to immunological malfunction in suicide. Therefore,
we seek to investigate at a cellular level the white matter abnormalities in suicide through epigenetic and
transcriptional studies of glial cells (specifically microglia and oligodendrocytes) involved in neuroimmune
processes and link these genomic alterations to identify genes and genetic variants associated with suicidal
behavior in at-risk Veterans participating in the Million Veteran Program (MVP). Herein, we propose a set of aims
that include: (1) investigation of neuroinflammatory markers in white matter tissue specimens in 168 well-
characterized postmortem brains from suicide decedent cases and controls who died by accidental causes, (2)
investigation of white matter oligodendrocyte and microglia transcriptional regulatory changes associated with
suicide within the same post mortem specimens, (3) leveraging data from the MVP participants and postmortem
brains from suicide decedents to derive genetically regulated gene expression in glia for development of a
polygenic transcriptional risk score (PTRS) for suicide with improved cross ancestry portability relative to
standard polygenic risk scores, and (4) in an exploratory fashion, examine whether incorporation of DNA
methylation data can improve suicide risk prediction using similar analytic approaches as in Aim 3. It is likely that
these line of investigations will identify genetic and transcriptionally regulated abnormalities that could improve
suicide risk predictions in Veterans, and across underrepresented populations.

## Key facts

- **NIH application ID:** 10805790
- **Project number:** 1I01BX006069-01A2
- **Recipient organization:** JAMES J PETERS VA  MEDICAL CENTER
- **Principal Investigator:** FATEMEH G HAGHIGHI
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2024-04-01 → 2028-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10805790

## Citation

> US National Institutes of Health, RePORTER application 10805790, Bidirectional validation of loci associated with suicide risk using the Million Veteran Data and postmortem human brain (1I01BX006069-01A2). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10805790. Licensed CC0.

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