# Investigating the Genomic Architecture of Anxiety and Overlap with Mental Health Disorders in the Million Veteran Program.

> **NIH VA IK2** · VA CONNECTICUT HEALTHCARE SYSTEM · 2022 · —

## Abstract

Project Summary/Abstract
 Anxiety disorders cause significant distress on a personal level, and cost >
$40,000,000,000 annually in the United States alone. They are common, with lifetime
prevalence estimated at about 28.8%. These disorders are frequently co-morbid with
other psychiatric disorders such as major depression (MDD) and post-traumatic stress
disorder (PTSD). These disorders may share commonalities in the underlying genetic
architecture that influences the risk for disease. More than 90% of patients with
generalized anxiety disorder (GAD) present with additional comorbid psychiatric
diagnoses. PTSD, sometimes considered an anxiety disorder, has been shown in a 20-
year longitudinal cohort of veterans to present more commonly as comorbid with anxiety
and/or depression than as a lone diagnosis. Up to 90% of individuals with PTSD may
present with comorbid anxiety disorders. We propose to study the underlying genetic
architecture of anxiety disorders and how they overlap, interact with and influence other
co-morbid disorders. We will perform genome-wide association studies in the Million
Veteran Program sample (~200,000 informative individuals and growing), UK Biobank
(~100,000 individuals), and All of Us (~36,000 informative individuals and growing)
using anxiety traits to investigate the genetic architecture of anxiety disorders. We will
perform sex and ancestry stratified as well as joint-analyses to search for sex or
ancestry specific variation. Sex-chromosome-wide association studies will be
conducted in the same samples. The sex chromosomes (and mitochondrial DNA) are
understudied in genetics, with most studies focused on the autosomes. This is despite
evidence for a role for the polyamine system in depression, stress disorders and suicide
and the gene for the rate-limiting enzyme in polyamine catabolism,
“spermidine/spermine N1-acetyltransferase 1” (SAT1) being found the X-chromosome.
It is critical to include the sex-chromosomes for a complete picture of the genetic
architecture of disease. Finally, we will seek to use functional genomics, polygenic risk
scoring, and causal inference to assay the functional importance of lead findings,
genetic overlap and liability to related traits, and potential for clinical translation of
findings.

## Key facts

- **NIH application ID:** 10436927
- **Project number:** 5IK2BX005058-02
- **Recipient organization:** VA CONNECTICUT HEALTHCARE SYSTEM
- **Principal Investigator:** Daniel F Levey
- **Activity code:** IK2 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2021-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10436927

## Citation

> US National Institutes of Health, RePORTER application 10436927, Investigating the Genomic Architecture of Anxiety and Overlap with Mental Health Disorders in the Million Veteran Program. (5IK2BX005058-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10436927. Licensed CC0.

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