# Decoding the Sex-Specific Biological Mechanisms of Psychiatric Disorders Using Genome-Wide Analyses

> **NIH NIH F32** · YALE UNIVERSITY · 2021 · $52,755

## Abstract

Abstract
 Phenotypic expression of psychiatric disorders (age of onset, severity, and comorbidities) often vary
between sexes. Genetic data from large-scale genome wide association studies (GWAS) establish that sex-
differences also exist in the genetic contribution to psychiatric disorders. We have previously demonstrated that
in sex-stratified cohorts, ADHD is genetically correlated with the behavioral phenotypes risk taking and age at
first sexual intercourse. Furthermore, the forkhead box P2 (FOXP2) gene, involved in human complex speech,
was significantly associated with ADHD in females, but is not detected in males. Genetic correlation results
combined with GWAS signatures suggest that sex differences in psychiatric disorders may be caused by sex
differences in biological mechanisms of the nervous system (e.g., FOXP2 expression is hormonally regulated by
androgens, which themselves demonstrate clear sex-specific expression). We hypothesize that genetic
liability to psychiatric disorders is affected by sex-specific mechanisms modulating nervous system
traits. To address this hypothesis, we propose four specific aims addressing (Aim 1) the genetic correlation and
overlap between sex-stratified psychiatric disorders and related traits, (Aim 2) the phenome-wide association of
1,202 genome-wide significant nervous system SNPs with the behavioral, anthropometric, and disease traits in
the UK Biobank and other repositories, (Aim 3) causal relationships between psychiatric disorders and nervous
system traits using a novel combination of latent causal variable and Mendelian randomization analyses, and
(Aim 4) enrichment of biological pathways and gene expression signatures in sex-stratified psychiatric disorders.
We expect to decipher the nuanced genetic correlations and causal relationships between sex-dichotomized
psychiatric phenotypes and the human phenome. Elucidating the underlying mechanisms and gene expression
signatures linking these traits also may contribute to developing pharmacological and nonpharmacological
therapies for various disorders and provide biological evidence supporting the use of such therapies in
combination with other interventions for mental health and/or psychiatric disorders.
 Through the described training plan, mastery will be developed in four key areas critical for a future career
in academia. These training areas are (1) Build a strong computational biology and bioinformatics skill set, (2)
Develop an operational knowledge of psychiatry and the genetics of complex traits, (3) Mentor trainees and
develop my teaching portfolio, and (4) Improve written and oral communication and presentation skills. To
accomplish these goals, a group of Co-Sponsors has been identified who will substantively contribute to the
proposed research and training trajectories, a series of bioinformatics, bioethics, and pedagogy workshops and
short-courses will be attended, and formal college-teaching certification will be obtained through a ...

## Key facts

- **NIH application ID:** 10236269
- **Project number:** 5F32MH122058-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** FRANK WENDT
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $52,755
- **Award type:** 5
- **Project period:** 2020-05-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10236269

## Citation

> US National Institutes of Health, RePORTER application 10236269, Decoding the Sex-Specific Biological Mechanisms of Psychiatric Disorders Using Genome-Wide Analyses (5F32MH122058-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10236269. Licensed CC0.

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