# Networks Tools to Understand Sex- and Gender-Specific Drivers of Disease

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2021 · $522,751

## Abstract

ABSTRACT
Complex human diseases including chronic obstructive pulmonary disease and many human cancers, exhibit
strong differences between males and females in risk, disease progression, and response to therapy. Our
previous work in normal and disease tissues from males and females has shown that while there are rarely
significant differences in genetic associations or gene expression that can explain the observed sex-based
differences, modeling gene regulatory processes can lead to key insights into the likely drivers of sex differences
in health and disease. This suggests that both sex-based factors and epigenetic variability likely work together
to help define risk and response. This observation is further supported by the fact that sex-based differences are
not static but rather evolve over the course of an individual’s lifespan, during which epigenetic state and hormonal
regulation of gene expression likely change in related to gender-associated factors. In this application, we
propose to merge the threads of DNA methylation variation, gene regulatory modeling, and sex-based regulatory
network assessments to better understand the factors that drive the observed sex and gender-related differences
in human diseases. We envision three specific aims within the context of our research plan, including:
Developing tools for the inclusion of sex chromosomes in network models and methods for comparing
male and female networks; Refinement of network tools for setting epigenetic priors and inclusion of
DNA methylation data as a primary data for studying sex differences informed by gender; and
Application to diseases with sex differences, including COPD and lung cancer as primary examples. We
expand network methods to develop tools to better incorporate the effects of the allosomes in the process of
gene regulation. This is particularly important as we have discovered current methods for normalization of sex
chromosome gene expression can influence observed gene regulatory interactions. We will refine tools to
incorporate epigenetic regulation into our sex-specific models, exploring how DNA methylation may capture
gender to influence gene regulatory network structure and disease risk. Understanding the sex- and gender-
related differences in this regulatory landscape will help us better understand human diseases and highlight
approaches to identify sex-aware therapeutic targets. This proposal is highly responsive to the goals of RFA-
OD-19-029: The Intersection of Sex and Gender Influences on Health and Disease as it will investigate a
systems/network based approach to investigating sex and gender influences in human disease, as well as
providing publicly available tools and networks to facilitate sex and gender research.

## Key facts

- **NIH application ID:** 10307441
- **Project number:** 1R01HG011393-01A1
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** DAWN L DEMEO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $522,751
- **Award type:** 1
- **Project period:** 2021-09-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10307441

## Citation

> US National Institutes of Health, RePORTER application 10307441, Networks Tools to Understand Sex- and Gender-Specific Drivers of Disease (1R01HG011393-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10307441. Licensed CC0.

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