# Elucidating the phenome-wide impact of sex and gender on disease

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2021 · $618,182

## Abstract

PROJECT SUMMARY
The goal of this proposal is to characterize and quantify the impact of (a) sex, (b) gender-related exposures,
and (c) their interactions on heritable disease across the entire medical phenome. The growing availability of
large-scale biobanks with electronic health records (EHRs) linked to biospecimens has created a powerful, but
still relatively untapped, opportunity for research aimed at understanding the impact of sex and gender-related
exposures on human health. The National Human Genome Research Institute (NHGRI) organized the
Electronic Medical Records and Genomics (eMERGE) network which brought together investigators around
the U.S. to facilitate EHR-based genomic research and the implementation of genomic medicine. We have
created a new collaborative between two of the original eMERGE centers that leverages the resources and
existing infrastructure at each site including a combined total of over 9 million patient records and over 100,000
genotyped samples linked to EHRs. Large patient cohorts like the Vanderbilt and Northwestern populations are
critical resources that enable research on sex and gender-related exposures and their interaction at scale
across the clinical phenome. Our preliminary data demonstrates that sex and gender-related exposures
including socioeconomic position and sexual assualt trauma can be mined from the medical record. Moreover,
we show that these factors are significantly associated with ~30% of the medical phenome. Finally, we provide
evidence that sex and gender-related exposures also moderate genetic risk for complex disease. These
findings lead to our central hypothesis that sex and gender-associated exposures interact to modify
risk for heritable complex diseases. Building on this preliminary data, our first Aim is to identify and validate
the effects of sex and gender-related exposures across the clinical phenome. In Aim 2 we employ a genetic
epidemiology approach to identify sex-differences in the genetic architecture of 1,051 clinically utilized
laboratory tests. Finally, in Aim 3 we bring these two lines of inquiry together to test whether the clinical
manifestations of polygenic risk scores (PRS) are modified by sex and gender-related exposures. The
proposed research includes both quantitative and qualitative analyses aimed at investigating the genetic,
clinical, and psychosocial risk factors that contribute to the development of complex disease in extremely large
samples with phenome-wide data and linked genotypes. These sex-aware analyses can be thought of as
essential, but currently missing, pieces of the precision approach to medicine.

## Key facts

- **NIH application ID:** 10308237
- **Project number:** 1R01HG011405-01A1
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Lea K Davis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $618,182
- **Award type:** 1
- **Project period:** 2021-09-21 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10308237

## Citation

> US National Institutes of Health, RePORTER application 10308237, Elucidating the phenome-wide impact of sex and gender on disease (1R01HG011405-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10308237. Licensed CC0.

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