# A novel approach for understanding how sex influences polygenic score associations

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2024 · $509,426

## Abstract

Polygenic scores — summaries of the genomic contribution to risk and resilience for biomedical
traits — are an emerging and promising approach for clinical risk assessment and personalized
medicine. All communities do not currently benefit from insights gained via studies of polygenic
scores because these groups have not been sufficiently characterized in this research. This must be addressed through recruitment as well as consideration of the effects of heterogeneity during
analysis. For example, our preliminary data show striking dissociations in suicide risk as
influenced by polygenic scores. Notably, these opposing associations are apparent only when sex-related effects are modeled, underscoring the imperative to parsing the heterogeneity of such
associations by sex. These results suggest value in genomic research in understanding both innate risk and resilience related to sex. The promise of genomic research informed by sex depends on the ability to capture the variability within each sex (e.g., facial morphology, autism-related sex differences). This difficulty results in many studies not sufficiently accounting for sex differences in genetic research. We propose to close this gap by calibrating and genetically characterizing a novel and broadly disseminable method for studying key sex-related differences for genomic research and broader research applications. First, we will facilitate partnership between scientists and stakeholders, and improve communication in this field of research, by building on our established community partnerships with a purposively recruited stakeholder panel (N=50). Next, we will validate the stakeholder-refined method in a large sample (N=10,000) of genotyped neurotypical and neurodivergent adults. Finally, to demonstrate proof-of-principle for how sex contextualizes patterns of association with polygenic scores, we will measure key health outcomes (both mental and physical), in a large, genetically informed sample enriched for neurodiversity (e.g., autism). The proposed research will provide value by seeking a better understanding of how polygenic scores apply across the sexes.

## Key facts

- **NIH application ID:** 10914060
- **Project number:** 5R01HG012697-03
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Jacob James Michaelson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $509,426
- **Award type:** 5
- **Project period:** 2022-09-26 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10914060

## Citation

> US National Institutes of Health, RePORTER application 10914060, A novel approach for understanding how sex influences polygenic score associations (5R01HG012697-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10914060. Licensed CC0.

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