# Genetics of Extreme Phenotypes of OSA and Associated Upper Airway Anatomy

> **NIH NIH P01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $490,642

## Abstract

ABSTRACT
 The overall objective of Project 01 is to improve our ability to identify genetic factors relevant to OSA by
studying upper airway anatomy and OSA extreme phenotypes. There are known anatomic risk factors (reduced
craniofacial skeleton and enlarged soft tissue structures, including tongue fat) for OSA that have been shown to
be heritable. We postulate that certain OSA genetic risk variants operate via changes in anatomy, leading to
heterogeneous and extreme OSA. A foundational aspect of this hypothesis is that studying genetic associations
with intermediate anatomical phenotypes known to cause OSA will facilitate identification of genetic factors in
the presence of heterogeneous etiologies. To address the overarching hypothesis, we have three Specific Aims.
In Aim 1 we apply automatic, large-scale, high-throughput and advanced machine-learning techniques to
clinically-obtained MR (magnetic resonance) and CT (computed tomography) images of the head and neck to
quantify upper airway anatomical risk factors for OSA in patients with linked biobank data. Using these
phenotypes, we will then perform genome-wide association studies (GWAS) to identify variants related to
anatomy which, in turn, are expected to influence risk for OSA. These data will be used to generate enhanced
polygenic risk scores for OSA that incorporate genetic predictors of anatomic risk factors (e.g., tongue fat,
mandibular length). In Aim 2 we will perform in silico analyses of genetic loci to identify core biological
mechanisms and prioritize likely causal variants and genes underlying association signals. These analyses will
provide insights into the significance of GWAS loci and be directly complemented by downstream analyses in
cell-based and model systems being performed in Project 04. Finally, in Aim 3 we will use an extreme phenotype
design to identify novel anatomical associations and rare genetic variants in genes prioritized in Aims 1-2, which
will be utilized to further enhance polygenic risk scores and understanding of disease mechanisms. This proposal
has a very strong investigative team, with expertise in both OSA anatomy and genetic analysis, and uses
innovative strategies including deep anatomic phenotyping, novel machine learning algorithms, and cutting-edge
analysis approaches for identifying and interrogating OSA-susceptibility loci. Findings from this proposal will
result in a greater understanding of the impact of genetics and upper airway anatomy on OSA heterogeneity, the
downstream clinical impact of these genomic alterations, and their biological underpinnings. This deep dive into
the genetic underpinnings of quantitative anatomic intermediate traits for OSA will significantly move the field
forward by connecting genetic variation to biological mechanisms, enhance the development of polygenic risk
scores that have wide-ranging applications from early detection and treatment to screening and case
identification of OSA in the electronic medical reco...

## Key facts

- **NIH application ID:** 10880318
- **Project number:** 5P01HL160471-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Richard J. Schwab
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $490,642
- **Award type:** 5
- **Project period:** 2023-07-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10880318

## Citation

> US National Institutes of Health, RePORTER application 10880318, Genetics of Extreme Phenotypes of OSA and Associated Upper Airway Anatomy (5P01HL160471-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10880318. Licensed CC0.

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