| Title: | EndoPRS: Incorporating endophenotype information to improve polygenic risk scores for clinical endpoints - A study in asthma |
| Journal: | American Journal of Human Genetics |
| Published: | 8 Apr 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/40203832/ |
| DOI: | https://doi.org/10.1016/j.ajhg.2025.03.008 |
Publication 14782
WARNING: the interactive features of this website use CSS3, which your browser does not support. To use the full features of this website, please update your browser.
Abstract
Polygenic risk score (PRS) prediction of complex diseases can be improved by leveraging related phenotypes. This has motivated the development of several multi-trait PRS methods that jointly model genetically correlated traits. However, these methods do not account for vertical pleiotropy, where one trait acts as a mediator for another. Here, we introduce endoPRS, a weighted lasso model that incorporates information from relevant endophenotypes to improve disease risk prediction without making assumptions about the genetic architecture underlying the endophenotype-disease relationship. Through extensive simulation analysis, we demonstrate the robustness of endoPRS in a variety of complex genetic frameworks. We also apply endoPRS to predict the risk of childhood-onset asthma in UK Biobank and All of Us by leveraging a paired genome-wide association study of eosinophil count, a relevant endophenotype. We find that endoPRS significantly improves prediction and transferability compared to many existing PRS methods, including multi-trait PRS methods MTAG and wMT-BLUP, which suggests advantages of endoPRS in real-life clinical settings.</p>
15 Keywords
- Asthma
- Child
- Endophenotypes
- Eosinophils
- Female
- Genetic Predisposition to Disease
- Genetic Risk Score
- Genome-Wide Association Study
- Humans
- Male
- Models, Genetic
- Multifactorial Inheritance
- Phenotype
- Polymorphism, Single Nucleotide
- Risk Factors
17 Authors
- Elena V Kharitonova
- Quan Sun
- Franklin Ockerman
- Brian Chen
- Laura Y Zhou
- Micah R Hysong
- Bjoernar Tuftin
- Hongyuan Cao
- Rasika A Mathias
- Paul L Auer
- Carole Ober
- Laura M Raffield
- Alexander P Reiner
- Nancy J Cox
- Samir N P Kelada
- Ran Tao
- Yun Li
1 Application
| Application ID | Title |
|---|---|
| 25953 | Transcriptome-wide Association Study of Cardiometabolic Traits in the UK Biobank Cohort |
Enabling scientific discoveries that improve human health