polygenic risk score predicting post stroke mortality

The following manuscript was poster presented at ASHG2021 and published in Scientific Report (https://doi.org/10.1038/s41598-022-16510-x)

See behind the paper at https://healthcommunity.nature.com/posts/generating-polygenic-risk-scores-from-gene-sets-why-how

Predicting Mortality Among Ischemic Stroke Patients Using Pathways-Derived Polygenic Risk Scores

Jiang Li, Durgesh Chaudhary, Christoph J Griessenauer, David J Carey, Regeneron Genetics Center, Ramin Zand, Vida Abedi

Geisinger Healthscare System

Objective: Our previous study identified pathway-specific polygenic risk scores (PRSs) associated with ischemic stroke (IS). We aim to determine whether IS-related PRSs are also associated with and further predict 3-year all-cause mortality.

Methods: 1,756 IS with European ancestry were identified by leveraging Electronic Health Record and chart review confirmation. The cohort was randomly split into discovery (n=1,226) and holdout (n=530) groups with 3-year post-event observations. Univariate Cox proportional hazards regression model (Coxph) was used for primary screening of individual prognostic PRSs. Only the significantly associated PRSs and clinical risk factors with the same direction for a causal relationship with IS were used to construct a multivariate Coxph. Feature selection was conducted by LASSO method.

Results: The univariate Coxph identified 31 out of 333 Gene Ontology (GO) pathway-specific PRSs associated with mortality (p<0.1). After feature selection, a prediction model with 11 disease-associated pathway-specific PRSs outperformed the base model, as demonstrated by a higher concordance index (0.751, 95%CI [0.693-0.809] versus 0.729, 95%CI [0.676-0.782]) in the holdout sample. A PRS derived from endothelial cell apoptosis showed independent predictability in the multivariate Coxph (Hazard Ratio=1.193 [1.027-1.385], p=0.021). These PRSs fine-tuned the model by better stratifying high, intermediate, and low-risk groups. Several pathway-specific PRS were associated with certain clinical risk factors in an age-dependent manner and further confirmed some known etiologies of IS and all-cause mortality.

Conclusions: Pathway-specific PRSs for IS are associated with all-cause mortality and the integrated multivariate risk model provides prognostic value in this context.