2025/11/27 by Joshua Richland, Richland, Joshua, Tuomo Kiiskinen +12
Biochemistry, Genetics and Molecular Biology · Mathematics · #62J07 #FOS: Computer and information sciences #Gene expression and cancer classification #Genetic Associations and Epidemiology #Methodology (stat.ME) #Statistical Methods and Inference
paper · pdf · doi:10.48550/arxiv.2511.22049
openalex publication_date 2025/11/27 · openalex created_date 2025/12/03 · openalex updated_date 2026/07/28
We present a scalable framework for computing polygenic risk scores (PRS) in high-dimensional genomic settings using the recently introduced Univariate-Guided Sparse Regression (uniLasso). UniLasso is a two-stage penalized regression procedure that leverages univariate coefficients and magnitudes to stabilize feature selection and enhance interpretability. Building on its theoretical and empirical advantages, we adapt uniLasso for application to the UK Biobank, a population-based repository comprising over one million genetic variants measured on hundreds of thousands of individuals from the United Kingdom. We further extend the framework to incorporate external summary statistics to increase predictive accuracy. Our results demonstrate that uniLasso attains predictive performance comparable to standard Lasso while selecting substantially fewer variants, yielding sparser and more interpretable models. Moreover, it exhibits superior performance in estimating PRS relative to its competitors, such as PRS-CS. Integrating external scores further improves prediction while maintaining sparsity.