SuSiE 2.0: improved methods and implementations for genetic fine-mapping and phenotype prediction

Sum of Single Effects regression (SuSiE) has become widely adopted for genetic fine-mapping, yet its original implementation faces architectural limitations that hinder extensibility and performance. We present SuSiE 2.0, featuring a modular redesign for extensibility, up to 5x speed improvements for summary statistics applications, and several useful extensions including SuSiE-ash, a new method that improves calibration when strong signals coexist with moderate effects. Simulations and real data benchmarks demonstrate performance across diverse genetic architectures, highlighting improved calibration of SuSiE-ash for fine-mapping under complex polygenic backgrounds with 1.5–3x FDR reduction while maintaining power, and revealing SuSiE-based methods as effective yet underappreciated tools for TWAS prediction.