Nonlinear dynamic genetic regulation identifies peripheral drivers of neurodegenerative disease progression

The dynamic genetic regulation of gene expression during the progression of common neurodegenerative diseases (NDDs) remains poorly characterized, obscuring the genetic architecture of longitudinal clinical traits. Here, we present 2sGen-GPS, a two-stage genetic Granger temporal causality framework designed to integrate genetic variants, intermediate longitudinal molecular traits, and disease progression phenotypes. In the discovery stage, we utilized multivariate polynomial temporal genetic association (MPTGA) analysis of peripheral blood to identify 774,533 time-dependent cis-eQTLs (11,936 eGenes), enabling the imputation of individual-level longitudinal expression trajectories. In the second stage, these imputed profiles were linked to NDD phenotypes to infer temporal causal relationships. Applying 2sGen-GPS to Parkinson's disease multi-omics cohorts, we identified a peripheral-to-central regulatory axis; specifically, the rs11241912-driven temporal expression of <i>C5orf63</i> exhibits a lagged causal association with cerebrospinal fluid LRP1 levels and motor symptom progression. Cross-regional single-cell analysis further revealed that rs11241912 carriers harbor a localized compensatory signature in excitatory neurons of the globus pallidus interna, characterized by the up-regulation of dopamine receptor signaling pathways. Extending 2sGen-GPS to Alzheimer's disease, we identified 328 genes linked to cognitive decline and prioritized drug compounds capable of reversing these expression signatures. Our study elucidates how dynamic genetic effects shape the trajectories of NDD-related traits and nominates peripherally accessible, causal genes as promising therapeutic targets for modulating disease progression.