ArticlemedRxiv : the preprint server for health sciences2026
Nonlinear dynamic genetic regulation identifies peripheral drivers of neurodegenerative disease progression.
Article in medRxiv : the preprint server for health sciences, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
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
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