A Module-Level Polygenic Risk Score-Based NetWAS Framework for Identifying AD Genetic Modules Mediated by Amygdala: An ADNI Study

Network-based GWAS (NetWAS) has advanced brain imaging research by identifying genetic modules associated with brain alterations. However, how imaging risk genes exert functions in brain diseases, particularly their mediation through imaging quantitative traits (iQTs), remains underexplored. We propose a module-level polygenic risk score (MPRS)-based NetWAS framework to uncover genetic modules associated with Alzheimer's disease (AD) through the mediation of an iQT, using amygdala density as a case study. Our framework integrates genotype data, brain imaging phenotypes, clinical diagnosis of AD, and protein-protein interaction (PPI) networks to identify AD-relevant modules (ADMs) influenced by iQT-associated genetic variants. Specifically, we conducted a genome-wide association study (GWAS) of amygdala density (N=1515) to identify variants associated with iQT. These variants were mapped onto a PPI network and network propagation was performed to prompt amygdala modules. The meta-GWAS of AD (N1=63,926; N2=455,267) was used to calculate MPRS to further identify AD-relevant modules (ADMs). Four modules that showed significant differences in MPRS between AD and controls were identified as ADM. Post-hoc analyses revealed that these ADMs demonstrated strong modularity, showed increased sensitivity to early stages of AD, and significantly mediated the link between ADMs and AD progression through the amygdala. Furthermore, these modules exhibited high tissue specificity within the amygdala and were enriched in AD-related biological pathways. Our MPRS-based framework bridges genetics, intermediate traits, and clinical outcomes and can be adapted for broader biomedical applications.