Shared genetic architecture between DTI-ALPS traits and neurodegenerative diseases.

INTRODUCTION: Diffusion tensor image analysis along the perivascular space (DTI-ALPS) index is associated with neurodegenerative diseases (NDDs), but its shared genetic basis with NDDs remains unclear. METHODS: By integrating genome-wide association datasets for three DTI-ALPS traits and seven NDDs, we quantified polygenic overlap using MiXeR, identified shared loci using conditional and conjunctional false discovery rate analyses, and performed gene mapping, enrichment, temporal expression, and transcriptome-wide association analyses. RESULTS: DTI-ALPS traits showed widespread but heterogeneous polygenic overlap with NDDs. We identified 22 shared loci, including novel associations implicating GAK and SIAH3, with the strongest convergence at 17q21.31. Shared loci mapped to 183 protein-coding genes enriched in the endolysosomal system and microtubule cytoskeleton. These genes showed similar temporal expression patterns, and 45 were associated with both DTI-ALPS traits and NDDs. DISCUSSION: These findings reveal a shared genetic architecture between DTI-ALPS traits and NDDs, highlighting mechanisms that may contribute to their overlap.