Background Major depressive disorder (MDD) and amyotrophic lateral sclerosis (ALS) are clinically distinct yet show intriguing comorbidity, often early in the disease course. We hypothesized a shared microglia-mediated synaptic pruning vulnerability, amplified differently by disorder-specific pathways, autophagy collapse in ALS versus RNA processing and immune dysregulation in MDD, thereby creating a biological continuum. Methods Using large-scale genome-wide association study (GWAS) from the Psychiatric Genomics Consortium (PGC) (MDD, N=829,249) and Project MinE (ALS, effective N=87,381), we applied Multi-marker Analysis of GenoMic Annotation (MAGMA) for gene- and set-level associations, Gene Set Enrichment Analysis (GSEA)/Differential Gene Set Enrichment Analysis (DGSEA) for pathway enrichment and differential enrichment, S-PrediXcan transcriptome-wide association study (TWAS) across 14 GTEx tissues, and linkage disequilibrium score regression (LDSC) for partitioned heritability and cross-trait genetic correlation. Eight gene sets (housekeeping controls, monoaminergic, neurosteroid, glutamatergic, synaptic pruning, autophagy/protein quality, RNA processing, and immune/neuroinflammation) were tested for convergence and divergence. Results Synaptic pruning emerged as the sole consistent cross-disorder signal, with robust enrichment in MDD (LDSC 1.32×, GSEA NES=1.415, p=0.0001) and nominal but consistent signals in ALS (GSEA NES=1.40, p=0.011; TWAS HLA-B). Autophagy dominated ALS (LDSC 2.20×, TWAS C9orf72 Z=13.43, GSEA NES=1.94) but was depleted in MDD. RNA processing and immune pathways were prominent in MDD (LDSC 1.48× and 1.89×, respectively), with only nominal signals in ALS. Overall genetic correlation was near zero (rg=-0.044, p=0.196). Conclusions These findings support a microglial pruning continuum model: shared pruning liability as the foundation, with autophagy failure driving ALS neurodegeneration and RNA/immune dysregulation shaping MDD stress sensitivity. The low rg explains the modest overlap, while pathway specificity accounts for comorbidity and divergent progression. This framework offers testable predictions for polygenic risk score (PRS) stratification, complement modulators in ALS mood subsets, and microglial therapies in treatment-resistant MDD.
