Genetic Re-Analysis Reveals Dual Pruning-Glutamatergic Liability in Anorexia Nervosa, Distinguished from Obsessive-Compulsive Disorder

Background: Anorexia nervosa (AN) is a severe eating disorder with substantial heritability, yet pathway-level genetic insights remain limited. Glutamatergic dysregulation and synaptic pruning have been hypothesized, but direct comparisons using large-scale polygenic data are scarce. This study re-analyzed the 2019 PGC AN GWAS to test these pathways and explore causal cognitive influences.Methods: Summary statistics from 16,992 AN cases and 55,525 controls (effective N ≈ 46,321) were examined using MAGMA for gene and competitive gene-set analysis, stratified LD-score regression for partitioned heritability, S-PrediXcan for transcriptome-wide associations in seven GTEx brain regions, and two-sample Mendelian randomization for cognitive traits. Predefined sets included glutamatergic signaling, synaptic pruning (shortened/expanded and pruning-specific excluding glutamatergic overlap), and negative controls.Results: MAGMA revealed 45 genome-wide significant genes and Bonferroni-corrected enrichment in expanded glutamatergic (p = 0.006) and pruning pathways (expanded and pruning-specific; p < 0.003), with pruning signals persisting independently. LDSC confirmed significant heritability partitioning into both pathways. TWAS showed directional effects consistent with excessive pruning (upregulated C4A; downregulated RHOA/CTNNB1) and glutamatergic hypofunction (downregulated PKA/CaMKII signaling). Mendelian randomization indicated causal risk elevation from higher genetically predicted intelligence and educational attainment (ORs 1.16–1.55). Contrasted with parallel obsessive-compulsive disorder findings emphasizing primary pruning dominance, AN exhibited a distinctive dual-pathway profile.Conclusions: These convergent results support a neurodevelopmental model of AN involving excessive adolescent synaptic pruning compounded by primary glutamatergic deficits and amplified by cognitive plasticity predispositions. This framework distinguishes AN from related disorders while suggesting novel targets for intervention.