A transcriptome-wide association study (TWAS) gene-set analysis of obsessive-compulsive disorder identified selective enrichment of the KEGG_AUTOPHAGY_ANIMAL pathway over an antidepressant-related gene comparator (NES = 1.166, p = 0.042, dNES = +0.2097). The signal held after removing overlapping genes and was driven by a signaling-execution module — MAPK3, MAP1LC3A, MAP2K1, MTOR, ATG2A, ATG10, MAPK8, BAD, and CALCOCO2 — rather than canonical ATG genes alone. Mann-Whitney U testing confirmed higher absolute Z-score distributions in the autophagy set (p = 0.047).
OCD's treatment-resistant minority — roughly 40–60% of patients achieve only partial remission on SSRIs plus exposure-response prevention — has long demanded mechanistic frameworks beyond monoamine signaling. This finding slots meaningfully into emerging neurobiology: cortical glutamatergic neurons and striatal medium spiny neurons, previously implicated in OCD GWAS, carry unusually high synaptic and mitochondrial energy loads, precisely the cellular contexts where autophagy and NAD⁺-dependent quality control matter most. The MTOR overlap with antidepressant genes is independently notable, given rapamycin's known autophagy-inducing and antidepressant-adjacent effects in animal models.
Critically, this is a single-center hypothesis-generating analysis from a small independent group, using indirect TWAS-derived statistics rather than direct functional data. Effect sizes are modest and multiple-testing burden is substantial. The author appropriately cautions against inferring any clinical utility for NMN or NAD⁺ precursors in OCD. The value here is directional: autophagy and mitochondrial quality-control biology deserve formal functional investigation as OCD stratification targets.