Rare Genetic Variants in Antisense Long Non-coding RNAs Contribute to Obsessive-Compulsive Disorder

Obsessive-compulsive disorder (OCD) is a prevalent neuropsychiatric disorder with an incompletely characterized genetic basis, hindering targeted treatment approaches. Using whole-genome sequencing from the All of Us cohort (2,276 OCD cases, 13,517 controls), we assessed rare variants within antisense long non-coding RNAs (lncRNAs). OCD cases exhibited significant enrichment of these variants, particularly within evolutionarily constrained antisense transcripts (relative risk = 1.52, P = 0.005). Burden analyses identified two lncRNAs robustly associated with OCD: A2ML1-AS1 (OR = 4.5, P = 0.001) and NFIB-AS1 (OR = 3.6, P = 0.002). Rare variants in these lncRNAs localized to regulatory regions influencing adjacent neurodevelopmental genes and correlated with gene expression in brain regions implicated in OCD. Given their critical roles in gene regulation, tissue-specific expression, and responsiveness to cellular states, antisense lncRNAs represent promising biomarkers and therapeutic targets. Our findings expand the genetic architecture of OCD and underscore the potential of RNA-based precision therapies for personalized clinical interventions.