Rare Variants in Antisense lncRNA-Protein Coding Gene Overlap Regions Contribute to Obsessive-Compulsive Disorder.

Obsessive-compulsive disorder (OCD) is a prevalent neuropsychiatric disorder with an incompletely understood genetic basis, limiting targeted therapeutic options. Although previous rare variant studies have primarily focused on protein-coding genes, the contribution of rare regulatory non-coding variants remains largely unexplored. We analyzed whole-genome sequencing data from 2,561 OCD cases and 12,974 controls from the All of Us Research Program to investigate rare, conserved variants (minor allele count ≤ 5, GERP++ > 0) within antisense long non-coding RNA (lncRNA) and protein-coding gene overlap regions. A burden analysis identified a significant association with OCD in the KNCN/MKNK1-AS1 overlap region (odds ratio: 5.1, FDR < 0.05). Expression analysis revealed strong co-expression of these genes in striatal brain regions implicated in OCD pathophysiology. Genes co-expressed with KNCN/MKNK1-AS1 were enriched for synaptic vesicle dynamics, calcium signaling, and established OCD risk genes, highlighting the importance of non-coding regulatory variation in psychiatric genetics.