Rare Variants in Antisense Long Noncoding RNA-Protein-Coding Gene Overlap Regions Contribute to Obsessive-Compulsive...

Area of Science:

• Neurogenetics
• Genomics
• Molecular Biology

Background:

• Obsessive-compulsive disorder (OCD) is a common neuropsychiatric condition with a poorly understood genetic foundation.
• Previous research has focused on protein-coding genes, overlooking the role of rare regulatory noncoding variants.

Purpose of the Study:

• To investigate the contribution of rare conserved variants in antisense long noncoding RNA (lncRNA)-protein-coding gene overlap regions to OCD susceptibility.
• To explore the genetic basis of OCD beyond protein-coding genes.

Main Methods:

• Whole-genome sequencing data from 2561 OCD cases and 12,974 controls were analyzed.
• Fisher's exact test and Optimal Sequence Kernel Association Test were used to identify associations in 992 lncRNA-protein-coding overlap regions.
• Expression analysis was performed to examine gene coexpression patterns in brain regions relevant to OCD.

Main Results:

• Significant enrichment of rare conserved variants was found in the KNCN/MKNK1-AS1 overlap region in OCD cases (OR=5.1, FDR<.05).
• This enrichment was particularly notable in genes with low evolutionary constraint.
• KNCN and MKNK1-AS1 showed strong coexpression in striatal regions (nucleus accumbens, putamen, caudate), which are implicated in OCD.
• Coexpressed genes were enriched for synaptic vesicle dynamics, calcium signaling, and known OCD risk genes.

Conclusions:

• Rare noncoding regulatory variants play a significant role in the genetic architecture of OCD.
• The KNCN/MKNK1-AS1 overlap region represents a potential genetic risk factor for OCD.
• Antisense lncRNA-protein-coding overlap regions may offer novel therapeutic targets for OCD.