New Insight on the Genetic and Neural Basis of Obsessive-Compulsive Disorder

Obsessive-compulsive disorder (OCD), which affects nearly 80 million people worldwide, is a heritable, neuropsychiatric disease characterized by debilitating thought processes and repetitive behaviors. Unfortunately, medical OCD therapy provides little relief for many people with this condition, underscoring the need to better understand its underlying biology.

Animal models have improved the understanding of OCD. Mouse models have demonstrated that the cortico-striatal neural pathway is key to compulsive behavior. Genome-wide association studies in dogs have identified genes associated with canine compulsive disorder (CD), which shares many similarities with human OCD, including high heritability.

However, current technologies that identify disease-associated genetic variants have limitations. Whole-genome sequencing, for example, is prohibitively expensive. Whole-exome sequencing focuses only on a genome’s coding regions, excluding the regulatory regions that could contain disease-causing genetic variants. In addition, these technologies benefit only a few populations, thus limiting the benefit of precision medicine at a population level.

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In a study recently published in Nature Communications, investigators used a novel analytical approach to identify genes and variants significantly associated with increased OCD risk. This approach, they noted, “holds promise for elucidating the biological basis of complex disease.”

Analyses

The investigators sequenced the coding and regulatory regions of 608 dog, human, and mouse genes with potential associations to OCD. The dog and mouse genes were, respectively, from animal models of canine CD and murine-compulsive grooming.

To identify functional genetic variants, the investigators performed targeted genetic sequencing in individuals of European ancestry with OCD and their ancestry-matched controls. They then used a novel analytical method named PolyStrat, which they developed to analyze the targeted-sequencing data. PolyStrat, the researchers noted, captures all genetic variants, rather than just ultra-rare variants, and can be used in modestly sized study cohorts.

Results

Sequencing and statistical analyses identified 4 genes—NRXN1, REEP3, CTTNBP2, HTR2A—with strong associations with OCD. The genes are “expressed in the striatum … involved in pathways relevant to brain function, and harbor variants that could alter OCD risk,” the investigators stated. For example, NRNX1 codes for neurexin 1α, a synapse cell-adhesion protein; its variants could disrupt normal binding interactions and increase OCD risk.

Interestingly, associations with OCD were stronger among the dog and mouse genes than the human genes. The investigators believed this was due to less stringent natural selection forces in research animals, allowing for higher frequencies of severe disease-causing genetic variants.

Sequencing analyses revealed 3 altered neural functions implicated in OCD development:

• Disrupted synaptic adhesion activity
• Disrupted serotonergic pathway activity
• Imbalance of excitatory and inhibitory neurotransmitter levels

The analyses also demonstrated a positive correlation between the ratio of coding to regulatory variants and a gene’s developmental importance (more coding variants, greater developmental importance). This observation, the researchers noted, aligns with a previous study’s finding that genes with critical developmental functions were least tolerant of major coding alterations. In the current study, CTTNBP2 and REEP3 contained high levels of regulatory variants, suggesting less developmental importance.

Looking Forward

This novel approach to targeted genetic sequencing and statistical analysis provides a pathway for identifying potential therapeutic targets for OCD, the researchers concluded. Such an approach, they said, could “extend the power of precision medicine to previously excluded populations.”

Dr. Pendergrass received her Doctor of Veterinary Medicine degree from the Virginia-Maryland College of Veterinary Medicine. Following veterinary school, she completed a postdoctoral fellowship at Emory University’s Yerkes National Primate Research Center. Dr. Pendergrass is the founder and owner of JPen Communications, a medical communications company.