A comprehensive multiomics approach towards understanding obsessive-compulsive disorder

Resumo

Obsessive-compulsive disorder (OCD) is a clinically heterogeneous neuropsychiatric disorder that affects around 1-3% of the population. It is characterized by intrusive and unwanted thoughts, urges or images (called obsessions) and repetitive behaviours or mental acts (called compulsions), which are performed to partially relieve the anxiety or distress caused by the obsessions. Family and twin studies have consistently reported that OCD involves both environmental and genetic risk factors. However, despite a number of genetic linkage, candidate genes and genome-wide association studies have been performed, very little progress has been made towards elucidating the genetic causes of OCD. In this project we have applied new omics approaches, including rare variant association studies (RVAS) and transcriptomics and metagenomics analyses, to focus on areas relatively underexplored in OCD, which could explain part of the missing heritability observed in this disorder. We have identified and replicated an enrichment of rare variants in TMEM63A, a gene that encodes for a calcium-permeable cation channel, through whole-exome sequencing, RVAS and targeted resequencing analyses. Moreover, we have observed an overrepresentation of genes enriched in rare variants in OCD cases related to calcium signalling, suggesting a potential role of calcium signalling dysfunction in the aetiology of OCD. Transcriptomic studies have identified differential expression of genes involved in neuronal development and function in OCD patients, such as NRCAM, which encodes for a neuronal cell adhesion molecule. Integration of our RVAS and transcriptomic results also uncover a possible role of semaphorins and axon guidance in OCD. Finally, metagenomics studies have confirmed the previously reported increase of the Rikenellaceae bacterial family in the gut microbiome as a potential biomarker of OCD and have shown a specific oro-pharyngeal dysbiotic signature in OCD patients, characterised by a significant higher Actinobacteria/Fusobacteria ratio compared to controls. In summary, our results support the high complexity of OCD and actively encourage further research in these areas through multiple omics approaches.