Obsessive-compulsive disorder (OCD) is a psychiatric disorder affecting one percent of the U.S. population, but the underlying causes of OCD remain relatively unknown. However, recent research has highlighted potential biological causes of this psychiatric outcome.
Characterized by chronic anxiety, depression, compulsive behavior, and a difficult quality of life, an understanding of OCD is important to help treat individuals who suffer from this disorder. A new study reporting the identification of rare de novo genetic mutations in OCD patients allows for a greater understanding of this disorder and might provide information for the development of new therapies.
Recent research suggests that genetic variation can constitute as a risk factor for OCD development. Previous genome-wide association studies (GWAS) alluded to a “de novo paradigm” hypothesis, suggesting that rare genetic variants might contribute to OCD development. In a new study, Guan Ning Lin, PhD, and colleagues at Shanghai Jiao Tong University in China investigated this hypothesis in order to identify specific de novo genetic mutations across the genome as an OCD risk factor. Their findings are published in an article in the journal Science Advances entitled, “De novo mutations identified by whole-genome sequencing implicate chromatin modifications in obsessive-compulsive disorder.” The authors claim this study to be the first genome-wide de-novo mutation profiling of families of trios with OCD.
Previous GWAS have suggested a connection between OCD heritability and de novo genetic mutations, or genetic alterations that are present for the first time due to a variant in a parental germ cell (sperm or egg). Lin and coworkers sought to identify which specific de novo variants predispose an individual to develop OCD.
Through sequencing genomic DNA of 53 unrelated parent-offspring families, the researchers found a subset of de novo genetic mutations implicated in the regulation of chromatin modification play a significant part as an OCD risk factor. As chromatin modification and regulation impact prenatal and postnatal development, chromatin-modifier genes are known to be associated with various neurodevelopmental disorders.
The studied de novo genetic mutations were found to be contributors to OCD pathology and neurotransmitter pathway modification. In the new article, the researchers state that de novo mutations in three high-confidence chromatin modifiers—SETD5, KDM3B, and ASXL3—are suggestive of “OCD candidate risk genes,” due to their ability to regulate neurotransmitter expression by epigenetic modification.
“We found that the overall expression between KDM3B and dopamine genes was significantly altered between OCD cases and controls,” the authors write. “In contrast, the overall co-expression between ASXL3 and glutamate and between ASXL3 and serotonin were marginally disrupted, [and] the co-expression between SETD5 and the serotonin gene HTR1D was significantly changed.”
A de novo structural variation
Moreover, a de novo structural variation within the genome of OCD-affected individuals alluded to a heterozygous de novo deletion of the FBL gene, resulting in an OCD phenotype. The research found that the “co-expression between FBL and dopamine gene SV2C significantly changed.”
The researchers state that these rare de novo mutations were “significantly enriched in the promoter-anchored chromatin loops… [and have] a significantly higher mutation occurrence within regions of zinc finger genes and repeated, which is characterized by high frequencies of histone marks H3K9me3, H4K20me3, and H3K36me3, and relatively low frequencies of other marks.” Moreover, the researchers observed that “de novo mutation genes were significantly more mutation tolerant than controls, consistent with the hypothesis that de novo mutations might be a significant risk factor for OCD.”
The genomic sequencing of these OCD trios allowed the researchers to compare de novo mutation patterns in OCD-affected individuals with Tardive Dyskinesia (TD), which exhibit several similarities. The researchers observed more gene overlaps between these disorders than expected, they note, stating that “we observed a strong positive correlation between enrichments of the two disorders…indicating that a number of functional biological pathways are shared between the two disorders.” This finding allows for an understanding of why OCD and TD often co-occur.
However, the research showed that genes harboring these mutations are differentially expressed in the brain: the OCD mutation genes are enriched in the dorsal thalamus and in astrocyte cells, while TD mutation genes are enriched in the occipital cortex and in GABAergic neurons. Through the analysis of OCD and TD, the researchers conclude that, “there are clear, distinct developmental patterns that separate these two disorders.”
“These results suggest that chromatin modifications involving SETD5, KDM3B, ASXL3, and FBL may be upstream regulators of neurotransmitter system expression, which controls necessary neurocognitive functions. Disruption of any part of this cascade may lead to abnormal obsessive phenotypes,” conclude the researchers.