Obsessive-compulsive disorder (OCD) can have a lifetime prevalence of up to 3% worldwide, its etiology is complex and pathological, and the influencing factors can include environment and genes. At this stage, one of the difficulties in the study of the pathogenesis of obsessive-compulsive disorder is: how are the two related to the emergence of the disease?
A growing body of research is beginning to demonstrate that mutations that are ultra-rare but may have a high penetrance rate may be an important factor in the pathogenesis of mental illness. Recently, The team of Professor Lin Guanning of the School of Biomedical Engineering of Shanghai Jiao Tong University and the team of chief physician Wang Zhen of the Affiliated Mental Health Center of Shanghai Jiao Tong University School of Medicine cooperated to conduct a genome-wide study of the core lineage (obsessive-compulsive disorder patients and their healthy parents) cohort of obsessive-compulsive disorder, which is the first in the world to distinguish ultra-rare OCD mutations from the whole genome level to study the causes of obsessive-compulsive disorder, and it is also the first time in the world that in addition to the often studied synaptic energy associated with the pathogenesis of OCD, Dysregulation of chromatin modifications in epigenetics, especially abnormalities of histone modifications, also plays a very important role in the development of OCD disease. This study uses epigenetic disorders as a pathway where environmental and genetic factors interact with each other, which has a very important role in future research.
The researchers first sequenced the whole genome of 53 core families, comprehensively obtained all the genetic variants carried by the obsessive-compulsive disorder patients and their healthy parents, and screened out the ultra-rare de novo mutations that were only present in the patients. Mutations with 24 single points and one large fragment deletion were found to significantly affect protein structure, and proteins affected by these mutations play a major role in regulating chromosomal structure in the human brain (Figure 1A). At the same time, researchers also found that many non-coding new mutations are also significantly concentrated on the structures and regions of chromosomes with key functions.
When the researchers further used human brain expression data to construct a network of brain gene interaction between embryonic and postnatal periods, it was found that the genes in which the above mutations were located were concentrated in a biological sub-network with "chromatin regulation" effects, which was strongly associated with many neurotransmitter-related genes. Therefore, the researchers reasoned that genetic mutations leading to chromosomal structural abnormalities are a key link in the genetic pathological mechanism of obsessive-compulsive disorder, and this abnormality may play a role by influencing the amount of downstream neurotransmitter expression (Figures 1B-2). The findings not only confirm that ultra-rare mutations (new severe mutations damaging de novo mutations) may have a significant effect on the onset of obsessive-compulsive disorder, but also suggest that abnormalities in the regulation of chromatin structure caused by these mutations may be an important factor in the pathological process of obsessive-compulsive disorder.
In addition, the study also found that about half of patients carried at least one serious new mutation, which also provided new evidence for the previously pending "new mutation hypothesis" of obsessive-compulsive disorder. In the past, it has been believed that the study of the genetic basis of obsessive-compulsive disorder has been difficult for a long time because most of the disease-causing mutations are newly occurred in patients, and they are directly eliminated by natural selection without being passed on to their offspring. However, genome-wide association analysis of common variants and complex genealogical studies of rare genetic variants from ancestors have found some pathogenic genetic factors, so some scholars are skeptical of the "emerging mutation hypothesis". This study confirms that a large part of the genetic factors that lead to the pathogenesis of obsessive-compulsive disorder are indeed composed of new mutations, which provides new supporting evidence for the "new mutation hypothesis" and provides a new solution to the bottlenecks encountered in previous genetic research on obsessive-compulsive disorder. The OCD pathogenic mutations obtained from this discovery and the disease pathways revealed can be targeted for pathological and drug studies.
Figure 1. Genome-wide genealogy studies have identified key mutational genes for OCD and the neurotransmitter system genes they may affect
Figure 2. Pathogenesis hypothesis of OCD epigenetics based on the interaction of environmental factors and genetic risks
In addition, by comparing the obsessive-compulsive disorder gene with the tic disorder gene, the researchers also found an interesting result: this is a mental illness with some similarity between two clinical phenotypes, although their pathogenic genes have highly similar underlying biological functions, but the researchers found that the genes of the two diseases are expressed at different stages of brain development, or brain regions and brain cell types. This result suggests that obsessive-OCD and tic disorder may be diseases with the same pathological process, but occur at different spatiotemporal sites and form two clinical phenotypes.
The paper "De novo mutations identified by whole-genome sequencing implicate chromatin modifications in obsessive-compulsive disorder" was published online by Science Advances on January 12. Wang Zhen, Chief Physician of the Mental Health Center Affiliated to Shanghai Jiao Tong University School of Medicine, and Professor Lin Guanning, School of Biomedical Engineering, Shanghai Jiao Tong University, are co-corresponding authors. The first authors are Professor Lin Guanning of the School of Biomedical Engineering of Shanghai Jiao Tong University, Song Weichen, a doctoral candidate at the Mental Health Center Affiliated to Shanghai Jiao Tong University School of Medicine, Wang Weidi, an assistant researcher, and Wang Pei, a resident physician, as the co-first authors of the paper. The research has been funded by the National Natural Science Foundation of China, the Shanghai Municipal Natural Science Foundation, the Shanghai Municipal Education Commission's Scientific Research and Innovation Program, and the Shanghai Municipal Health Commission.