A large brain study to find the source of mental illness

Researchers analyzed massive brain samples to find out the association between mental illness and genes. Image source: Science Photo Library

It has long been known that schizophrenia and autism are highly heritable, but the etiology of these neuropsychiatric diseases is very complicated, and the number of regulatory genes involved is numerous, and the pathogenesis is still unclear.

Recently, researchers at the PsychENCODE project have published several papers in Science and its publications. There have been some unprecedented discoveries based on thousands of massive analyses of brain tissue, or the pathogenesis of neuropsychiatric diseases. Play a driving role.

"Psychiatric disease itself is a complex multi-gene disease, but the core organ is the brain. We directly study human brain tissue and study the differences in gene expression regulation." Associate Professor Chen of the School of Life Sciences, Central South University Super said in an interview with the Journal of Chinese Sciences. As one of the PsychENCODE project participants, Chen Chao and Liu Chunyu, a professor at the School of Life Sciences of Central South University, published three research results in Science and the journal Science-Transformation Medicine.

Pathogenesis

Unlike the diseases caused by single gene mutations, the premise of neuropsychiatric diseases such as schizophrenia is complex, and there are hundreds of related genes.

Gene-level variability leads to abnormalities in gene transcription, which further manifests as functional or structural abnormalities in the brain. These different small premise are related to each other, functioning, and finally lead to symptoms manifested at the level of external behavior.

In the past few decades, scientists have discovered a number of genetic variants associated with mental illness. How do they interact with environmental factors during brain development to affect mental illness? This is a problem that needs to be further resolved.

However, there are many genes associated with pathogenesis, and the effects of individual genes are limited. More complicated is that in the non-coding region, even if the product of DNA transcription is not a protein, some chemicals that play a regulatory role are produced.

Chen Chao et al.'s research brings together genes, small RNAs and non-coding RNAs. From the network level, we extract and extract the parts that are highly correlated with the disease, and then determine which are upstream and core in the network. The regulatory element of action.

"This situation requires a relatively large sample size to find these relatively small differences in gene expression. The amount of sample affects the significance and reliability of the results." Chen Chao said.

Open the clouds

The PsychENCODE project, in which Chen Chao and his colleagues participated, was initiated by the National Institutes of Health in 2015. The project provides a large number of human brain tissue samples and genome sequencing data, aiming to study the pathogenesis of neuropsychiatric diseases through genomics.

Based on the sequencing data of 1695 human brain samples of PsychENCODE project, Chen Chao and his collaborators found that schizophrenia, two-way affective disorder and brains of autistic patients have compared with the common human brain through differential expression analysis in the whole genome. More than 25% of the gene transcriptomes have differential expression or differential splicing, which provides ideas for clinical drug treatment of neuropsychiatric diseases. The study was published in Science a few days ago.

In addition, Chen Chao et al. also found that different types of cells, such as schizophrenia and two-way affective disorder, play different roles in neurons and glial cells.

They integrated three sets of different human brain transcriptome data consisting of 394 brain samples. In the constructed co-expression network, a gene co-expression module related to schizophrenia was discovered. This module is enriched and carried rare. The variable schizophrenia risk gene, the transcription factor POU3F2 is a key regulator of the module, which regulates the expression of small RNA and other messenger RNA in the module.

Non-coding RNAs were previously thought to be "dark matter" and "chicken ribs" in the genome. In previous studies, researchers were less concerned with non-coding RNA functions in the CNV (copy number variation) region. However, another study published by Chen Chao et al. in Science-Transformation Medicine is the opposite, focusing on long-chain non-coding RNAs in 10 CNV regions and finding one of the CNV regions (22q11.2). Long-chain non-coding RNA with more "discourse power" - DGCR5.

Chen Chao told the Journal of Chinese Academy of Sciences that if the influence of each gene on the risk of disease is like a reservoir, other elements play a role in “small tricks”, while DGCR5 is more like a “large faucet”.

"DGCR5 is upstream of the entire functional chain and affects the differentiation and development of nerves. Its abnormalities lead to abnormalities in neural differentiation. This partly explains why the absence of 22q11.2 in the CNV region leads to the onset of schizophrenia. The risk is increasing." Chen Chao said.

The next step of the job

“They used a large number of human brain samples, which is very remarkable.” Xu Zhiheng, a researcher at the Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, commented.

“This series of studies provides us with a lot of information about mental disorders such as schizophrenia, including pathogenesis and related networks. It also provides a lot of ideas for follow-up research, including the selection of genes and signaling pathways for animal model research. Clinical treatment and diagnosis will also have potential help. If these results can be verified in animal models, it is more meaningful to understand the pathogenesis of schizophrenia," Xu said.

For Chen Chao and other researchers, there is more research to be done in the future. Taking schizophrenia as an example, "it is not to say that when a person is 20 years old, the brain will suddenly change. In fact, from the fertilized egg to the full development of the adult brain, the pathogenesis is reflected throughout the developmental stage. Chen Chao said.

"The next study may also focus on different regulatory aspects, such as different levels of methylation changes, changes in protein levels, etc., revealing the regulatory role of genetic signals in different stages of brain development," Chen Chao said.

Chen Chao said, "The core organ that can support the study of mental illness is still the human brain. Our paper is also a direct study of human brain tissue."

At present, there are human brain tissue library collaboration alliances in China. "But there are fewer samples of mental illness such as autism and schizophrenia that can be collected. There are still some gaps in quality and quantity compared with foreign resources." Chen Chao said. (trainee reporter Ren Fangyan)

Source: Chinese Journal of Science