A new analytical method for determining the genetic mechanisms of mental diseases development
The method is based on the use of brain cells grown in the laboratory from embryonic stem cells. A team of researchers from the University of California at Los Angeles studied the process of differentiation of neurons for specific roles and found, that changes in the expression of specific genes in the development of the nervous system were strongly associated with the genetic risk of schizophrenia.
Our method gave us understanding, how different parts of the genome associated with an increased risk of mental illness work together in the process of regulating the molecular and cellular functions, responsible for the development of the central nervous system. This is a promising discovery that provides a completely new concept in the study of the genetic risks of mental pathologies. Now we have the opportunity to study the specific hereditary mechanisms of the etiology of schizophrenia in a laboratory model.
– Anil Ori, study coauthor
Due to the incredible complexity of determining the genetic mechanisms of mental disorders, studying the heritability of the biological basis of schizophrenia in models is not an easy task.
The results of large-scale demographic studies indicate that mental disorders are associated with heredity, and hundreds, if not thousands of genes are responsible for the risk of developing such disorders.
– Roel Ophoff, senior author, PhD
Such an accumulation of many small gene effects is called polygenic risk.
Nowadays, one of the main scientific challenges in psychiatry is the discovery of the principles of transferring polygenic risk to neuroscience. This article highlights a new approach to work in this area.
– John H. Krystal, Editor of Biological Psychiatry
The new method allows to reveal the polygenic nature of schizophrenia due to the observation of gene expression in the differentiation of stem cells of the nervous system. Using the integration of gene expression profiles with a full-genome risk database for schizophrenia, the first author of the study, Anil Ori and his colleagues, found that, during the development of the CNS, the differentially expressed genes, that is, genes whose expression is affected by various extranuclear factors, are associated with a polygenic risk of schizophrenia. Using a different sample, they obtained an identical result.
In the differential expression, the final structure of mRNA depends largely on the regulatory action of the cytoplasm and the macromolecules or determinants of morphogenesis located in it. During embryogenesis, different genes are expressed differently in different parts of the embryo.
The macromolecules of the cytoplasm, as transcription regulators, essentially determine the morphology of future tissues, organs, and the organism as a whole. The function of these determinants is inevitably associated with the manifestations of the activity of each gene under their control, that is, including the development of pathologies. Thus, a detailed review of their work is necessary to understand the complete picture of the formation of the final phenotype.
The authors claim that their discovery will help narrow the search for key pathogenetic processes that are responsible for the risk of developing pathologies. Identified in this study, the genes associated with pathological risk, carried a synaptic function, that is, were responsible for the processes of cell communication and signal transmission inside the brain.
The emergence of a new platform for further research holds great promise.
– Anil Ori
After the in vitro model of the development of the nervous system proved its efficacy in studying mental diseases, scientists can refine it to establish how environmental factors modify risk and use this information to better understand the nature of mental disorders.
Roel Ophoff convinced, that with ongoing large-scale genetic studies of psychiatric diseases, the results of his and his colleagues work will help to identify and explain how the risk of pathology distributed over the genome is involved in the etiology of these disorders.