Developing therapeutics that will effectively relieve mental illness means understanding what is causing those disorders in the first place. To that end, scientists at the University of California Los Angeles have now created a way to study how genetics plays a part in psychiatric disease. By growing brain cells in the lab, they investigated how neurons are assigned specific roles; they determined that the expression of certain genes change during neural development. The findings were reported in Biological Psychiatry.
"Our approach allowed us to model how multiple regions in the genome that increase risk for psychiatric disorders act in concert to affect molecular and cellular function that is relevant for neurodevelopment. This is exciting as it provides a novel framework to study genetic risk of psychiatric disease and shows that we can capture parts of the heritability of schizophrenia in a lab model system," said first author and graduate candidate Anil Ori.
Scientists have had a hard time deciphering how genes contribute to the heritability and physiology of schizophrenia because so many genes are involved, and some contribute in only a small way. The genetics of psychiatric disorders is complex.
"[Large-scale population studies] have shown that psychiatric disorders are heritable traits in which hundreds if not thousands of genes throughout the human genome contribute to disease risk," explained senior author Roel Ophoff, Ph.D. When small changes in many genes create an impact together, it’s called polygenic risk.
"The translation of polygenic risk to neurobiology is one of the major scientific challenges for psychiatry in this era. This paper highlights a novel approach to begin this work," said John Krystal, MD, Editor of Biological Psychiatry.
The investigators followed the expression of many genes during the development of human neural stem cells. They integrated genome-wide schizophrenic risk data with the gene expression profiles, finding that genes with differential expression and increased expression during development are linked to psychiatric disorders. Of the diseases, their strongest evidence was for schizophrenia risk.
This work can indicate who the major players are in disease risk, said the authors. In this case, the genes that were linked to schizophrenia normally function in synapses, which are connections between neurons where communication takes place.
"Establishing this platform for further study has great potential benefit," said Ori. Now that the study has established in vitro neural development as a model for psychiatric disease, researchers can tweak the model to investigate how different environments might affect disease risk, and use this to understand the biology of mental illnesses.
"As large-scale genetic studies of psychiatric disorders will continue to expand, our study provides a valuable genomic tool to help investigate and understand how risk that is distributed across the genome contributes to the etiology of psychiatric disorders," said Ophoff.
The video above features a lecture by Ophoff on the Genetics of Psychiatric Disorders.