Current Progress in Understanding Schizophrenia
Research by: Dr. Shani Stern
Schizophrenia is a devastating and complex mental disorder with a high heritability factor. Patients experience a variety of symptoms, with hallucinations and delusions distinguishing them from other psychiatric illnesses. According to the World Health Organization (WHO), schizophrenia affects approximately 24 million people worldwide and has a prevalence of ~1%. In the last ten years collaborations and team effort by scientists from different parts of the world has resulted in genome wide association studies (GWAS) which has shed light on the genes that could have important role in its epidemiology. However, identifying the genes that cause schizophrenia remains difficult, and also integrating the different studies for an overall picture. The lack of definite causative genes and the unique symptoms of the schizophrenia patients makes it difficult to study the disease in animal models. At the Stern lab for precision disease modelling, they have synthesized and provided a quantitative meta-analytical update of the knowledge collected from many genetic studies to find well replicated genes associated in Schizophrenia. This study that was led by Dr. Shani Stern and was recently published in Schizophrenia Research. Participated in the study Dr. Ashwani Choudhary (first author of the paper) and David Peles, two students from the Stern lab. They found the majority of the GWAS were either done in populations with European or East Asian ancestry. Their additional analysis revealed that, while some genes were exclusively associated in either European or East Asian populations (as reported in several studies), there were also a significant number of common genes that were associated in Schizophrenia regardless of ancestry. The top associated gene in the general population was found to be CACNA1C, a gene that gives instructions to make calcium channels. Another highly associated gene is the LINC1470; This is a non-coding RNA (which means there is no protein that is made from the RNA transcripts, yet it is highly associated with the disease). Another interesting gene is the NRGN gene which codes for the neurogranin protein that that is involved in the synaptic machinery and in calcium signalling. The team further analyzed different published studies to find the genes that were common between GWAS (that relate to DNA changes) as well as transcriptomic studies (that relate to changes in the expression of genes). Such kind of analysis helps in understanding if the associated genes are also dysregulated at the level of mRNA or protein and in finding their biological role. Here, they found that the most affected genes are NRGN (involved in calcium signalling), TCF4 that provides instructions for a protein that is involved in many aspects of development, and COA8 that codes for a protein that promotes programmed cell death. The team mapped the expression of the most involved genes and saw that the areas in the brain that are mostly affected are the cortex and the hippocampus. The Stern lab have also conducted a large meta-analysis of induced Pluripotent Stem Cell (iPSC)-based models of Schizophrenia in order to comprehend the various disease phenotypes and genetic pathways affected in neural cells from the schizophrenia patients. iPSCs are derived directly from patients’ cells (skin cells or blood cells) and are an excellent laboratory model because they can be differentiated into any type of human cell or tissue. Because these are directly from patients, no genetic modifications are required to model these diseases. Prof. Shinya Yamanaka won the Nobel prize in physiology and medicine for this groundbreaking discovery. The team has summarized the outcomes gained from the iPSC models created from Schizophrenia patients from various studies published in the last ten years and have found important molecular and cellular pathways that are shared throughout the studies. These include neuronal hypoexcitability, a reduction in synaptic connections, reduced dendritic arborization, mitochondrial dysfunction, and reduced proliferation. This comprehensive summary will aid in our understanding of recent developments in pre-clinical research in the field of Schizophrenia and will pave the way for the creation of more accurate diagnostic tools and precision medicine.