Examination of the Effective Genetic Pathways in the Development of Schizophrenia, Using GWAS Catalog Database

Schizophrenia is a mental disorder with frequent psychosis, whose symptoms include delusions, hallucinations, disordered speech or behavior, and impaired cognitive ability. The cause of this disease becoming a debilitating disorder for patients and their families is its early onset and chronic course, which affects one percent of the population. Antipsychotic drugs are only effective in treating half of the patients, and the pathological mechanism of schizophrenia is not fully understood. In addition, these drugs improve generally positive symptoms (such as hallucinations and thought disorders that are at the core of the disease), but negative (such as social isolation) and cognitive symptoms (such as learning and attention disorders) remain untreated. On the other hand, these drugs have severe neurological and metabolic side effects and may lead to sexual dysfunction. Schizophrenia is a multifactorial disorder that involves the interaction of several genes, environmental factors, and epigenetic processes. Over the past ten years, genetic research has yielded new findings that have given rise to hope for the biological origins of schizophrenia. The genetic role is caused by a large number of alleles, including alleles with small effects that can be identified by GWAS studies. The drug treatments that are available for schizophrenia have poor efficacy for many patients in which the mentioned genetic factors are very effective.  Identifying the causes of this disease is an important step in the field of improving the treatment for this disorder, which is estimated to be half to one third of the genetic factors influencing the development of schizophrenia by common alleles reported in GWAS studies. Thus, GWAS studies are potentially an important tool for understanding the biological process of schizophrenia. GWAS Catalog is a complete collection of all published studies at the genome level, which makes it possible to investigate and identify the cause, understand the mechanism of the disease, and identify new treatment methods in this disease. In recent years, many efforts have been made to identify biomarkers in the diagnosis, prevention and treatment of schizophrenia, each of which introduces specific genes and pathways that overlap with other mental disorders. In this study, in order to investigate important genes and biological pathways in the development of schizophrenia, the genes reported in the GWAS catalog bioinformatics database were examined so that in the future, with more studies, it can help to treat and diagnose these patients more accurately.

In the present study, using the GWAS catalog database and searching for the word Schizophrenia, a list of 3344 SNPs was extracted from 80 research articles. In the next step, the SNPs that cause schizophrenia and other related diseases were extracted (1165 SNPs that were the result of 19 studies). Then, among the SNPs obtained in the previous steps, those with lower and equal p-values were 5*10^-8, isolated and checked using ensemble.org in the BioMart section, in order to find the closest genes. Then, the results of BioMart were sorted and collected based on the obtained genes, and the duplicates were removed (removal of duplicate genes) and finally 336 genes were obtained. (In general, for 554 SNPs, the gene was identified, and for the other 574 SNPs, the gene name was not found, which are extragenic.) In the next step, the above list was entered in BioMart and the names of the desired genes were obtained. (Part of Ensemble genes 107; NCBI gene (formerly Entrezgene) accession) which resulted in a total of 339 genes.
In the last step, the genes obtained from the previous step were checked using the Enrich R site, and through this site, the pathways that were related to the studied genes were extracted and compared with the results of different articles.

In this study, after entering the results in Biomart, 339 genes were obtained. Also, after entering the above list in the Enrich R site, the important pathways in which these genes are active were obtained. Pathways which Adjusted-P value was below 0.05 were considered as reliable results.

This study was conducted on schizophrenia by analyzing the data of GWAS catalog database to identify the mechanism of the disease and the pathways involved as well as the main and important genes of drug candidates. One of the important pathways in this study was Glucuronidation, which was one of the first pathways obtained from Wiki Pathway studies, which is often involved in the metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids. and bile acids play a role. This pathway is mainly carried out in the liver, although the enzyme responsible for its catalysis. UGTs are widely expressed in the brain, but at lower levels than in the liver. Brain UGTs are inducible or inhibitable that affect drug release in the central nervous system. UGTs, cytochrome P450s, and transporters act together to influence the pharmacokinetics of drugs in the brain. After glucuronidation, many drugs have the ability to cross the blood-brain barrier. Another pathway is ascorbate metabolism. Ascorbate (vitamin C) is a vital antioxidant molecule in the brain. However, it has several other important functions, participating as a cofactor in several enzymatic reactions, including catecholamine synthesis, collagen production, and HIF-1α regulation. Ascorbate is transported to the brain and neurons through the sodium-dependent vitamin C transporter (SVCT2), which causes the accumulation of ascorbate in cells against a concentration gradient. The highest concentrations of ascorbate in the body are found in the brain and neuroendocrine tissues such as the adrenals, although the brain is the hardest organ to deplete ascorbate. Together with the regional asymmetry in the distribution of ascorbate in different regions of the brain, this shows the important role of ascorbate in the brain. The next pathway was the porphyrin metabolism pathway, which disruption in this pathway can cause neurological symptoms, neuropathy and a wide range of psychiatric symptoms in addition to specific diseases, until in 1939, Waldenstrn reported that schizophrenia in families with Acute intermittent porphyria (AIP) is very common, but no statistics were provided. Another study found that 5 of 40 AIP probands had hallucinations, suggesting a possible link between psychosis and AIP. A study in Sweden found that people with AIP were four times more likely to develop schizophrenia or bipolar disorder. In addition, first-degree relatives of these people are twice as likely to be diagnosed with schizophrenia and bipolar disorder. The other pathway was the pathway of retinoid metabolism, the first evidence linking this pathway to schizophrenia is that retinoid toxicity or deficiency frequently leads to the manifestation of symptoms that, although more severe in scope, are similar to those of schizophrenia. For example, mental disorder, mental defect, large ventricles, microcephaly and various major and minor congenital anomalies, among which cranial anomalies are prominent. Such deficits have been reported frequently among schizophrenic samples. With the increasing documentation of the prominent role of retinoids in the development of the central nervous system, the possibility of retinoid involvement in schizophrenia is strengthened. Another important pathway was drug metabolism, which drugs that are widely used today in the treatment of mental disorders, including depression, psychosis, and mood stabilizers, in many cases are associated with many side effects, and only a small number of patients respond appropriately to These drugs show Many factors, including genetic factors, are effective in the effectiveness of drugs, which are of interest today. According to the present study, it can be concluded that genetics and especially polymorphisms play a very important role in the development of schizophrenia and that these genes can be used in the diagnosis and treatment of this disease. In the future, the genes of these pathways can be studied more reliably in schizophrenia for diagnostic and therapeutic purposes. The genes obtained in this research can be suitable and new options for future studies on schizophrenia and optimization of treatment methods.