Shrivaths Sriprasad
Genetic Diseases
Mrs. Salemme
April 1st, 2019
Schizophrenia Defined By Four Different Genes
For quite some time, Schizophrenia was defined by hundreds of different genes as a result of ‘big data’ studies, which loosely roped in countless genes that happened to be present across various subjects with schizophrenia. A study conducted by New York University School of Medicine has narrowed this list of 90+ genes down to 4 specific genes that determine Schizophrenia. What does this mean? Schizophrenia is classified as psychosis, and affects an individual’s thinking, sense of self, and perception. The actual cause for this diseases was always considered to be because of a combination of physical, genetic, psychological, and environmental factors. While this is still true, the case study conducted by NYU Medical School determines that the missense coding polymorphisms or novel mutations (“carriersâ€) in any of four genes that act in different signaling pathways will lead to this psychosis. But what does it mean? This means that if you get tested for these 4 genes, it may be possible for individuals to realize their risk of getting schizophrenia, and might be able to take measures to avoid it.
These four genes are: PTPRG (Protein Tyrosine Phosphatase, Receptor Type G); SLC39A13 (Solute Carrier Family 39 (Zinc Transporter) Member 13); TGM5(Transglutaminase 5); and ARMS/KIDINS220 (Ankyrin Repeat-Rich Membrane-Spanning Protein or Kinase D-Interacting Substrate of 220 kDa). These genes were identified because each gene is highly expressed in the central nervous system, involved in signaling pathways for neuronal network integration, stabilization, and connectivity. This is all in addition to the presence of rare missense coding polymorphisms and/or novel mutations in a sporadic case in comparison to healthy parents. These four genes are heavily involved in the different processes that occur in the central nervous system, and all have the potential to be relevant in psychosis. The actual case study took individuals with chronic psychosis were recruited from clinical treatment settings if they were taking stable medication doses for at least one month. Healthy controls were recruited from Internet postings and university announcements. The subjects underwent targeted exome capture in order to identify the genetic variation across the subjects. Brief clinical vignettes were prepared for cases with missense coding polymorphisms (minor allele frequency < .01) or novel mutations (“carriersâ€), categorized as follows: “1†for PTPRG carriers; “2†for SLC39A13; “3†for TGM5; and “4†for ARMS/KIDINS220 carriers. Cases carrying two of these genes were categorized in the order mentioned earlier for the first gene, an asterisk (*) indicating that they carried others of these genes. The sequenced cases with common variants in all of these genes were categorized as “non-carriers†for comparison, even though they certainly have other genetic susceptibility. The carrier groups were statistically compared to groups of non-carrier cases and healthy controls. Each gene carrier group was then independently compared to the non-carrier case group by separate ANCOVA analyses utilizing a Bonferroni corrected significance level of p < .01 in light of the multiple testing.
Fifteen of the 48 cases (31.25%) carried missense coding ultra-rare polymorphisms or novel mutations: 5 in PTPRG, 4 in SLC39A13, 4 in TGM5, and 5 in ARMS/KIDINS220. Three carried more than one rare missense coding polymorphism in different genes considered in this analysis: one case harbored PTPRG and SLC39A13 polymorphisms; another harbored rare polymorphisms in both SLC39A13 and ARMS/KIDINS220; and the third case had rare missense coding polymorphisms in ARMS/KIDINS220 and TGM5. The latter case had chronic psychosis but did not meet strict DSM-IV schizophrenia or schizoaffective criteria based on confounding by continuous substance abuse. One PTPRG and one ARMS/KIDINS220 variant carrier did not complete all assessments. Known risk factors for psychosis were common in the carrier cases, including premorbid brain injury, substance abuse, prematurity, and a family history of psychosis. Thyroid disorders were common to all carrier groups, despite none having received lithium pharmacotherapy. Comparing the four carrier groups to non-carrier cases showed no differences in sex, age, or ethnicity. In this manner, it became evident after conducting the case study that the individuals that each gene had a connotated phenotype. For example, Childhood learning disorders were present in 100% of all PTPRG carriers and in 0% of TGM5 carriers.
What does this mean? Well, it means that schizophrenia is not a single disease, but is similar to a complex trait, in the sense that it is characterized by a group of distinct disorders for which major influential genes harboring rare disruptive variants may be discerned and for which specific treatments may be developed in the future. What this means is that because schizophrenia as a whole is defined by various phenotypes(such as losing touch with reality, missense of perception and of self), the 4 different genes can be connotated to the various phenotypes we attribute to schizophrenia. For example, a missense coding and ‘malfunction’ of the PTPRG gene could lead to an individual losing their sense of perception. What this allows for, in the field of medicine, is the possibility to target these individuals genes and ensure that they are tracked and could possibly be treated individually. So if someone is diagnosed with schizophrenia, it is possible for them to receive medication and/or treatment for the malfunction of a specific gene instead of trying to address all of the symptoms and the entirety of the disease at once. This means that specialized treatment would be possible for schizophrenia and could help many individuals who are beginning to see signs of schizophrenia and prevent their disease/case from worsening any more. “Despite the relatively small-sized subgroups based on the harboring of rare missense polymorphisms in any of four different genes in this study, group differences were demonstrated on multiple levels of the phenotype. Knowledge about these genes may be useful to identify relevant genetic architectures for psychosis and in the development of person-specific treatmentsâ€(Ebiomedicine). As the case study concluded, these findings and new research could allow for schizophrenia to be less of a ‘hit-or-miss’ situation and would allow for medical professionals to structurally break down the treatment and eventual elimination of the disease.