Genetic and Neurobiological Basis of Schizophrenia
Schizophrenia has emerged as one of the most debilitating psychiatric disorders, and it impacts on an individual’s quality of life. Its prevalence is approximately 1.0%, whereas its incidence ranges from 0.16 to 0.42/1000 individuals. Evidence indicates that genetics have an integral role in the onset of schizophrenia. Some of genes involved in the development of schizophrenia include RELN gene, GRM3 gene, COMT gene, and NOS1AP gene. Similarly, neurological dysfunctions including dopamine and glutamate dysfunction have been identified as some of the main factors underlying the pathophysiology of the disorder. Overall, there is evidence that support the biological basis of schizophrenia.
Schizophrenia has emerged as one of the most debilitating psychiatric disorders. It impacts on an individual’s quality of life, as well as causing severe biological and social consequences. Overall, schizophrenia is characterized by several hallmark presentation features. The main characteristics that are associated with schizophrenia include avolition, catatonic behavior, hallucinations, alogia, disorganized speech, delusions, and affective flattening (American Psychiatric Association, 2013; Kimuyu, 2018). These presentation features can occur across the continuum of the disease process ranging from the acute to chronic phases. From the epidemiological lens, schizophrenia is associated with a high rate of suicidal behavior. According to epidemiological data, 15% of schizophrenic patients are reported to commit suicide. Other epidemiological studies project the prevalence of schizophrenia within the general population as 1.0%, whereas its incidence ranges from 0.16 to 0.42/1000 individuals (Jablensky, 1995). Despite the old literature that stated that the prevalence of schizophrenia occurs equally among women and men, there is emerging evidence that men have a higher risk compared to women (Aleman, 2003). Despite the clinical and social impacts of schizophrenia, it is apparent that there is no substantial knowledge base regarding the etiology and pathophysiology of schizophrenia (Steen, Mull, McClure, Hamer & Lieberman, 2006). Over the decades, there has been an extensive inquiry on the underlying pathophysiological mechanisms of schizophrenia. Therefore, this papers aims at providing insight on the biological basis of schizophrenia. In this context, it is suggestive that genetics and neurological mechanisms are the underlying factors which are responsible for the pathophysiology of schizophrenia.
Genetic Basis of Schizophrenia
In retrospect, epidemiological studies reveal that genetic mechanisms could be responsible for the onset of schizophrenia among the global population. Initial studies linked the risk of schizophrenia to genetics based on the findings which revealed the existence of the disorder among biologic relatives. In these studies, it was found out that schizophrenia did not occur in adopted relatives in the same magnitude as compared to its prevalence in biologic relatives (Ketty et al., 1994). Findings indicate that first-degree relatives of schizophrenic patients have a high risk of suffering from schizophrenia. This group of people experience as high as 10% of schizophrenia risk. One the other hand, the risk of schizophrenia among children who are born of schizophrenic parents is estimated at 40%, primarily when both parents are suffering from the disorder. Further findings reveal that twins bear differing risks in which monozygotic twins are reported to a schizophrenic concordance of 40% to 50% compared to 10% reported in dizygotic twins (Frankenburg, 2015).
Over the past few decades, extensive genomic studies have been conducted to investigate the genetic basis of schizophrenia. These studies have led to the identification of the key genes which are involved in the onset of schizophrenia. An outstanding genome-wide study which provided insight into the genetic basis of schizophrenia is the recent study that was carried out by Ripke et al. (2014). In this study, investigators identified 108 genetic loci which are associated to schizophrenia. Most of these genetic loci had not been identified in the previous studies. Overall findings in this study indicated that the identified gene loci were involved in the expression of key genes in the brain, as well as the immune system tissues. Some of the genetic loci which have became candidates for genetic study on the genetic basis of schizophrenia include RELN gene, GRM3 (metabotrophic glutamate receptor 3) gene, COMT (catechol-O-methyltransferase) gene, and NOS1AP (nitric oxide synthase adaptor protein) gene.
In retrospect, the biological functions of these genes have been documented though their association with schizophrenia had not been established. Therefore, the existence of these variant genes reveals that genetics plays an integral role in schizophrenia. For instance, evidence shows that the existence of RELN gene variants in women increases the risk of schizophrenia (Shifman et al., 2008). Biologically, RELN gene is responsible for regulating GABAergic activity, as well as brain development through reelin protein. This implies that defects in this gene have devastating physiological consequences in the brain. Another study that investigated the role of GRM3 gene in the development of schizophrenia showed that GRM3 variants increased the risk of psychotic disorders, including schizophrenia, bipolar disorder and alcohol dependence (O'Brien et al., 2014). Similarly, COMT gene variants were found to cause neurological consequences which underlie the pathophysiology of schizophrenia. Biologically, COMT gene is involved in the production of COMT enzyme which controls the activity of catecholamine neurotransmitters including norepinephrine, epinephrine and dopamine. Overall, prospective studies indicate that the expression of valine-valine variant potentiates psychotic symptoms among patients by degrading dopamine faster. In addition, valine-methionine variants are also responsible for the development of psychotic symptoms though at a lower magnitude compared to valine-valine variants (Caspi et al., 2005). Moreover, there is a growing knowledge base regarding the expression of NOS1AP gene. This gene codes for nitric oxide synthase, an enzyme which is present in the brain’s inhibitory neurons. Biologically, nitric oxide synthase controls the synthesis of nitric oxide which is involved in intracellular communication. Therefore, the presence of nucleotide polymorphism in postmortem brain samples for schizophrenic patients reveals a link between NOS1AP gene variant and the onset of schizophrenia (Wratten et al., 2009).
On the other hand, changes in the gene structures have also been found to be associated with schizophrenia. Foremost, duplications and deletions at some DNA regions have been found to create gene variants which increase the risk of schizophrenia. Some of the loci where genetic changes have been identified include 22q11.2, 1q21.1, 16q13.11, 15q11.2, 16q11.2, 1q21.1, and 22q11.2. In one genomic-wide study, it was found out that the presence of copy number variant at different loci was associated to the occurrence of psychiatric disorders and congenital anomalies including cognitive impairment and developmental delay (Sahoo et al., 2011). Similarly, changes in neurodevelopmental genes have been found to increase the risk of schizophrenia. Some of the genes whose disruption has been identified as the principal factor for their involvement in schizophrenia pathology include RGS4, DISC1, DTNBP1, NRG1, AKT1, and KCNH2 (Frankenburg, 2015).
Neurobiological Basis of Schizophrenia
In retrospect, the pathophysiology is largely associated to neurological dysfunctions as explained by the main schizophrenia theories. According to the glutamate hypothesis, the pathophysiology of schizophrenia is related to the function of glutamate which acts as one of the key neurotransmitters. It is also reported that impaired activity of NMDA glutamate receptor contributes to the development of schizophrenia symptoms. Evidence indicates that schizophrenic patients have low concentrations of glutamate receptors compared to normal individuals. For instance, a prospective laboratory study showed that postmortem brain samples of schizophrenic patients contain low levels of these receptors (Konradi & Heckers, 2003). In general, impaired glutamate function has been found to be responsible for reduced functioning of hippocampal and the front lobe. This explains why schizophrenic patients experience difficulties in cognitive tests.
The second hypothesis that explains the pathophysiology of schizophrenia is the dopamine hypothesis. According to this hypothesis, excessive activation of dopamine D2 receptors contributes to the positive symptoms associated with schizophrenia. This perspective has been evidenced by studies which have investigated the effect of antipsychotic drugs on the nervous system. Overall, evidence reaffirms that the role of dopamine in the dopamine mesolimbic pathways forms the basis for the pathophysiology of schizophrenia. For instance, hyperactivity of dopamine D2 receptors leads to the development of positive symptoms, whereas hypoactivity of D1 receptors, especially in the prefrontal cortex is responsible for the negative symptoms (Abi-Dargham & Prefrontal, 2003).
Another hypothesis that is related to the glutamate hypothesis is the interneuron dysfunction. Evidence indicates that schizophrenic patients experience impairment of parvalbumin interneurons. These revelations were obtained from studies that investigated the levels of specific proteins and GAD67 mRNA. Biologically, interneurons play integral roles in the brain, and they are GABAergic in nature (Gonzalez-Burgos, Hashimoto & Lewis, 2010).
Conclusively, schizophrenia seems to be impacting immensely on the lives of the affected individuals. Foremost, it decreases the quality of life and social consequences. Its hallmark presentation features include hallucination and delusions which are attributable to the pathophysiology of the disorder. From an epidemiological perspective, the pathophysiology of schizophrenia is associated to genetic and neurological mechanisms. First, genetic changes in some loci explain why schizophrenia runs within family lines; affecting biologic relatives more than adoptive relatives. Second, neurological mechanisms such as dopamine, glutamate and interneuron dysfunctions explain the occurrence of the main symptoms observed in schizophrenic patients. Therefore, the evidence reviewed in this paper provides evidence of the biological basis of schizophrenia.
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- Patrick Kimuyu (Author), 2018, Genetic and Neurobiological Basis of Schizophrenia, Munich, GRIN Verlag, https://www.grin.com/document/411952