Genomics of Schizophrenia

Although schizophrenia has been better described as an underpinning multifactorial aetiology with a complex polygenic genetic architecture, genetic epidemiology investigations have demonstrated that schizophrenia is substantially heritable. Evidence has been presented in favour of the involvement of several environmental factors that may contribute to the aetiology of schizophrenia, as well as frequent and unusual genetic variations linked to the development of the disorder¹⁸. while more than 100 genetic risk loci for schizophrenia have been found by recent genome-wide association studies (GWAS), their total contribution to the risk of schizophrenia is minimal. Furthermore, it has been proposed that the polygenic risk score could help identify the relationship between intermediate phenotypes, like the structural changes in the brain that occur in schizophrenic individuals, and schizophrenia. Furthermore, five CNV areas associated with schizophrenia have been revealed to contain genes that were found to express differently in schizophrenia, according to a recent systematic review of research using copy number variants (CNVs). With a 25-fold increase in the chance of developing schizophrenia, the 22q11.2 deletion syndrome is the most thoroughly studied CNV linked to an elevated risk of schizophrenia¹⁹ and people with SCZ also have higher peripheral FKBP5 expression. However, beyond genetic susceptibility, epigenetics also plays a crucial role in the development of schizophrenia. The interaction of genetic and environmental factors during the foetal to developmental stages can potentially impact and alter the psychopathological course of the illness. Additionally, other post-developmental factors may influence the onset of schizophrenia through an epigenetic mechanism. These factors are known as epigenetic factors^20,21.

Aspects of Trauma in Childhood

The capability of a caregiver to provide a safe and healthy environment is directly proportional to the quality of a child's attachment style. A child's relationship with the caregiver plays a vital role in early attachment style formation. Children with responsive caregivers develop secure attachments and are more open to seeking support when faced with difficulties. On the other hand, children with unreliable caregivers who fail to care for their needs tend to develop an avoidant and resistant attachment style, learning to be emotionally self-reliant at an early age. Childhood exposure to violence can have negative long-term effects on one's emotional, physical, and mental well-being. The different ways of childhood trauma are depicted in (Figure 2)²².

Figure 2. The different ways of childhood trauma

DISCUSSION
Though various theories have been postulated for the pathophysiology of schizophrenia there is a gap in the literature regarding the environmental effects on the developing brain which leads to the disease. Differential clinical presentations of schizophrenia spectrum disorders have been linked to several environmental factors, including childhood adversity, substance use and abuse, minority and ethnicity status, birth season, urbanity, and pregnancy and perinatal problems²³.

Childhood Trauma and its Effect on the Developing Brain
Severe stress, or ChT, can leave people in susceptible mental states and increase their risk of developing mental health conditions like SCZ. Numerous studies show that ACEs increase the likelihood of psychosis and SCZ development. Higher levels of ChT cause more heightened positive, general, and depressed symptoms as well as worse global functioning in ultra-high-risk (UHR) persons. Individuals at UHR frequently have histories of emotional abuse, physical abuse, emotional neglect, and sexual abuse²⁴. Findings were found in a recent South African study investigating the connection between childhood trauma and SCZ. One physical or emotional trauma experience did not significantly correlate with schizophrenia. However, those who experienced more than two of these traumas had a higher chance of developing schizophrenia, indicating that, even in rare cases, physical and emotional childhood adversity does not always raise the risk of schizophrenia. However, the likelihood and intensity of sexual assault increase after just one incident²⁵.

Relationship between Childhood Trauma and Schizophrenia in Genetic Approach
A gene called FKBP5 is connected to the hypothalamic-pituitary-adrenal (HPA) axis' stress response. Notably, the FKBP5 gene plays a role in the development of SCZ when subjected to acute or prolonged stress. Increased cortisol secretion in ChT-positive schizophrenic patients points to a link between ChT and the dysfunction of the HPA axis in SCZ²⁶. In addition to the interaction between genes and environmental factors, specifically ChT, studies have also shown a direct correlation between symptoms of schizophrenia-type disorder (SCZ) and the genetic component brain-derived neurotrophic factor (BDNF) Val66Met polymorphism. A typical observation in SCZ is the loss of volume in brain regions such as the hippocampus. When glucocorticoids are used as a stress inducer in animal models, there is a reduction in hippocampal BDNF levels after both acute and long-term stress. When used in medical treatments, cortisol can exacerbate symptoms. SCZ patients exhibit a flattened reactivity to stress and lower thresholds than controls during and after stress exposure, supporting that SCZ patients have a significant impairment in their stress response. It's interesting to note that teenagers who are very susceptible to SCZ have elevated cortisol levels at rest, which can be attributed to environmental factors such as emotional abuse from family members and a poor self-image^27,28.

Chemical Changes with Childhood Trauma
ChT always exhibits modification on the HPA axis. People who have experienced maltreatment as children have hyperactivity of the axis, which changes dopamine levels, the autonomic nervous system, the shape of the brain, and neural function, all of which raise the risk of developing psychosis. Individuals who experienced childhood hardship showed increased striatal dopamine function, suggesting a link between associative striatum elevation and psychogenic stress, particularly physical and sexual abuse²⁹. As previously mentioned, the primary theory about the pathogenesis of SCZ is that dopamine overstimulates the brain's D2 receptors. Research suggests that one important aspect of SCZ is stress sensitization, which lowers the sensitivity threshold in SCZ patients. Stress can trigger the HPA axis, which makes dopamine in the mesolimbic area more sensitive and increases dopamine release in the striatum³⁰.

 Brain Anatomical and Physiological Links to Childhood Trauma

In schizophrenia patients, emotional neglect was inversely correlated with grey matter volume overall and, more especially, with the volume and density of the dorsolateral prefrontal cortex, which was predictive of disorganization. It's interesting to note that in cases of schizophrenia, there have been reports of additive effects of childhood trauma and being a BDNF met carrier on volume reduction in the hippocampal subregions of CA2/3 and CA4/dentate gyrus. Abuse in childhood has been linked to both decreased hippocampus volume and elevated amygdala reactivity³¹. Childhood trauma was linked to activity of the dorsomedial prefrontal cortex, precuneus, and posterior cingulate gyrus in patients with schizophrenia during a theory-of-mind task that mirrored social cognition. Furthermore, patients who experienced significant degrees of physical and/or sexual abuse as children have reduced connections between the amygdala and the posterior cingulate/precuneus region³².

CONCLUSIONS

This review expands on the research that is currently accessible by recognizing the potential for hardship experienced throughout childhood and adolescence to manifest into adulthood. However, a resilience-promoting environment-that is, an environment that integrates interventions to increase a positive outcome, despite adversities, to implement wellbeing-is frequently absent from many mental health services, despite the recovery-oriented approach that is necessary for the management of schizophrenic patients.

In recent times, acknowledging personal life experiences has demonstrated advantageous effects on the treatment of many mental illnesses. The main goal of this study is to highlight how crucial it is to assess patients holistically, taking into account the impact of their past experiences on the emergence of present symptoms. Research points to the brain's neurobiological reactions to trauma as a risk factor for SCZ development. To demonstrate the realistic potential of neurological effect regulation, it will be imperative in further trials to assess the advantages of early trauma detection and the accessibility of early support. Finding a beneficial effect on neurobiology ought to motivate additional primary care physicians to include early trauma screening in child wellbeing visits. In a perfect world, early identification of adversity in individuals would result in the prompt introduction of resources that help address mental and emotional dysregulations; this might be a crucial step in reducing the annual diagnostic rate and severity of schizophrenia in the general population.

Author Contributions: My co-authors' contributions to the creation of this review are greatly appreciated. I sincerely thank everyone who contributed equally to the creation of this review. Zareen Zohara and Ajeeth Rehman Abdul Jaffar Azad. Conceptualized the Project: Ajeeth Rehman Abdul Jaffar Azad handled the methodology; Faizal Khan. Handled the software: Zareen Zohara and Ajeeth Rehman Abdul Jaffar Azad validated the work; Zareen Zohara conducted the formal analysis; Zareen Zohara, Faizal Khan, and Ajeeth Rehman Abdul Jaffar Azad conducted the investigation; Zareen Zohara and Ajeeth Rehman Abdul Jaffar Azad handled the resources; Zareen Zohara and Ajeeth Rehman Abdul Jaffar Azad prepared the data; Zareen Zohara prepared the original draft; Ajeeth Rehman Abdul Jaffar Azad handled the writing; Zareen Zohara and Ajeeth Rehman Abdul Jaffar Azad handled the review and editing; Zareen Zohara. Zohara Zareen. Each author has reviewed the published version of the manuscript and given their approval.
Funding: There is no funding to declare