Browsing by Author "Nour El Huda Abd Rahim, Ph.D"

Obesity is a major health issue among individuals with schizophrenia, contributing to increased morbidity, premature mortality and reduced quality of life. Emerging evidence suggests that the biological mechanisms linking obesity and schizophrenia may be influenced by shared genetic susceptibility. Since both conditions involve disruption in lipid metabolism and inflammation, apolipoprotein genes such as apolipoprotein L2 (APOL2) and apolipoprotein E (APOE) have been proposed to play a role in susceptibility to neuropsychiatric and metabolic disorders. However, the contribution of these genetic variations to schizophrenia and obesity in the Malaysian population remains unclear. This study aimed to assess the association of apolipoprotein genetic variants with schizophrenia and obesity. The research was carried out in two stages. Firstly, a pilot study was conducted to investigate the candidate genes in three schizophrenia patients with a strong family history. Their DNA samples were subjected to whole-genome sequencing, focusing on structural variations. The identified variants, including CHRNA7, NRG1, NRXN1 and APOL2, were cross-referenced with Ensembl, ClinVar and UniProt. Although CHRNA7 and NRG1 were detected in two out of three patients, APOL2 copy number variation (CNV) was prioritised for further analysis based on cross-reference findings due to its role in lipid metabolism, which provides a biological link between schizophrenia and metabolic dysregulation. In parallel, the APOE polymorphisms were included as an additional candidate variant of interest. In the second stage, a case-control association study on APOL2 CNV and APOE polymorphisms was conducted involving a total of 185 schizophrenia patients and 222 controls stratified by obesity status (70 and 92 obese, respectively). The BMIs were classified based on the Malaysian Clinical Practice Guideline, Management of Obesity (2023), with obesity defined as BMI ≥27.5 kg/m². Both variants were analysed using the TaqMan RT-PCR assays. This study showed no association of APOL2 CNV with schizophrenia or obesity. However, the APOE polymorphisms were found to be linked with the risk of schizophrenia and obesity in a gender-dependent manner. Specifically, the APOE ε4 allele increased the risk of schizophrenia in females (OR = 2.377, 95% CI: 1.225 – 4.613, p = 0.009), even after controlling for obesity (OR = 2.950, 95% CI: 0.997 – 8.727, p = 0.043) and also associated with an increased risk of obesity in schizophrenia (OR = 1.896, 95% CI: 1.090 – 3.298, p = 0.002), with this association retaining statistical significance only among males (OR = 2.660, 95% CI: 1.266 – 5.591, p = 0.008). In contrast, the APOE ε2 allele reduced the risk of obesity in schizophrenia (OR = 0.291, 95% CI: 0.109 – 0.775, p = 0.009), with statistical significance retained only among females (OR = 0.206, 95% CI: 0.043 – 0.990, p = 0.032). These findings suggest a complex genetic interplay between neuropsychiatric and metabolic disorders, especially regarding gender-specific effects. Therefore, these findings may contribute to future investigations exploring genetically informed therapeutic strategies to address schizophrenia and obesity. Further understanding of the role of these genes and their interactions may contribute to potential therapeutic targets, allowing personalised treatments in schizophrenia patients with obesity.

Schizophrenia is a chronic and disabling mental illness with unknown cause and incompletely understood pathogenesis. Evidence from genome-wide association studies (GWAS) and experimental studies had suggested the role of two immune related proteins, the complement C4, coded partly by the C4A gene, and the CUB and Sushi Multiple Domains 1 (CSMD1). However, there was no available report on the association between schizophrenia and DNA methylation of the C4A and CSMD1 genes. Such study is important because DNA methylation is a modifiable factor that can affect candidate genes’ expression and therefore explain the genetic-environment interaction in schizophrenia’s pathogenesis. Both genes also have copy number variation (CNV) which can influence gene expression. This study aims to compare the DNA methylation level and the copy number of C4A and CSMD1 genes between schizophrenia patients and healthy controls, and to evaluate their relationship with schizophrenia psychopathology. A total of 183 schizophrenia patients and 212 healthy controls were included in this comparative cross-sectional study. DNA methylation levels and gene copy number were determined from peripheral blood samples using MethyLightTM analysis and droplet digital polymerase chain reaction (ddPCR) respectively. C4 plasma levels was measured using immunoturbidimetry. Psychopathological data of patients were measured using the Positive and Negative Syndrome Scale (PANSS) and the Personal and Social Performance (PSP) scale. Plasma C4 levels were found to be significantly higher in schizophrenia patients compared to controls (p < 0.001). While C4A DNA methylation levels and copy number were both positively correlated with plasma C4 levels (p < 0.001), there was no significant difference in the two variables between patients and controls. The DNA methylation levels of CSMD1 were significantly lower in schizophrenia patients compared to healthy controls (p = 0.001), but its copy number did not differ significantly between the groups. C4A deletion and higher CSMD1 DNA methylation levels were also associated with lesser positive symptom severity (p = 0.027). In multivariate analysis, both CSMD1 DNA methylation levels and plasma C4 levels were significant predictors for schizophrenia. Overall, the results suggested the potential involvement of DNA methylation of C4A and CSMD1 in schizophrenia pathophysiology, particularly in pathways relevant to the positive symptoms. Since DNA methylation may be reversed, this could be a useful target in for the development of new treatment in the future. Further studies are required to identify the underlying mechanism for these findings.