APOL2 copy number variation and APOE polymorphisms in schizophrenia with obesity

Abstract

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.