Mechanisms of action of telomere-related genes and telomere length-related proteins in relation to psychiatric disorders: A multi-method Mendelian Randomization study

Abstract

Background Psychiatric disorders (PD) refer to disorders that affect individual thinking, emotional regulation, and behavior. Notably, PD are associated with factors such as genes, proteins, and telomere-associated methylation. Method This study used GWAS, single-cell expression quantitative trait loci (sc-eQTL), and brain tissue eQTL and mQTL data of eleven psychiatric diseases for summary data-based Mendelian randomization analysis (SMR). A pQTL with a two-sample Mendelian randomization study was also used to investigate the mechanisms of telomere-related gene expression regulation and the causal relationship between telomere-related proteins and PD. Result Multiple telomere-related risk genes that are associated with PD were identified using SMR analysis. These genes were mainly expressed in cell types such as oligodendrocytes, excitatory neurons, dopaminergic neurons, and OPCs. Furthermore, several methylation-gene-disease regulatory signals were screened. Using a Mendelian randomization analysis, associations between seven telomere length-associated proteins i.e., GUSB, PSG5, MDM4, SPDEF, TNS2, MSP, and PLK1 and four PD i.e., bipolar disorder, major depressive disorder, neuroticism, and schizophrenia were identified. Conclusion The collective findings in this study suggest an association between PD and telomere-related genes. Further, it was observed that specific genes are expressed in specific cell types in the brain tissue and play an important role in the pathogenesis of PD. In addition, there is a causal relationship between telomere length and PD, and methylation may play a role in the relationship between telomere stability and PD. Taken together, telomere-related genes and proteins have important roles in the onset and development of PD. These findings provide a new understanding of the pathological mechanisms of PD and offer potential novel targets for their diagnosis and treatment. Future studies will help in further elucidating the relationship between telomeres and PD and potential therapeutic strategies in this regard.