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Overlapping Genetic Architecture Between Schizophrenia and Neurodegenerative Disorders.

ABSTRACT: Epidemiological and clinical studies have suggested comorbidity between schizophrenia and several neurodegenerative disorders. However, little is known whether there exists shared genetic architecture. To explore their relationship from a genetic and transcriptomic perspective, we applied polygenic and linkage disequilibrium-informed methods to examine the genetic correlation between schizophrenia and amyotrophic lateral sclerosis (ALS), Parkinson's disease, Alzheimer's disease and frontotemporal dementia. We further combined genome-wide association summary statistics with large-scale transcriptomic datasets, to identify putative shared genes and explore related pathological tissues. We identified positive and significant correlation between schizophrenia and ALS at genetic (correlation 0.22; 95% CI: 0.16-0.28; p = 4.00E-04) and transcriptomic (correlation 0.08; 95% CI: 0.04-0.11; p = 0.034) levels. We further demonstrated that schizophrenia- and ALS-inferred gene expression overlap significantly in four tissues including skin, small intestine, brain cortex and lung, and highlighted three genes, namely GLB1L3, ZNHIT3 and TMEM194A as potential mediators of the correlation between schizophrenia and ALS. Our findings revealed overlapped gene expression profiles in specific tissues between schizophrenia and ALS, and identified novel potential shared genes. These results provided a better understanding for the pleiotropy of schizophrenia, and paved way for future studies to further elucidate the molecular drivers of schizophrenia.

SUBMITTER: Li C

PROVIDER: S-EPMC8740133 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundConsidered as the representatives of neurodegenerative diseases, Alzheimer's disease (AD) and glaucoma are complex progressive neuropathies affected by both genetic and environmental risk factors and cause irreversible damages. Current research indicates that there are common features between AD and glaucoma in terms of epidemiology and pathophysiology. However, the understandings and explanations of their comorbidity and potential genetic overlaps are still limited and insufficient.MethodGenetic pleiotropy analysis was performed using large genome-wide association studies summary statistics of AD and glaucoma, with an independent cohort of glaucoma for replication. Conditional and conjunctional false discovery rate methods were applied to identify the shared loci. Biological function and network analysis, as well as the expression level analysis were performed to investigate the significance of the shared genes.ResultsA significant positive genetic correlation between AD and glaucoma was identified, indicating that there were significant polygenetic overlaps. Forty-nine shared loci were identified and mapped to 11 shared protein-coding genes. Functional genomic analyses of the shared genes indicate their modulation of critical physiological processes in human cells, including those occurring in the mitochondria, nucleus, and cellular membranes. Most of the shared genes indicated a potential modulation of metabolic processes in human cells and tissues. Furthermore, human protein-protein interaction network analyses revealed that some of the shared genes, especially MTCH2, NDUFS3, and PTPMT1, as well as SPI1 and MYBPC3, may function concordantly. The modulation of their expressions may be related to metabolic dysfunction and pathogenic processes.ConclusionOur study identified a shared genetic architecture between AD and glaucoma, which may explain their shared features in epidemiology and pathophysiology. The potential involvement of these shared genes in molecular and cellular processes reflects the "inter-organ crosstalk" between AD and glaucoma. These results may serve as a genetic basis for the development of innovative and effective therapeutics for AD, glaucoma, and other neurodegenerative diseases.

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Overlapping Genetic Architecture Between Schizophrenia and Neurodegenerative Disorders.

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