Category Ranking
98%
Total Visits
921
Avg Visit Duration
2 minutes
Citations
20
Article Abstract
Background: The impact of genetic variants on gene expression has been intensely studied at the transcription level, yielding in valuable insights into the association between genes and the risk of complex disorders, such as schizophrenia (SCZ). However, the downstream impact of these variants and the molecular mechanisms connecting transcription variation to disease risk are not well understood.
Results: We quantitated ribosome occupancy in prefrontal cortex samples of the BrainGVEX cohort. Together with transcriptomics and proteomics data from the same cohort, we performed cis-Quantitative Trait Locus (QTL) mapping and identified 3,253 expression QTLs (eQTLs), 1,344 ribosome occupancy QTLs (rQTLs), and 657 protein QTLs (pQTLs) out of 7,458 genes quantitated in all three omics types from 185 samples. Of the eQTLs identified, only 34% have their effects propagated to the protein level. Further analysis on the effect size of prefrontal cortex eQTLs identified from an independent dataset showed clear post-transcriptional attenuation of eQTL effects. To investigate the biological relevance of the attenuated eQTLs, we identified 70 expression-specific QTLs (esQTLs), 51 ribosome-occupancy-specific QTLs (rsQTLs), and 107 protein-specific QTLs (psQTLs). Five of these omics-specific QTLs showed strong colocalization with SCZ GWAS signals, three of them are esQTLs. The limited number of GWAS colocalization discoveries from omics-specific QTLs and the apparent prevalence of eQTL attenuation prompted us to take a complementary approach to investigate the functional relevance of attenuated eQTLs. Using S-PrediXcan we identified 74 SCZ risk genes, 34% of which were novel, and 67% of these risk genes were replicated in a MR-Egger test. Notably, 52 out of 74 risk genes were identified using eQTL data and 70% of these SCZ-risk-gene-driving eQTLs show little to no evidence of driving corresponding variations at the protein level.
Conclusion: The effect of eQTLs on gene expression in the prefrontal cortex is commonly attenuated post-transcriptionally. Many of the attenuated eQTLs still correlate with SCZ GWAS signal. Further investigation is needed to elucidate a mechanistic link between attenuated eQTLs and SCZ disease risk.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10592607 | PMC |
| http://dx.doi.org/10.1101/2023.06.04.543603 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Jiangtang Decoction for Type 2 Diabetes and NAFLD: Integrative Analysis Network Pharmacology, Mendelian Randomization, Molecular Docking, and Validation.
Endocr Metab Immune Disord Drug Targets
August 2025
Ningbo Municipal Hospital of TCM, Affiliated Hospital of Zhejiang Chinese Medical University, Ningbo, China.
Introduction: Jiangtang Decoction (JTD) demonstrates notable efficacy in managing Type 2 Diabetes Mellitus (T2DM) and Non-Alcoholic Fatty Liver Disease (NAFLD). This study aimed to elucidate JTD's causal targets and therapeutic mechanisms by integrating network pharmacology, Summary-data Mendelian Randomization (SMR), and molecular docking, complemented by validation.
Materials And Methods: JTD's targets were cross-matched with genes associated with T2DM or NAFLD.
Atheroma transcriptomics identifies ARNTL as a smooth muscle cell regulator and with clinical and genetic data improves risk stratification.
Eur Heart J
January 2025
Vascular Surgery, Department of Molecular Medicine and Surgery, Karolinska University Hospital and Karolinska Institutet, BioClinicum J8:20, Visionsgatan 4, SE-171 76 Stockholm, Sweden.
Background And Aims: The role of vascular smooth muscle cells (SMCs) in atherosclerosis has evolved to indicate causal genetic links with the disease. Single cell RNA sequencing (scRNAseq) studies have identified multiple cell populations of mesenchymal origin within atherosclerotic lesions, including various SMC sub-phenotypes, but it is unknown how they relate to patient clinical parameters and genetics. Here, mesenchymal cell populations in atherosclerotic plaques were correlated with major coronary artery disease (CAD) genetic variants and functional analyses performed to identify SMC markers involved in the disease.
View Article and Find Full Text PDFGenome-wide association study of susceptibility to hospitalised respiratory infections.
Wellcome Open Res
November 2023
Department of Population Health Sciences, University of Leicester, Leicester, UK.
Article Synopsis
- Respiratory infections are a major global health issue, but the genetic factors influencing them are not well understood, leading to this study that aimed to investigate genetic determinants through genome-wide association studies (GWAS).
- The research analyzed data from 19,459 patients with respiratory infections and 101,438 controls in Stage 1, discovering 56 significant genetic signals, including one strong signal related to a gene important for immune response, but the follow-up Stage 2 study did not replicate these findings.
- Possible reasons for the lack of replication include variations in how the studies were conducted and differences in patient populations, but the research suggests a novel gene may be linked to susceptibility to respiratory infections, warranting further investigation.
Unraveling the molecular mechanisms of Ace2-mediated post-COVID-19 cognitive dysfunction through systems genetics approach.
Exp Neurol
November 2024
Shandong Technology Innovation Center of Molecular Targeting and Intelligent Diagnosis and Treatment, Binzhou Medical University, Shandong, Yantai 264003, China. Electronic address:
The dysregulation of Angiotensin-converting enzyme 2 (ACE2) in central nervous system is believed associates with COVID-19 induced cognitive dysfunction. However, the detailed mechanism remains largely unknown. In this study, we performed a comprehensive system genetics analysis on hippocampal ACE2 based on BXD mice panel.
View Article and Find Full Text PDFThe impact of common variants on gene expression in the human brain: from RNA to protein to schizophrenia risk.
bioRxiv
November 2023
Center for Human Genetics, The Brown foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Background: The impact of genetic variants on gene expression has been intensely studied at the transcription level, yielding in valuable insights into the association between genes and the risk of complex disorders, such as schizophrenia (SCZ). However, the downstream impact of these variants and the molecular mechanisms connecting transcription variation to disease risk are not well understood.
Results: We quantitated ribosome occupancy in prefrontal cortex samples of the BrainGVEX cohort.