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Published on: February 7, 2018
Integrated multi-omics insight into the molecular networks of oxidative stress in triggering multiple sclerosis
Yudi Xu1, Xiaowei Zhang2, Yuyuan Zhang2
1Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.
Abstract:
Oxidative stress (OS) is a key pathophysiological mechanism in multiple sclerosis (MS). However, the underlying mechanisms by which OS triggered MS remain unknown. To identify potential causal targets of 1216 OS-related genes for MS, a summary-data-based Mendelian randomization (SMR) method was applied. Given that genes can exert their biological functions through different omics levels, the multi-omics SMR integrating expression, methylation, and protein quantitative trait loci (eQTL, mQTL, and pQTL) of OS-related genes from blood and brain tissues was utilized. Bayesian colocalization test was conducted to examine potential regulatory mechanisms of QTL risk variation in MS. To verify the robustness of our results, we validated these findings in FinnGen cohort. Furthermore, the QTL evidence levels, colocalization findings, and replication cohort results were integrated and potential target genes were categorized into three levels. Consequently, three genes (BACH2, TRAF3, and MAPK3) were identified as potential contributors to MS in blood, and four genes (HMGCL, TSFM, TRAF3 and HLA-B) were identified as potential contributors to MS in brain tissue. Additionally, HMGCL and TSFM from brain tissue were supported by first-level evidence related to MS and were validated via in vitro experiments. This research not only contributed to fundamental research of OS in MS but also supported the identification of potential targets for clinical interventions in MS.
Insights
Oxidative stress contributes to multiple sclerosis (MS). This study identified key genes like HMGCL and TSFM in brain tissue as potential targets for MS, validated through in vitro experiments, offering new avenues for clinical intervention.
Area of Science:
- Neuroimmunology
- Genetics
- Molecular Biology
Background:
- Oxidative stress (OS) is a critical factor in multiple sclerosis (MS) pathogenesis.
- The precise molecular mechanisms linking OS to MS onset remain unclear.
- Identifying causal genes is crucial for understanding MS development.
Purpose of the Study:
- To identify potential causal genes linking oxidative stress to multiple sclerosis (MS).
- To investigate the role of multi-omics data (eQTL, mQTL, pQTL) in OS-related genes in MS.
- To explore potential therapeutic targets for MS based on genetic associations.
Main Methods:
- Applied summary-data-based Mendelian randomization (SMR) to 1216 OS-related genes.
- Utilized multi-omics SMR integrating expression, methylation, and protein quantitative trait loci (eQTL, mQTL, pQTL) from blood and brain tissues.
- Performed Bayesian colocalization tests and validated findings in the FinnGen cohort and in vitro experiments.
Main Results:
- Identified three genes (BACH2, TRAF3, MAPK3) associated with MS in blood.
- Identified four genes (HMGCL, TSFM, TRAF3, HLA-B) associated with MS in brain tissue.
- HMGCL and TSFM in brain tissue showed strong evidence and were validated in vitro, suggesting a direct role in MS.
Conclusions:
- This study pinpoints specific genes, particularly HMGCL and TSFM in brain tissue, as potential causal contributors to MS.
- The findings advance fundamental understanding of oxidative stress in MS.
- Identified genes offer promising targets for future clinical interventions in MS treatment.
