Mitochondrial related genome-wide Mendelian randomization identifies putatively causal genes for multiple cancer types

Li, Yanni; Sundquist, Kristina; Zhang, Naiqi; Wang, Xiao; Sundquist, Jan; Memon, Ashfaque A.

doi:10.1016/j.ebiom.2022.104432

Cited by 30 publications

(19 citation statements)

References 38 publications

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“…In osteosarcoma cell lines and HeLa cells, FDPS was also able to change the ECM organization and promote proliferation and DNA repair (32). Finally, FDPS has been proposed as a biomarker of breast cancer development (33). Squalene epoxidase (SQLE) is capable to promote tumor growth by inhibiting apoptosis (34) and is able to interact with TGFb-SMAD axis to promote EMT and metastatic capacity (35).…”

Section: Discussionmentioning

confidence: 99%

Application of graph models to the identification of transcriptomic oncometabolic pathways in human hepatocellular carcinoma

Barace,

Santamaría,

Infante

et al. 2024

Preprint

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Whole tissue transcriptomic analyses have been helpful to characterize molecular subtypes of hepatocellular carcinoma (HCC). Metabolic subtypes of human HCC have been defined, yet whether these different metabolic classes are clinically relevant or derive in actionable cancer vulnerabilities is still an unanswered question. Publicly available gene sets or gene signatures have been used to infer functional changes through gene set enrichment methods. However, me-tabolism-related gene signatures are poorly coexpressed when applied to a biological context. Here, we apply a simple method to infer highly consistent signatures using graph models. Using The Cancer Genome Atlas Liver Hepatocellular cohort (LIHC), we describe the main metabolic clusters and their relationship with commonly used molecular classes, and with the presence of TP53 or CTNNB1 driver mutations. We find similar results in our validation cohort, the LIRI-JP cohort. We describe how previously described metabolic subtypes could not have therapeutic rel-evance due to their overall downregulation when compared to non-tumoral liver, and identify N-Glycan, Mevalonate and Sphingolipid biosynthetic pathways as the hallmark of the oncogenic shift of the use of Acetyl-coenzyme A in HCC metabolism. Finally, using DepMap data, we demonstrate metabolic vulnerabilities in HCC cell lines.

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Section: Discussionmentioning

confidence: 99%

Application of graph models to the identification of transcriptomic oncometabolic pathways in human hepatocellular carcinoma

Barace,

Santamaría,

Infante

et al. 2024

Preprint

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“…To further validate the results of the SMR analysis, the two-sample MR approach was employed to estimate the effect on outcomes by using eQTL of druggable genes as instruments ( Li et al., 2023 ). We assessed the strength of the correlation between instrumental variables and exposure using the F-statistic (>10) ( Burgess and Thompson, 2011 ).…”

Section: Methodsmentioning

confidence: 99%

Mendelian randomization analysis identifies druggable genes and drugs repurposing for chronic obstructive pulmonary disease

Wang,

Li,

Cai

et al. 2024

Front. Cell. Infect. Microbiol.

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BackgroundChronic obstructive pulmonary disease (COPD) is a prevalent condition that significantly impacts public health. Unfortunately, there are few effective treatment options available. Mendelian randomization (MR) has been utilized to repurpose existing drugs and identify new therapeutic targets. The objective of this study is to identify novel therapeutic targets for COPD.MethodsCis-expression quantitative trait loci (cis-eQTL) were extracted for 4,317 identified druggable genes from genomics and proteomics data of whole blood (eQTLGen) and lung tissue (GTEx Consortium). Genome-wide association studies (GWAS) data for doctor-diagnosed COPD, spirometry-defined COPD (Forced Expiratory Volume in one second [FEV1]/Forced Vital Capacity [FVC] <0.7), and FEV1 were obtained from the cohort of FinnGen, UK Biobank and SpiroMeta consortium. We employed Summary-data-based Mendelian Randomization (SMR), HEIDI test, and colocalization analysis to assess the causal effects of druggable gene expression on COPD and lung function. The reliability of these druggable genes was confirmed by eQTL two-sample MR and protein quantitative trait loci (pQTL) SMR, respectively. The potential effects of druggable genes were assessed through the phenome-wide association study (PheWAS). Information on drug repurposing for COPD was collected from multiple databases.ResultsA total of 31 potential druggable genes associated with doctor-diagnosed COPD, spirometry-defined COPD, and FEV1 were identified through SMR, HEIDI test, and colocalization analysis. Among them, 22 genes (e.g., MMP15, PSMA4, ERBB3, and LMCD1) were further confirmed by eQTL two-sample MR and protein SMR analyses. Gene-level PheWAS revealed that ERBB3 expression might reduce inflammation, while GP9 and MRC2 were associated with other traits. The drugs Montelukast (targeting the MMP15 gene) and MARIZOMIB (targeting the PSMA4 gene) may reduce the risk of spirometry-defined COPD. Additionally, an existing small molecule inhibitor of the APH1A gene has the potential to increase FEV1.ConclusionsOur findings identified 22 potential drug targets for COPD and lung function. Prioritizing clinical trials that target these identified druggable genes with existing drugs or novel medications will be beneficial for the development of COPD treatments.

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“…Mitochondria are critical organelles regulating cellular energy production, metabolism, proliferation, and apoptosis (1). They possess their own genome known as mitochondrial DNA (mtDNA), which is a circular, intron-free, double-stranded, haploid molecule approximately 16.6 kb in size.…”

Section: Introductionmentioning

confidence: 99%

The role of mitochondrial DNA copy number in neuropsychiatric disorders: A bidirectional two-sample Mendelian randomization study

Niu,

Chen,

Maes

2024

Preprint

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Background. Inconsistent findings characterize studies on mitochondrial DNA copy number (mtDNA-CN) and its relation to neuropsychiatric disorders. This bidirectional two-sample Mendelian Randomization (MR) study explores potential causal links between mtDNA-CN and neuropsychiatric disorders, including Alzheimer's disease, Attention-deficit/hyperactivity disorder, Anorexia nervosa, Autism spectrum disorder (ASD), Bipolar disorder, Major depressive disorder, Obsessive-compulsive disorder, Schizophrenia, Anxiety disorders, and Post-traumatic stress disorder. Methods. Genetic associations with mtDNA-CN were drawn from the UK Biobank's GWAS data (n = 395,718), while neuropsychiatric disorder data came from the Psychiatric Genomics Consortium and FinnGen Consortium. Three MR methods, Inverse Variance Weighting (IVW), MR-Egger, and Weighted Median, were used to establish relationships. Cochran Q test, MR-PRESSO, and MR-Egger intercept test assessed heterogeneity and pleiotropy. A leave-one-out analysis evaluated the impact of individual SNPs on MR results, and a bidirectional analysis examined the relationship between mtDNA-CN and neuropsychiatric disorders. Results. The MR analysis indicated a causal relationship between mtDNA-CN and ASD using the IVW method (OR = 0.735,95%CI:0.597 to 0.905; P = 0.004). Conversely, a causal relationship was identified between Anxiety disorders and mtDNA-CN (β= 0.029,95%CI:0.010 to 0.048; P = 0.003). No causal associations were found for other disorders. Sensitivity tests corroborated the robustness of these findings. Conclusion. In this study, potential causal relationships between mtDNA-CN and both ASD and Anxiety disorders were established. These findings provide insights into the biological mechanisms of mtDNA-CN on ASD and underscore the significance of mtDNA copy number as a potential biomarker for Anxiety disorders.

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Mitochondrial related genome-wide Mendelian randomization identifies putatively causal genes for multiple cancer types

Cited by 30 publications

References 38 publications

Application of graph models to the identification of transcriptomic oncometabolic pathways in human hepatocellular carcinoma

Application of graph models to the identification of transcriptomic oncometabolic pathways in human hepatocellular carcinoma

Mendelian randomization analysis identifies druggable genes and drugs repurposing for chronic obstructive pulmonary disease

The role of mitochondrial DNA copy number in neuropsychiatric disorders: A bidirectional two-sample Mendelian randomization study

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