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Mendelian Randomization Approaches to Explore Complex Disease Susceptibility and Comorbidity

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (10 February 2024) | Viewed by 9176

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Special Issue Editor

Dr. Lara M. Bossini-Castillo

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Guest Editor

Department of Genetics, University of Granada, Granada, Spain
Interests: complex diseases; polymorphisms; genome-wide association studies; multi-omics; Mendelian randomization

Special Issue Information

Dear Colleagues,

The identification of genetic markers for complex diseases has experienced an unprecedented advance in the past decade due to the implementation of both high-throughput genotyping and next-generation sequencing technologies in large study cohorts. However, the environmental risk factors and exposures that trigger the onset of such disorders in genetically predisposed individuals often remain unknown. Moreover, the molecular causes that predispose some specific individuals to disease comorbidities and complications remain obscure in the majority of the cases. Mendelian randomization methods rely on genetic variants as the instrumental variables with which to identify causal relationships between exposures and outcomes. The implementation of one-sample and two-sample Mendelian randomization studies on different complex diseases has proven fruitful for identifying the possible functional links between different risk factors and disease. This Special iIsue aims to compile original articles and reviews on the different uses of Mendelian randomization approaches to cast light on the molecular connection between environmental risk factors and comorbidities associated with complex human disorders, with a special focus on immune-mediated diseases. We aim to provide the research community with substantial studies that will increase our knowledge about the mechanisms connecting a specific environmental exposure or comorbidity with the onset and progression of a complex disease.

Topics of this Special Issue include, but are not limited to:

One-sample Mendelian randomization studies to identify the environmental risk factors of complex diseases
Two-sample Mendelian randomization studies to identify environmental risk factors of complex diseases
One-sample Mendelian randomization studies to characterize disease comorbidities
Two-sample Mendelian randomization studies to characterize disease comorbidities
Methodological development of Mendelian randomization approaches
Mendelian randomization strategies on genome-wide association studies
Mendelian randomization strategies on biobank datasets
Mendelian randomization studies in non-European cohorts

Dr. Lara M. Bossini-Castillo
Guest Editor

Manuscript Submission Information

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Keywords

Mendelian randomization
risk factor
comorbidity
polymorphisms
complex diseases

Published Papers (5 papers)

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17 pages, 1972 KiB

Open AccessArticle

Strengthening the Evidence for a Causal Link between Type 2 Diabetes Mellitus and Pancreatic Cancer: Insights from Two-Sample and Multivariable Mendelian Randomization

by Te-Min Ke, Artitaya Lophatananon and Kenneth R. Muir

Int. J. Mol. Sci. 2024, 25(9), 4615; https://doi.org/10.3390/ijms25094615 - 23 Apr 2024

Viewed by 297

Abstract

This two-sample Mendelian randomization (MR) study was conducted to investigate the causal associations between type 2 diabetes mellitus (T2DM) and the risk of pancreatic cancer (PaCa), as this causal relationship remains inconclusive in existing MR studies. The selection of instrumental variables for T2DM was based on two genome-wide association study (GWAS) meta-analyses from European cohorts. Summary-level data for PaCa were extracted from the FinnGen and UK Biobank databases. Inverse variance weighted (IVW) and four other robust methods were employed in our MR analysis. Various sensitivity analyses and multivariable MR approaches were also performed to enhance the robustness of our findings. In the IVW and Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) analyses, the odds ratios (ORs) for each 1-unit increase in genetically predicted log odds of T2DM were approximately 1.13 for PaCa. The sensitivity tests and multivariable MR supported the causal link between T2DM and PaCa without pleiotropic effects. Therefore, our analyses suggest a causal relationship between T2DM and PaCa, shedding light on the potential pathophysiological mechanisms of T2DM’s impact on PaCa. This finding underscores the importance of T2DM prevention as a strategy to reduce the risk of PaCa. Full article

(This article belongs to the Special Issue Mendelian Randomization Approaches to Explore Complex Disease Susceptibility and Comorbidity)

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8 pages, 583 KiB

Open AccessCommunication

Contribution of Telomere Length to Systemic Sclerosis Onset: A Mendelian Randomization Study

by Inmaculada Rodriguez-Martin, Gonzalo Villanueva-Martin, Alfredo Guillen-Del-Castillo, Norberto Ortego-Centeno, José L. Callejas, Carmen P. Simeón-Aznar, Javier Martin and Marialbert Acosta-Herrera

Int. J. Mol. Sci. 2023, 24(21), 15589; https://doi.org/10.3390/ijms242115589 - 25 Oct 2023

Viewed by 1375

Abstract

Although previous studies have suggested a relationship between telomere shortening and systemic sclerosis (SSc), the association between these two traits remains poorly understood. The objective of this study was to assess the causal relationship between telomere length in leukocytes (LTL) and SSc using the two-sample Mendelian randomization approach, with the genome-wide association study data for both LTL and SSc. The results of inverse-variance weighted regression (OR = 0.716 [95% CI 0.528–0.970], p = 0.031) and the Mendelian randomization pleiotropy residual sum and outlier method (OR = 0.716 [95% CI 0.563–0.911], p = 0.035) indicate an association between telomere length and SSc. Specifically, longer genetically predicted LTL is associated with a reduced risk of SSc. Sensitivity tests highlight the significant roles of the variants rs10936599 and rs2736100 annotated to the TERC and TERT genes, respectively. Our findings suggest an influence of telomere length in leukocytes on the development of SSc. Full article

(This article belongs to the Special Issue Mendelian Randomization Approaches to Explore Complex Disease Susceptibility and Comorbidity)

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16 pages, 2862 KiB

Open AccessArticle

Integrated Analyses of Single-Cell Transcriptome and Mendelian Randomization Reveal the Protective Role of Resistin in Sepsis Survival in Intensive Care Unit

by Hanghang Chen, Haihua Luo, Tian Tian, Shan Li and Yong Jiang

Int. J. Mol. Sci. 2023, 24(19), 14982; https://doi.org/10.3390/ijms241914982 - 07 Oct 2023

Viewed by 1956

Abstract

The high morbidity and mortality rates associated with sepsis highlight the challenges of finding specific remedies for this condition in the intensive care unit (ICU). This study aimed to explore the differentially expressed genes (DEGs) specific to cell types in sepsis and investigate the role of resistin in the survival of sepsis patients through Mendelian randomization (MR) analyses. We used single-cell and bulk transcriptome data to identify cell type-specific DEGs between sepsis and healthy controls. MR analyses were then conducted to investigate the causal relationships between resistin (one of the identified DEGs) levels and the survival of sepsis patients. Additionally, we utilized meQTL (methylation quantitative trait loci) to identify cytosine-phosphate-guanine (CpG) sites that may directly affect sepsis. We identified 560 cell type-specific DEGs between sepsis and healthy controls. Notably, we observed the upregulation of resistin levels in macrophages during sepsis. In bulk transcriptome, RETN is also upregulated in sepsis samples compared with healthy controls. MR analyses revealed a negative association existed between the expression of resistin, at both gene and protein levels, and the mortality or severity of sepsis patients in ICU. Moreover, there were no associations observed between resistin levels and death or organ failure due to other causes. We also identified three methylation CpG sites, located in RETN or its promoter region—cg06633066, cg22322184, and cg02346997—that directly affected both resistin protein levels and sepsis death in the ICU. Our findings suggest that resistin may provide feasible protection for sepsis patients, particularly those with severe cases, without serious side effects. Therefore, resistin could be a potential drug candidate for sepsis treatment. Additionally, we identified two CpG sites, cg06633066 and cg22322184, that were associated with RETN protein levels and sepsis death, providing novel insights into the underlying mechanisms of sepsis. Full article

(This article belongs to the Special Issue Mendelian Randomization Approaches to Explore Complex Disease Susceptibility and Comorbidity)

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17 pages, 1146 KiB

Open AccessArticle

Celiac Disease Is a Risk Factor for Mature T and NK Cell Lymphoma: A Mendelian Randomization Study

by Rafael Martín-Masot, Marta Herrador-López, Víctor Manuel Navas-López, Francisco David Carmona, Teresa Nestares and Lara Bossini-Castillo

Int. J. Mol. Sci. 2023, 24(8), 7216; https://doi.org/10.3390/ijms24087216 - 13 Apr 2023

Cited by 3 | Viewed by 2942

Abstract

Celiac disease (CeD) is an immune-mediated disorder triggered by gluten ingestion that damages the small intestine. Although CeD has been associated with a higher risk for cancer, the role of CeD as a risk factor for specific malignancies, such as enteropathy-associated T-cell lymphoma (EATL), remains controversial. Using two-sample Mendelian randomization (2SMR) methods and the summarized results of large genome-wide association studies from public repositories, we addressed the causal relationship between CeD and eight different malignancies. Eleven non-HLA SNPs were selected as instrumental variables (IVs), and causality estimates were obtained using four 2SMR methods: random-effects inverse variance-weighted, weighted median estimation, MR-Egger regression, and MR pleiotropy residual sum and outlier (MR-PRESSO). We identified a significant causal relationship between CeD and mature T/NK cell lymphomas. Under a multivariate Mendelian randomization model, we observed that the causal effect of CeD was not dependent on other known lymphoma risk factors. We found that the most instrumental IV was located in the TAGAP locus, suggesting that aberrant T cell activation might be relevant in the T/NK cell malignization process. Our findings provide new insights into the connection between immune imbalance and the development of severe comorbidities, such as EATL, in patients with CeD. Full article

(This article belongs to the Special Issue Mendelian Randomization Approaches to Explore Complex Disease Susceptibility and Comorbidity)

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Other

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9 pages, 763 KiB

Open AccessBrief Report

Genetic Predisposition to Elevated Levels of Circulating ADAM17 Is Associated with the Risk of Severe COVID-19

by Mengyu Pan, Isabel Goncalves, Andreas Edsfeldt, Jiangming Sun and Per Swärd

Int. J. Mol. Sci. 2023, 24(21), 15879; https://doi.org/10.3390/ijms242115879 - 01 Nov 2023

Viewed by 1464

Abstract

High levels of ADAM17 activity have emerged as an important mediator in severe COVID-19. This study aims to characterize eventual causal relationships between ADAM17 and COVID-19. Using Mendelian randomization analyses, we examined the causal effects of circulating ADAM17 on COVID-19 outcomes using summary statistics from large, genome-wide association studies of ADAM17 (up to 35,559 individuals) from the Icelandic Cancer Project and deCODE genetics, as well as critically ill COVID-19 patients (cases: 13,769; controls: 1,072,442), hospitalized COVID-19 patients (cases: 32,519; controls: 2,062,805) and reported SARS-CoV-2 infections (cases: 122,616; controls: 2,475,240) from the COVID-19 Host Genetics Initiative. The Mendelian randomization (MR) analyses demonstrated that a 1 standard deviation increase in genetically determined circulating ADAM17 (extracellular domain) was associated with an increased risk of developing critical ill COVID-19 (odds ratio [OR] = 1.26, 95% confidence interval [CI]:1.03–1.55). The multivariable MR analysis suggested a direct causal role of circulating ADAM17 (extracellular domain) in the risk of developing critical COVID-19 (OR = 1.09; 95% CI:1.01–1.17) when accounting for body mass index. No causal effect for the cytoplasmic domain of ADAM17 on COVID-19 was observed. Our results suggest that an increased genetic susceptibility to elevated levels of circulating ADAM17 (extracellular domain) is associated with a higher risk of suffering from severe COVID-19, strengthening the idea that the timely selective inhibition of ADAM17 could be a potential therapeutic target worthy of investigation. Full article

(This article belongs to the Special Issue Mendelian Randomization Approaches to Explore Complex Disease Susceptibility and Comorbidity)

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