Exploration of Lung Cancer-Related Genetic Factors via Mendelian Randomization Method Based on Genomic and Transcriptomic Summarized Data

Lung carcinoma is one of the most deadly malignant tumors in mankind. With the rising incidence of lung cancer, searching for the high effective cures become more and more imperative. There has been sufficient research evidence that living habits and situations such as smoking and air pollution are associated with an increased risk of lung cancer. Simultaneously, the influence of individual genetic susceptibility on lung carcinoma morbidity has been confirmed, and a growing body of evidence has been accumulated on the relationship between various risk factors and the risk of different pathological types of lung cancer. Additionally, the analyses from many large-scale cancer registries have shown a degree of familial aggregation of lung cancer. To explore lung cancer-related genetic factors, Genome-Wide Association Studies (GWAS) have been used to identify several lung cancer susceptibility sites and have been widely validated. However, the biological mechanism behind the impact of these site mutations on lung cancer remains unclear. Therefore, this study applied the Summary data-based Mendelian Randomization (SMR) model through the integration of two GWAS datasets and four expression Quantitative Trait Loci (eQTL) datasets to identify susceptibility genes. Using this strategy, we found ten of Single Nucleotide Polymorphisms (SNPs) sites that affect the occurrence and development of lung tumors by regulating the expression of seven genes. Further analysis of the signaling pathway about these genes not only provides important clues to explain the pathogenesis of lung cancer but also has critical significance for the diagnosis and treatment of lung cancer.

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The impact of personality on the risk and survival of breast cancer: a Mendelian randomization analysis

Psychological Medicine ◽

10.1017/s0033291721001562 ◽

2021 ◽

pp. 1-7

Author(s):

Li Ying ◽

Songzan Chen ◽

Ling Li ◽

Zhijun Pan

Keyword(s):

Breast Cancer ◽

Mendelian Randomization ◽

Association Studies ◽

Causative Role ◽

Genome Wide Association Studies ◽

Luminal A ◽

Mendelian Randomization Analysis ◽

Increased Risk ◽

The Impact ◽

Randomization Analysis

Abstract Background It has long been hypothesized that personality plays a causative role in incidence and outcome of breast cancer (BC), but epidemiological evidence of association between personality and BC is inconsistent. Method We used two-sample Mendelian randomization analysis to estimate the impact of personality on the risk and survival of BC. In total, 109 single nucleotide polymorphisms (SNPs) were utilized as instruments of neuroticism from a large-scale Genome-Wide Association Studies (GWAS), and five SNPs were utilized as instruments of extraversion from Genetic of Personality Consortium and 23andMe. Genetic association with the risk and survival of overall and individual subtype BC were obtained from the Breast Cancer Association Consortium. Result Neuroticism is significantly associated with the risk of overall BC [odds ratio (OR) 1.06; 95% confidence interval (CI) 1.01–1.11; p = 0.015] and the risk of luminal A BC (OR 1.09; 95% CI 1.03–1.16; p = 0.004). Extraversion is not associated with the risk of BC. None of neuroticism or extraversion is associated with the survival of BC. Conclusion Neuroticism was associated with a modest increased risk of BC and particularly luminal A BC.

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A description of large-scale metabolomics studies: increasing value by combining metabolomics with genome-wide SNP genotyping and transcriptional profiling

Journal of Endocrinology ◽

10.1530/joe-12-0144 ◽

2012 ◽

Vol 215 (1) ◽

pp. 17-28 ◽

Cited By ~ 18

Author(s):

Georg Homuth ◽

Alexander Teumer ◽

Uwe Völker ◽

Matthias Nauck

Keyword(s):

Blood Cells ◽

Large Scale ◽

Genetic Factors ◽

Association Studies ◽

Transcriptional Profiling ◽

Genome Wide Association Studies ◽

Protein Levels ◽

Future Developments ◽

Genome Wide ◽

Metabolome Data

The metabolome, defined as the reflection of metabolic dynamics derived from parameters measured primarily in easily accessible body fluids such as serum, plasma, and urine, can be considered as the omics data pool that is closest to the phenotype because it integrates genetic influences as well as nongenetic factors. Metabolic traits can be related to genetic polymorphisms in genome-wide association studies, enabling the identification of underlying genetic factors, as well as to specific phenotypes, resulting in the identification of metabolome signatures primarily caused by nongenetic factors. Similarly, correlation of metabolome data with transcriptional or/and proteome profiles of blood cells also produces valuable data, by revealing associations between metabolic changes and mRNA and protein levels. In the last years, the progress in correlating genetic variation and metabolome profiles was most impressive. This review will therefore try to summarize the most important of these studies and give an outlook on future developments.

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Evaluating the effects of alcohol and tobacco use on cardiovascular disease using multivariable Mendelian randomization

10.1101/757146 ◽

2019 ◽

Cited By ~ 1

Author(s):

Daniel B. Rosoff ◽

George Davey Smith ◽

Nehal Mehta ◽

Toni-Kim Clarke ◽

Falk W. Lohoff

Keyword(s):

Risk Factors ◽

Cardiovascular Disease ◽

Alcohol Use ◽

Tobacco Use ◽

Mendelian Randomization ◽

Association Studies ◽

Density Lipoprotein ◽

Genome Wide Association Studies ◽

Cvd Risk ◽

Increased Risk

ABSTRACTAlcohol and tobacco use, two major modifiable risk factors for cardiovascular disease (CVD), are often consumed together. Using large publicly available genome-wide association studies (results from > 940,000 participants), we conducted two-sample multivariable Mendelian randomization (MR) to simultaneously assess the independent effects of alcohol and tobacco use on CVD risk factors and events. We found genetic instruments associated with increased alcohol use, controlling for tobacco use, associated with increased high-density-lipoprotein-cholesterol (HDL-C), decreased triglycerides, but not with coronary heart disease (CHD), myocardial infarction (MI), nor stroke; and instruments for increased tobacco use, controlling for alcohol use, associated with decreased HDL-C, increased triglycerides, and increased risk of CHD and MI. Exploratory analysis found associations with HDL-C, LDL-C, and intermediate-density-lipoprotein metabolites. Consistency of results across complementary methods accommodating different MR assumptions strengthened causal inference, providing strong genetic evidence for the causal effects of modifiable lifestyle risk factors on CVD risk.

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Daytime sleepiness, night sleep changes and ALS: a Mendelian randomization study

10.21203/rs.3.rs-34260/v1 ◽

2020 ◽

Author(s):

Gan Zhang ◽

Linjing Zhang ◽

Tao Huang ◽

Dongsheng Fan

Keyword(s):

Sleep Duration ◽

Daytime Sleepiness ◽

Mendelian Randomization ◽

Association Studies ◽

Sleep Efficiency ◽

Genome Wide Association Studies ◽

Night Sleep ◽

Inverse Variance ◽

Point Increase ◽

Increased Risk

Abstract Background Observational studies have indicated that there is a high prevalence of daytime sleepiness and night sleep changes in amyotrophic lateral sclerosis (ALS). However, the actual relation between these symptoms and ALS remains unclear. We aimed to determine whether daytime sleepiness and night sleep changes have an effect on ALS. Methods We used 2-sample mendelian randomization to estimate the effects of daytime sleepiness, sleep efficiency, number of sleep episodes and sleep duration on ALS. Summary statistics we used was from resent and large genome-wide association studies on the traits we chosen (n = 85,670–452,071) and ALS (cases n = 20,806, controls n = 59,804). Inverse variance weighted method was used as the main method for assessing causality. Results A genetically predicted 1-point increase in the assessment of daytime sleepiness was significantly associated with an increased risk of ALS (inverse-variance-weighted (IVW) odds ratio = 2.70, 95% confidence interval (CI): 1.27–5.76; P = 0.010). ALS was not associated with a genetically predicted 1-SD increase in sleep efficiency (IVW 1.01, 0.64–1.58; P = 0.973), Number of sleep episodes (IVW 1.02, 0.80–1.30; P = 0.859) or sleep duration (IVW 1.00, 1.00–1.01; P = 0.250). Conclusions Our results provide novel evidence that daytime sleepiness causes an increase in the risk of ALS and indicate that daytime sleepiness may be inherent in preclinical and clinical ALS patients, rather than simply affected by potential influencing factors.

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A Review of the Hereditary Component of Triple Negative Breast Cancer: High- and Moderate-Penetrance Breast Cancer Genes, Low-Penetrance Loci, and the Role of Nontraditional Genetic Elements

Journal of Oncology ◽

10.1155/2019/4382606 ◽

2019 ◽

Vol 2019 ◽

pp. 1-10 ◽

Cited By ~ 11

Author(s):

Darrell L. Ellsworth ◽

Clesson E. Turner ◽

Rachel E. Ellsworth

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Large Scale ◽

Triple Negative ◽

Association Studies ◽

African Ancestry ◽

Genome Wide Association Studies ◽

Genetic Elements ◽

Genome Wide ◽

Increased Risk

Triple negative breast cancer (TNBC), representing 10-15% of breast tumors diagnosed each year, is a clinically defined subtype of breast cancer associated with poor prognosis. The higher incidence of TNBC in certain populations such as young women and/or women of African ancestry and a unique pathological phenotype shared between TNBC and BRCA1-deficient tumors suggest that TNBC may be inherited through germline mutations. In this article, we describe genes and genetic elements, beyond BRCA1 and BRCA2, which have been associated with increased risk of TNBC. Multigene panel testing has identified high- and moderate-penetrance cancer predisposition genes associated with increased risk for TNBC. Development of large-scale genome-wide SNP assays coupled with genome-wide association studies (GWAS) has led to the discovery of low-penetrance TNBC-associated loci. Next-generation sequencing has identified variants in noncoding RNAs, viral integration sites, and genes in underexplored regions of the human genome that may contribute to the genetic underpinnings of TNBC. Advances in our understanding of the genetics of TNBC are driving improvements in risk assessment and patient management.

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Family history of venous thromboembolism as a risk factor and genetic research tool

Thrombosis and Haemostasis ◽

10.1160/th15-04-0306 ◽

2015 ◽

Vol 114 (11) ◽

pp. 890-900 ◽

Cited By ~ 15

Author(s):

Xinjun Li ◽

Henrik Ohlsson ◽

Jianguang Ji ◽

Jan Sundquist ◽

Kristina Sundquist ◽

...

Keyword(s):

Risk Factor ◽

Venous Thromboembolism ◽

Family History ◽

Genetic Factors ◽

Familial Aggregation ◽

Association Studies ◽

Genetic Research ◽

Research Tool ◽

Genome Wide Association Studies ◽

Venous Diseases

SummaryFamilial clustering of venous thromboembolism (VTE) was described as far back as 1905 by Briggs. Although Egeberg discovered inherited deficiency of antithrombin in 1965, it was not until Dahlback discovered resistance to activated protein C in 1993 that it became clear that genetic factors are common risk factors of VTE. Several genes have been linked to familial aggregation of VTE and genome-wide association studies have found several novel gene loci. Still, it has been estimated that much of the heritability for VTE remains to be discovered. Family history (FH) of VTE is therefore still important to determine whether a patient has an increased genetic risk of VTE. FH has the potential to represent the sum of effects and interactions between environmental and genetic factors. In this article the design, methodology, results, clinical and genetic implications of FH studies of VTE are reviewed. FH in first-degree relatives (siblings and/or parents) is associated with a 2–3 times increased familial relative risk (FRR). However, the FRR is dependent on age, number of affected relatives, and presentation of VTE (provoked/unprovoked). Especially high familial risks are observed in individuals with two or more affected siblings (FFR> 50). However, the familial risk for recurrent VTE is much lower or non-significant. Moreover, FH of VTE appears mainly to be important for venous diseases (i. e. VTE and varicose veins). The familial associations with other diseases are weaker. In conclusion, FH of VTE is an important research tool and a clinically potential useful risk factor for VTE.

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Univariable and Multivariable Two-Sample Mendelian Randomization Investigating the Effects of Leisure Sedentary Behaviors on the Risk of Lung Cancer

Frontiers in Genetics ◽

10.3389/fgene.2021.742718 ◽

2021 ◽

Vol 12 ◽

Author(s):

Haoxin Peng ◽

Xiangrong Wu ◽

Yaokai Wen ◽

Yiyuan Ao ◽

Yutian Li ◽

...

Keyword(s):

Lung Cancer ◽

Computer Use ◽

Mendelian Randomization ◽

Causal Effect ◽

Association Studies ◽

Sensitivity Analyses ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Sedentary Behaviors ◽

Watching Tv

Background:Leisure sedentary behaviors (LSB) are widespread, and observational studies have provided emerging evidence that LSB play a role in the development of lung cancer (LC). However, the causal inference between LSB and LC remains unknown.Methods: We utilized univariable (UVMR) and multivariable two-sample Mendelian randomization (MVMR) analysis to disentangle the effects of LSB on the risk of LC. MR analysis was conducted with genetic variants from genome-wide association studies of LSB (408,815 persons from UK Biobank), containing 152 single-nucleotide polymorphisms (SNPs) for television (TV) watching, 37 SNPs for computer use, and four SNPs for driving, and LC from the International Lung Cancer Consortium (11,348 cases and 15,861 controls). Multiple sensitivity analyses were further performed to verify the causality.Results: UVMR demonstrated that genetically predisposed 1.5-h increase in LSB spent on watching TV increased the odds of LC by 90% [odds ratio (OR), 1.90; 95% confidence interval (CI), 1.44–2.50; p < 0.001]. Similar trends were observed for squamous cell lung cancer (OR, 1.97; 95%CI, 1.31–2.94; p = 0.0010) and lung adenocarcinoma (OR, 1.64; 95%CI 1.12–2.39; p = 0.0110). The causal effects remained significant after adjusting for education (OR, 1.97; 95%CI, 1.44–2.68; p < 0.001) and body mass index (OR, 1.86; 95%CI, 1.36–2.54; p < 0.001) through MVMR approach. No association was found between prolonged LSB spent on computer use and driving and LC risk. Genetically predisposed prolonged LSB was additionally correlated with smoking (OR, 1.557; 95%CI, 1.287–1.884; p < 0.001) and alcohol consumption (OR, 1.010; 95%CI, 1.004–1.016; p = 0.0016). Consistency of results across complementary sensitivity MR methods further strengthened the causality.Conclusion: Robust evidence was demonstrated for an independent, causal effect of LSB spent on watching TV in increasing the risk of LC. Further work is necessary to investigate the potential mechanisms.

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Association of 25 hydroxyvitamin D concentration with risk of COVID-19: a Mendelian randomization study

10.1101/2020.08.09.20171280 ◽

2020 ◽

Author(s):

Di Liu ◽

Qiuyue Tian ◽

Jie Zhang ◽

Haifeng Hou ◽

Wei Wang ◽

...

Keyword(s):

Causal Relationship ◽

Mendelian Randomization ◽

Association Studies ◽

Sensitivity Analyses ◽

Genome Wide Association Studies ◽

Causal Association ◽

Hydroxyvitamin D ◽

Increased Risk ◽

25Ohd Concentration ◽

25 Hydroxyvitamin D

Background In observational studies, 25 hydroxyvitamin D (25OHD) concentration has been associated with an increased risk of Coronavirus disease 2019 (COVID-19). However, it remains unclear whether this association is causal. Methods We performed a two-sample Mendelian randomization (MR) to explore the causal relationship between 25OHD concentration and COVID-19, using summary data from the genome-wide association studies (GWASs) and using 25OHD concentration-related SNPs as instrumental variables (IVs). Results MR analysis did not show any evidence of a causal association of 25OHD concentration with COVID-19 susceptibility and severity (odds ratio [OR]=1.136, 95% confidence interval [CI] 0.988-1.306, P=0.074; OR=0.889, 95% CI 0.549-1.439, P=0.632). Sensitivity analyses using different instruments and statistical models yielded similar findings, suggesting the robustness of the causal association. No obvious pleiotropy bias and heterogeneity were observed. Conclusion The MR analysis showed that there might be no linear causal relationship of 25OHD concentration with COVID-19 susceptibility and severity.

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Causal Association between Serum Thyroid-Stimulating Hormone and Obesity: A Bidirectional Mendelian Randomization Study

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgab183 ◽

2021 ◽

Author(s):

Xichang Wang ◽

Xiaotong Gao ◽

Yutong Han ◽

Fan Zhang ◽

Zheyu Lin ◽

...

Keyword(s):

Mendelian Randomization ◽

Association Studies ◽

Epidemiological Studies ◽

Thyroid Stimulating Hormone ◽

Genome Wide Association Studies ◽

Causal Association ◽

Free Triiodothyronine ◽

The Impact ◽

Serum Tsh ◽

Stimulating Hormone

Abstract Context The association between serum thyroid-stimulating hormone (TSH) and obesity traits has been investigated previously in several epidemiological studies. However, the underlying causal association has not been established. Objective To determine and analyze the causal association between serum TSH level and obesity-related traits (BMI and obesity). Design, Setting, Participants The latest genome-wide association studies (GWASs) on TSH, BMI and obesity were searched to obtain full statistics. Bidirectional two-sample Mendelian randomization (MR) was performed to explore the causal relationship between serum TSH and BMI and obesity. The inverse variance-weighted (IVW) and MR-Egger methods were used to combine the estimation for each SNP. Based on the preliminary MR results, free thyroxine (fT4) and free triiodothyronine (fT3) levels were also set as outcomes to further analyze the impact of BMI on them. Main Outcome Measures BMI and obesity were treated as the outcomes to evaluate the effect of serum TSH on them, and TSH was set as the outcome to estimate the effect of BMI and obesity on it. Results Both IVW and MR-Egger results indicated that genetically driven serum TSH did not causally lead to changes in BMI or obesity. Moreover, the IVW method showed that the TSH level could be significantly elevated by genetically predicted high BMI (β=0.038, se=0.013, p=0.004). In further MR analysis, the IVW method indicated that BMI could causally increase the fT3 (β=10.123, se=2.523, p<0.001) while not significantly affecting the fT4 level. Conclusion Together with fT3, TSH can be significantly elevated by an increase in genetically driven BMI.

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Genetically Predicted Circulating Concentrations of Micronutrients and Risk of Amyotrophic Lateral Sclerosis: A Mendelian Randomization Study

Frontiers in Genetics ◽

10.3389/fgene.2021.811699 ◽

2022 ◽

Vol 12 ◽

Author(s):

Changqing Mu ◽

Yating Zhao ◽

Chen Han ◽

Dandan Tian ◽

Na Guo ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Large Scale ◽

Mendelian Randomization ◽

Association Studies ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Inverse Variance ◽

Effective Role ◽

Copper Zinc ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive and devastating neurodegenerative disease with increasing incidence and high mortality, resulting in a considerable socio-economic burden. Till now, plenty of studies have explored the potential relationship between circulating levels of various micronutrients and ALS risk. However, the observations remain equivocal and controversial. Thus, we conducted a two-sample Mendelian randomization (MR) study to investigate the causality between circulating concentrations of 9 micronutrients, including retinol, folate acid, vitamin B12, B6 and C, calcium, copper, zinc as well as magnesium, and ALS susceptibility. In our analysis, several single nucleotide polymorphisms were collected as instrumental variables from large-scale genome-wide association studies of these 9 micronutrients. Then, inverse variance weighted (IVW) approach as well as alternative MR-Egger regression, weighted median and MR-pleiotropy residual sum and outlier (MR-PRESSO) analyses were performed to evaluate causal estimates. The results from IVW analysis showed that there was no causal relationship of 9 micronutrients with ALS risk. Meanwhile, the three complementary approaches obtained similar results. Thus, our findings indicated that supplementation of these 9 micronutrients may not play a clinically effective role in preventing the occurrence of ALS.

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