scholarly journals Salicylic acid and risk of colorectal cancer: a two sample Mendelian randomization study

2021 ◽  
Author(s):  
Aayah Nounu ◽  
Rebecca C Richmond ◽  
Isobel D Stewart ◽  
Praveen Surendran ◽  
Nicholas J. Wareham ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Salicylic Acid ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Significant Snps ◽  
Nucleotide Polymorphisms ◽  
Functional Snps ◽  
Genome Wide ◽  
Inverse Variance ◽  
Colon Cancer Family Registry

Background Salicylic acid (SA) is a metabolite that can be obtained from the diet via fruit and vegetable ingestion, of which increased consumption has observationally been shown to decrease risk of colorectal cancer (CRC). Whilst primary prevention trials of SA and CRC risk are lacking, there is strong evidence from clinical trials and prospective cohort studies that aspirin (acetylsalicylic acid) is an effective primary and secondary chemopreventative agent. Since aspirin is rapidly deacetylated to form SA, it follows that SA may have a central role for aspirin chemoprevention. Through a Mendelian randomization (MR) approach, we aimed to address whether levels of SA affected CRC risk, and whether aspirin intake as a proxy for increased SA levels was required to identify an effect. Methods and Findings A two sample MR analysis was carried out using genome-wide association study summary statistics of SA from INTERVAL and EPIC-Norfolk (N= 14,149) and CRC from Colon Cancer Family Registry (CCFR), Colorectal Cancer Transdisciplinary Study (CORECT), Genetics and Epidemiology of Colorectal Cancer (GECCO) consortia and UK Biobank (55,168 cases and 65,160 controls). The Darmkrebs: Chancen der Verhütung durch Screening (DACHS) study (4,410 cases and 3,441 controls) was used for replication and stratification of aspirin-users and non-users. Single nucleotide polymorphisms (SNPs) for SA were selected via three methods: (1) Functional SNPs that influence aspirin and SA metabolising enzymes' activity; (2) Pathway SNPs, those that are present in the coding regions of genes involved in aspirin and SA metabolism; and (3) genome-wide significant SNPs associated with levels of circulating SA. No association was found between the functional SNPs and SA levels, therefore they were not taken forward in an MR analysis. We identified 2 pathway SNPs (explaining 0.03% of the variance in SA levels and with an F statistic of 1.74) and 1 genome-wide independent SNP (explaining 0.05% of the variance and with an F statistic of 7.44) to proxy for SA levels. Using the pathway SNPs, an inverse variance weighted approach found no association between an SD increase in SA and CRC risk (GECCO OR:1.03, 95% CI: 0.84-1.27 and DACHS OR:1.10, 95% CI:0.58-2.07) and no association was found upon stratification between aspirin users and non-users in the DACHS study (OR:0.93, 95% CI:0.23-3.73 and OR:1.24, 95% CI:0.57-2.69, respectively). Wald ratio results using the genome-wide SNP also showed no association between an SD increase in SA and CRC risk (GECCO OR: 1.08, 95% CI:0.86-1.34 and DACHS OR: 1.01, 95% CI:0.44-2.31) and no effect was observed upon stratification by aspirin use (users OR:0.66, 95% CI: 0.11-4.12 and non-users OR: 1.12, 95% CI: 0.42-2.97). Conclusions We found no evidence to suggest that an SD increase in genetically predicted SA protects against CRC risk in the general population and upon stratification by aspirin use. However, based on the calculated variance explained by the SNPs and the F statistic, we acknowledge the possibility of weak instrument bias and the need to find better instruments for SA levels.

scholarly journals Salicylic Acid and Risk of Colorectal Cancer: A Two-Sample Mendelian Randomization Study

Nutrients ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 4164
Author(s):  
Aayah Nounu ◽  
Rebecca C. Richmond ◽  
Isobel D. Stewart ◽  
Praveen Surendran ◽  
Nicholas J. Wareham ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Salicylic Acid ◽  
Mendelian Randomization ◽  
Significant Snps ◽  
Summary Statistics ◽  
Uk Biobank ◽  
Coding Regions ◽  
Chemopreventive Agent ◽  
Functional Snps ◽  
Genome Wide

Salicylic acid (SA) has observationally been shown to decrease colorectal cancer (CRC) risk. Aspirin (acetylsalicylic acid, that rapidly deacetylates to SA) is an effective primary and secondary chemopreventive agent. Through a Mendelian randomization (MR) approach, we aimed to address whether levels of SA affected CRC risk, stratifying by aspirin use. A two-sample MR analysis was performed using GWAS summary statistics of SA (INTERVAL and EPIC-Norfolk, N = 14,149) and CRC (CCFR, CORECT, GECCO and UK Biobank, 55,168 cases and 65,160 controls). The DACHS study (4410 cases and 3441 controls) was used for replication and stratification of aspirin-use. SNPs proxying SA were selected via three methods: (1) functional SNPs that influence the activity of aspirin-metabolising enzymes; (2) pathway SNPs present in enzymes’ coding regions; and (3) genome-wide significant SNPs. We found no association between functional SNPs and SA levels. The pathway and genome-wide SNPs showed no association between SA and CRC risk (OR:1.03, 95% CI: 0.84–1.27 and OR: 1.08, 95% CI:0.86–1.34, respectively). Results remained unchanged upon aspirin use stratification. We found little evidence to suggest that an SD increase in genetically predicted SA protects against CRC risk in the general population and upon stratification by aspirin use.

scholarly journals Periodontal disease increases the host susceptibility to COVID-19 and its severity: a Mendelian randomization study

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Yi Wang ◽  
Hui Deng ◽  
Yihuai Pan ◽  
Lijian Jin ◽  
Rongdang Hu ◽  
...  
Keyword(s):  
Periodontal Disease ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Host Susceptibility ◽  
Sensitivity Analyses ◽  
Nucleotide Polymorphisms ◽  
Genome Wide ◽  
Inverse Variance ◽  
Weighted Median ◽  
First Time

Abstract Background Emerging evidence shows that periodontal disease (PD) may increase the risk of Coronavirus disease 2019 (COVID-19) complications. Here, we undertook a two-sample Mendelian randomization (MR) study, and investigated for the first time the possible causal impact of PD on host susceptibility to COVID-19 and its severity. Methods Summary statistics of COVID-19 susceptibility and severity were retrieved from the COVID-19 Host Genetics Initiative and used as outcomes. Single nucleotide polymorphisms associated with PD in Genome-wide association study were included as exposure. Inverse-variance weighted (IVW) method was employed as the main approach to analyze the causal relationships between PD and COVID-19. Three additional methods were adopted, allowing the existence of horizontal pleiotropy, including MR-Egger regression, weighted median and weighted mode methods. Comprehensive sensitivity analyses were also conducted for estimating the robustness of the identified associations. Results The MR estimates showed that PD was significantly associated with significantly higher susceptibility to COVID-19 using IVW (OR = 1.024, P = 0.017, 95% CI 1.004–1.045) and weighted median method (OR = 1.029, P = 0.024, 95% CI 1.003–1.055). Furthermore, it revealed that PD was significantly linked to COVID-19 severity based on the comparison of hospitalization versus population controls (IVW, OR = 1.025, P = 0.039, 95% CI 1.001–1.049; weighted median, OR = 1.030, P = 0.027, 95% CI 1.003–1.058). No such association was observed in the cohort of highly severe cases confirmed versus those not hospitalized due to COVID-19. Conclusions We provide evidence on the possible causality of PD accounting for the susceptibility and severity of COVID-19, highlighting the importance of oral/periodontal healthcare for general wellbeing during the pandemic and beyond.

scholarly journals A causal association between schizophrenia and bipolar disorder on rheumatoid arthritis: A two-sample Mendelian randomization study

2021 ◽  
Author(s):  
Gonul Hazal Koc ◽  
Fatih Ozel ◽  
Kaan Okay ◽  
Dogukan Koc
Keyword(s):  
Rheumatoid Arthritis ◽  
Bipolar Disorder ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
European Ancestry ◽  
Nucleotide Polymorphisms ◽  
Causal Association ◽  
Genome Wide ◽  
Inverse Variance ◽  
Weighted Median

Background: Schizophrenia(SCZ) and bipolar disorder(BD) are both associated with several autoimmune/inflammatory disorders including rheumatoid arthritis(RA). However, a causal association of SCZ and BD on RA is controversial and elusive. In the present study, we aimed to investigate the causal association of SCZ and BD with RA by using the Mendelian randomization (MR) approach. Methods: A two-sample MR(2SMR) study including the inverse-variance weighted(IVW), weighted median, simple mode, weighted mode and MR-Egger methods were performed. We employed summary-level genome-wide association study(GWAS) data including BD and SCZ as exposure and RA as an outcome. We utilized data from the Psychiatric Genomics Consortium(PGC) for BD(n= 41,917) and SCZ(n= 33,426), whereas RA GWAS dataset (58,284 individuals) from the European ancestry. Results: We obtained independent (r2 <0.001) 48 and 52 single nucleotide polymorphisms (SNPs) from BD and SCZ data at genome-wide significance (p <5x10-8), respectively. Next, these SNPs were utilized as instrumental variables(IVs) in 2SMR analysis to explore the causality of BD and SCZ on RA. The two out of five MR methods showed a statistically significant inverse causal association between BD and RA: weighted median method(odds ratio (OR), 0.869, [95% CI, 0.764-0.989]; P= 0.034) and inverse-variance weighted(IVW) method (OR, 0.810, [95% CI, 0.689-0.953]; P= 0.011). However, we did not find any significant association of SCZ with RA (OR, 1.008, [95% CI, 0.931-1.092]; P= 0.829, using the IVW method). Conclusions: These results provide support for an inverse causal association between BD and RA. Further investigation is needed to explain the underlying protective mechanisms in the development of RA.

scholarly journals Causal Associations between Serum Urea and Cancer: A Mendelian Randomization Study

Genes ◽  
2021 ◽  
Vol 12 (4) ◽  
pp. 498
Author(s):  
Yandi Sun ◽  
Jingjia Li ◽  
Zihao Qu ◽  
Ze Yang ◽  
Xueyao Jia ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Sensitivity Analyses ◽  
Nucleotide Polymorphisms ◽  
Serum Urea ◽  
Urea Level ◽  
Genome Wide ◽  
Inverse Variance ◽  
Weighted Median ◽  
First Time

Urea is largely derived from the urea cycle reactions through hepatic detoxification of free ammonia and cleared by urination, and the serum urea level is a crucial medical indicator for measuring the kidney function in patients with nephropathy; however, investigative revelations pointing to the serum urea level as a risk factor for cancer are very scarce, and relevant studies are restricted by potential biases. We aimed to explore the causal relationships of the serum urea level with cancer development by focusing on renal cell carcinoma (RCC) using the Mendelian randomization (MR) analyses. Summary estimates were collected from the inverse-variance weighted (IVW) method based on six single nucleotide polymorphisms (SNPs). The selected SNPs related to the serum urea were obtained from a large genome-wide association study (GWAS) of 13,312 European participants. The summary statistics of RCC were also available from public databases (IARC, n = 5219 cases, n = 8011 controls). Sensitivity analyses included the weighted median and MR-Egger methods. Serum urea was inversely associated with RCC in females (effect = 1.93; 95% CI: 1.24 to 3.01; p = 0.004) but exhibited null association with RCC in males, breast cancer (BRCA) in both genders and prostate cancer (PCa) in males. Similar conclusions were also drawn from the weighted median and MR-Egger. These findings reveal an intriguing link between serum urea and cancer risks for the very first time. Without ambiguity, the serum urea is causatively related to RCC specifically in females, although the mechanism(s) by which urea is involved in RCC development remains to be experimentally/clinically investigated. Our studies may well provide novel insights for RCC diagnosis, intervention and/or therapy.

scholarly journals Adiposity, metabolites, and colorectal cancer risk: Mendelian randomization study

BMC Medicine ◽  
2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Caroline J. Bull ◽  
Joshua A. Bell ◽  
Neil Murphy ◽  
Eleanor Sanderson ◽  
George Davey Smith ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Genome Wide Association Studies ◽  
Metabolic Alterations ◽  
Genome Wide ◽  
Inverse Variance ◽  
Colon Cancer Family Registry

Abstract Background Higher adiposity increases the risk of colorectal cancer (CRC), but whether this relationship varies by anatomical sub-site or by sex is unclear. Further, the metabolic alterations mediating the effects of adiposity on CRC are not fully understood. Methods We examined sex- and site-specific associations of adiposity with CRC risk and whether adiposity-associated metabolites explain the associations of adiposity with CRC. Genetic variants from genome-wide association studies of body mass index (BMI) and waist-to-hip ratio (WHR, unadjusted for BMI; N = 806,810), and 123 metabolites from targeted nuclear magnetic resonance metabolomics (N = 24,925), were used as instruments. Sex-combined and sex-specific Mendelian randomization (MR) was conducted for BMI and WHR with CRC risk (58,221 cases and 67,694 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry). Sex-combined MR was conducted for BMI and WHR with metabolites, for metabolites with CRC, and for BMI and WHR with CRC adjusted for metabolite classes in multivariable models. Results In sex-specific MR analyses, higher BMI (per 4.2 kg/m2) was associated with 1.23 (95% confidence interval (CI) = 1.08, 1.38) times higher CRC odds among men (inverse-variance-weighted (IVW) model); among women, higher BMI (per 5.2 kg/m2) was associated with 1.09 (95% CI = 0.97, 1.22) times higher CRC odds. WHR (per 0.07 higher) was more strongly associated with CRC risk among women (IVW OR = 1.25, 95% CI = 1.08, 1.43) than men (IVW OR = 1.05, 95% CI = 0.81, 1.36). BMI or WHR was associated with 104/123 metabolites at false discovery rate-corrected P ≤ 0.05; several metabolites were associated with CRC, but not in directions that were consistent with the mediation of positive adiposity-CRC relations. In multivariable MR analyses, associations of BMI and WHR with CRC were not attenuated following adjustment for representative metabolite classes, e.g., the univariable IVW OR for BMI with CRC was 1.12 (95% CI = 1.00, 1.26), and this became 1.11 (95% CI = 0.99, 1.26) when adjusting for cholesterol in low-density lipoprotein particles. Conclusions Our results suggest that higher BMI more greatly raises CRC risk among men, whereas higher WHR more greatly raises CRC risk among women. Adiposity was associated with numerous metabolic alterations, but none of these explained associations between adiposity and CRC. More detailed metabolomic measures are likely needed to clarify the mechanistic pathways.

scholarly journals Genome-Wide Association study Identifies a Novel Association Between a Cardiovascular Gene Polymorphism and Superior Athletic Performance

2020 ◽  
Author(s):  
Mohamed Elrayess ◽  
Fatima Al-Khelaifi ◽  
Noha Yousri ◽  
Omar Al-Bagha
Keyword(s):  
Athletic Performance ◽  
Genome Wide Association Study ◽  
Endurance Athlete ◽  
Meta Analysis ◽  
Significant Snps ◽  
Nucleotide Polymorphisms ◽  
Replication Studies ◽  
Genome Wide ◽  
Small Effect Size ◽  
Metabolomics Analysis

Research into the genetic predisposition to superior athletic performance has been a hindered by the underpowered studies and the small effect size of identified genetic variants. The aims of this study were to investigate the association of common single-nucleotide polymorphisms (SNPs) with endurance athlete status in a large cohort of elite European athletes using GWAS approach, followed by replication studies in Russian and Japanese elite athletes and functional validation using metabolomics analysis. Results: The association of 476,728 SNPs of Illumina DrugCore Gene chip and endurance athlete status was investigated in 796 European international-level athletes (645 males, 151 females) by comparing allelic frequencies between athletes specialized in sports with high (n=662) and low/moderate (n=134) aerobic component. Validation of results was performed by comparing the frequencies of the most significant SNPs between 242 and 168 elite Russian high and low/moderate aerobic athletes, respectively, and between 60 elite Japanese endurance athletes and 406 controls. A meta-analysis has identified rs1052373 (GG homozygotes) in Myosin Binding Protein (MYBPC3; implicated in cardiac hypertrophic myopathy) gene to be associated with endurance athlete status (P=1.43E-08, odd ratio 2.2). Homozygotes carriers of rs1052373 G allele in Russian athletes had significantly greater VO2max than carriers of the AA+AG (P = 0.005). Subsequent metabolomics analysis revealed several amino acids and lipids associated with rs1052373 G allele (1.82x10-05) including the testosterone precursor androstenediol (3beta, 17beta) disulfate. Conclusion: This is the first report of genome-wide significant SNP and related metabolites associated with elite athlete status. Further investigations of the functional relevance of the identified SNPs and metabolites in relation to enhanced athletic performance are warranted.

scholarly journals Assessing causality in associations between cannabis use and schizophrenia risk: a two-sample Mendelian randomization study

2016 ◽  
Vol 47 (5) ◽  
pp. 971-980 ◽  
Author(s):  
S. H. Gage ◽  
H. J. Jones ◽  
S. Burgess ◽  
J. Bowden ◽  
G. Davey Smith ◽  
...  
Keyword(s):  
Fixed Effects ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Positive Control ◽  
Negative Control ◽  
Study Data ◽  
Nucleotide Polymorphisms ◽  
Genome Wide ◽  
Genome Wide Data

BackgroundObservational associations between cannabis and schizophrenia are well documented, but ascertaining causation is more challenging. We used Mendelian randomization (MR), utilizing publicly available data as a method for ascertaining causation from observational data.MethodWe performed bi-directional two-sample MR using summary-level genome-wide data from the International Cannabis Consortium (ICC) and the Psychiatric Genomics Consortium (PGC2). Single nucleotide polymorphisms (SNPs) associated with cannabis initiation (p < 10−5) and schizophrenia (p < 5 × 10−8) were combined using an inverse-variance-weighted fixed-effects approach. We also used height and education genome-wide association study data, representing negative and positive control analyses.ResultsThere was some evidence consistent with a causal effect of cannabis initiation on risk of schizophrenia [odds ratio (OR) 1.04 per doubling odds of cannabis initiation, 95% confidence interval (CI) 1.01–1.07, p = 0.019]. There was strong evidence consistent with a causal effect of schizophrenia risk on likelihood of cannabis initiation (OR 1.10 per doubling of the odds of schizophrenia, 95% CI 1.05–1.14, p = 2.64 × 10−5). Findings were as predicted for the negative control (height: OR 1.00, 95% CI 0.99–1.01, p = 0.90) but weaker than predicted for the positive control (years in education: OR 0.99, 95% CI 0.97–1.00, p = 0.066) analyses.ConclusionsOur results provide some that cannabis initiation increases the risk of schizophrenia, although the size of the causal estimate is small. We find stronger evidence that schizophrenia risk predicts cannabis initiation, possibly as genetic instruments for schizophrenia are stronger than for cannabis initiation.

scholarly journals Genetically Determined Levels of Serum Metabolites and Risk of Neuroticism: A Mendelian Randomization Study

2020 ◽  
Author(s):  
Li Qian ◽  
Yajuan Fan ◽  
Fengjie Gao ◽  
Binbin Zhao ◽  
Bin Yan ◽  
...  
Keyword(s):  
Uric Acid ◽  
Lower Risk ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Strong Predictor ◽  
Causal Effects ◽  
Sensitivity Analyses ◽  
Nucleotide Polymorphisms ◽  
Genetic Associations ◽  
Inverse Variance

Abstract Background Neuroticism is a strong predictor for a variety of social and behavioral outcomes, but the etiology is still unknown. Our study aims to provide a comprehensive investigation of causal effects of serum metabolome phenotypes on risk of neuroticism using Mendelian randomization (MR) approaches. Methods Genetic associations with 486 metabolic traits were utilized as exposures, and data from a large genome-wide association study of neuroticism were selected as outcome. For MR analysis, we used the standard inverse-variance weighted (IVW) method for primary MR analysis and 3 additional MR methods (MR-Egger, weighted median, and MR pleiotropy residual sum and outlier) for sensitivity analyses. Results Our study identified 31 metabolites that might have causal effects on neuroticism. Of the 31 metabolites, uric acid and paraxanthine showed robustly significant association with neuroticism in all MR methods. Using single nucleotide polymorphisms as instrumental variables, a 1-SD increase in uric acid was associated with approximately 30% lower risk of neuroticism (OR: 0.77; 95% CI: 0.62–0.95; PIVW = 0.0145), whereas a 1-SD increase in paraxanthine was associated with a 7% higher risk of neuroticism (OR: 1.07; 95% CI: 1.01–1.12; PIVW = .0145). Discussion Our study suggested an increased level of uric acid was associated with lower risk of neuroticism, whereas paraxanthine showed the contrary effect. Our study provided novel insight by combining metabolomics with genomics to help understand the pathogenesis of neuroticism.

scholarly journals Carnitine and COVID-19 Susceptibility and Severity: A Mendelian Randomization Study

2021 ◽  
Vol 8 ◽  
Author(s):  
Chunyu Li ◽  
Ruwei Ou ◽  
Qianqian Wei ◽  
Huifang Shang
Keyword(s):  
Causal Relationship ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Sensitivity Analyses ◽  
Nucleotide Polymorphisms ◽  
Carnitine Level ◽  
Standard Deviation Increase ◽  
Inverse Variance ◽  
Weighted Median ◽  
Genetically Determined

Background: Carnitine, a potential substitute or supplementation for dexamethasone, might protect against COVID-19 based on its molecular functions. However, the correlation between carnitine and COVID-19 has not been explored yet, and whether there exists causation is unknown.Methods: A two-sample Mendelian randomization (MR) analysis was conducted to explore the causal relationship between carnitine level and COVID-19. Significant single nucleotide polymorphisms from genome-wide association study on carnitine (N = 7,824) were utilized as exposure instruments, and summary statistics of the susceptibility (N = 1,467,264), severity (N = 714,592) and hospitalization (N = 1,887,658) of COVID-19 were utilized as the outcome. The causal relationship was evaluated by multiplicative random effects inverse variance weighted (IVW) method, and further verified by another three MR methods including MR Egger, weighted median, and weighted mode, as well as extensive sensitivity analyses.Results: Genetically determined one standard deviation increase in carnitine amount was associated with lower susceptibility (OR: 0.38, 95% CI: 0.19–0.74, P: 4.77E−03) of COVID-19. Carnitine amount was also associated with lower severity and hospitalization of COVID-19 using another three MR methods, though the association was not significant using the IVW method but showed the same direction of effect. The results were robust under all sensitivity analyses.Conclusions: A genetic predisposition to high carnitine levels might reduce the susceptibility and severity of COVID-19. These results provide better understandings on the role of carnitine in the COVID-19 pathogenesis, and facilitate novel therapeutic targets for COVID-19 in future clinical trials.

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