Genetically Predicted Longer Telomere Length May Reduce Risk of Hip Osteoarthritis

Objective: This two-sample Mendelian randomization (MR) study aimed to examine the potential causal association of telomere length (TL) with the risk of osteoarthritis (OA).Method: The summary-level data for OA was derived from the United Kingdom Biobank cohort, including 50,508 individuals of European descent. Eighteen single nucleotide polymorphisms associated with TL were identified as instrumental variables from the most up-to-date TL genome-wide association study (GWAS) involving over 78,592 individuals of European descent. Based on the GWASs data, MR was performed using established statistical analysis methods including the inverse variance weighted, weighted median, MR-Egger, and MR pleiotropy residual sum and outlier.Results: Genetically determined TL was not associated with the risk of total OA (IVW odds ratio [OR] = 1.00, 95% confidence interval [CI] = 0.83, 1.21). In subgroup analyses stratified by OA site, no evidence in favor of association between genetically determined TL and knee OA was found (IVW OR = 1.18, 95% CI = 0.89, 1.58). However, using WM method, we observed a limited protective effect of longer TL on the risk of hip OA (OR = 0.60, 95% CI = 0.36–0.99), whereas the results of the IVW (p = 0.931) and MR-PRESSO (p = 0.932) showed that TL had no effect on hip OA.Conclusions: This study does not support a causal association between TL and total OA. A potential protective association between longer TL and hip OA, though possible, remains less certain.

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

Frontiers in Nutrition ◽

10.3389/fnut.2021.780205 ◽

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

10.1101/2021.08.12.21261493 ◽

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.

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Genetically Predicted Telomere Length and Its Relationship With Alzheimer’s Disease

Frontiers in Genetics ◽

10.3389/fgene.2021.595864 ◽

2021 ◽

Vol 12 ◽

Author(s):

Guangping Yu ◽

Leihong Lu ◽

Zaihong Ma ◽

Shouhai Wu

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Telomere Length ◽

Genome Wide Association Study ◽

Nucleotide Polymorphisms ◽

Genome Wide ◽

Inverse Variance ◽

A Genome ◽

Summary Effect ◽

Weighted Median

Are shorter telomeres causal risk factors for Alzheimer’s disease (AD)? This study aimed to examine if shorter telomeres were causally associated with a higher risk of AD using Mendelian randomization (MR) analysis. Two-sample MR methods were applied to the summary effect sizes and standard errors from a genome-wide association study for AD. Twenty single nucleotide polymorphisms of genome-wide significance were selected as instrumental variables for leukocyte telomere length. The main analyses were performed primarily using the random-effects inverse-variance weighted method and complemented with the other three methods: weighted median approaches, MR-Egger regression, and weighted mode approach. The intercept of MR-Egger regression was used to assess horizontal pleiotropy. We found that longer telomeres were associated with lower risks of AD (odds ratio = 0.79, 95% confidence interval: 0.67, 0.93, P = 0.004). Comparable results were obtained using weighted median approaches, MR-Egger regression, and weighted mode approaches. The intercept of the MR-Egger regression was close to zero. This may show that there was not suggestive of horizontal pleiotropy. Our findings provided additional evidence regarding the putative causal association between shorter telomere length and the higher risk of AD.

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

The International Journal of Neuropsychopharmacology ◽

10.1093/ijnp/pyaa062 ◽

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.

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Serum 25-hydroxyvitamin D levels and risk of lung cancer and histologic types: a Mendelian randomisation analysis of the HUNT study

European Respiratory Journal ◽

10.1183/13993003.00329-2018 ◽

2018 ◽

Vol 51 (6) ◽

pp. 1800329 ◽

Cited By ~ 4

Author(s):

Yi-Qian Sun ◽

Ben M. Brumpton ◽

Carolina Bonilla ◽

Sarah J. Lewis ◽

Stephen Burgess ◽

...

Keyword(s):

Lung Cancer ◽

Cohort Study ◽

Population Based ◽

Mendelian Randomisation ◽

Nucleotide Polymorphisms ◽

Hydroxyvitamin D ◽

Inverse Variance ◽

25 Hydroxyvitamin D ◽

Histologic Types ◽

Genetically Determined

We aimed to investigate potential causal associations between serum 25-hydroxyvitamin D (25(OH)D) levels and incidence of lung cancer overall and histologic types.We performed a Mendelian randomisation analysis using a prospective cohort study in Norway, including 54 580 individuals and 676 incident lung cancer cases. A 25(OH)D allele score was generated based on the vitamin D-increasing alleles rs2282679, rs12785878 and rs10741657. Hazard ratios with 95% confidence intervals for incidence of lung cancer and histologic types were estimated in relation to the allele score. The inverse-variance weighted method using summarised data of individual single nucleotide polymorphisms was applied to calculate the Mendelian randomisation estimates.The allele score accounted for 3.4% of the variation in serum 25(OH)D levels. There was no association between the allele score and lung cancer incidence overall, with HR 0.99 (95% CI 0.93–1.06) per allele score. A 25 nmol·L−1increase in genetically determined 25(OH)D level was not associated with the incidence of lung cancer overall (Mendelian randomisation estimate HR 0.96, 95% CI 0.54–1.69) or any histologic type.Mendelian randomisation analysis did not suggest a causal association between 25(OH)D levels and risk of lung cancer overall or histologic types in this population-based cohort study.

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The causal effect of educational attainment on Alzheimer’s disease: A two-sample Mendelian randomization study

10.1101/127993 ◽

2017 ◽

Cited By ~ 5

Author(s):

Emma L Anderson ◽

Kaitlin H Wade ◽

Gibran Hemani ◽

Jack Bowden ◽

Roxanna Korologou-Linden ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Educational Attainment ◽

Genome Wide Association Study ◽

Causal Effect ◽

Sensitivity Analyses ◽

Nucleotide Polymorphisms ◽

Inverse Variance ◽

Higher Educational Attainment ◽

Years Of Schooling

ABSTRACTBackgroundObservational evidence suggests that higher educational attainment is protective for Alzheimer’s disease (AD). It is unclear whether this association is causal or confounded by demographic and socioeconomic characteristics. We examined the causal effect of educational attainment on AD in a two-sample MR framework.MethodsWe extracted all available effect estimates of the 74 single nucleotide polymorphisms (SNPs) associated with years of schooling from the largest genome-wide association study (GWAS) of educational attainment (N=293,723) and the GWAS of AD conducted by the International Genomics of Alzheimer’s Project (n=17,008 AD cases and 37,154 controls). SNP-exposure and SNP-outcome coefficients were combined using an inverse variance weighted approach, providing an estimate of the causal effect of each SD increase in years of schooling on AD. We also performed appropriate sensitivity analyses examining the robustness of causal effect estimates to the various assumptions and conducted simulation analyses to examine potential survival bias of MR analyses.FindingsWith each SD increase in years of schooling (3.51 years), the odds of AD were, on average, reduced by approximately one third (odds ratio= 0.63, 95% confidence interval [CI]: 0.48 to 0.83, p<0.001). Causal effect estimates were consistent when using causal methods with varying MR assumptions or different sets of SNPs for educational attainment, lending confidence to the magnitude and direction of effect in our main findings. There was also no evidence of survival bias in our study.InterpretationOur findings support a causal role of educational attainment on AD, whereby an additional ∼3.5 years of schooling reduces the odds of AD by approximately one third.

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

Journal of Translational Medicine ◽

10.1186/s12967-021-03198-2 ◽

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.

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Blood Pressure and Risk of Cardiovascular Disease in UK Biobank

Hypertension ◽

10.1161/hypertensionaha.120.16138 ◽

2021 ◽

Author(s):

Eric Yuk Fai Wan ◽

Wing Tung Fung ◽

C. Mary Schooling ◽

Shiu Lun Au Yeung ◽

Man Ki Kwok ◽

...

Keyword(s):

Blood Pressure ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

Randomization Test ◽

Sensitivity Analyses ◽

Nucleotide Polymorphisms ◽

Causal Association ◽

Uk Biobank ◽

Cvd Risk ◽

The Uk

This study aims to evaluate the causal association of blood pressure (BP) with cardiovascular diseases (CVDs). Two-sample Mendelian randomization was performed using a large genome-wide association study (n=299 024) and the UK Biobank cohort (n=375 256). We identified 327 and 364 single-nucleotide polymorphisms strongly and independently associated with systolic BP and diastolic BP, respectively, as genetic instruments to assess the causal association of BP with total CVD, CVD mortality, and 14 cardiovascular conditions. Nonlinearity was examined with nonlinear instrumental variable assumptions. Genetically predicted BP was significantly positively associated with total CVD (systolic BP, per 10 mm Hg: odds ratio [OR], 1.32 [95% CI, 1.25–1.40]; diastolic BP, per 5 mm Hg: OR, 1.20 [95% CI, 1.15–1.26]). Similar positive causal associations were observed for 14 cardiovascular conditions including ischemic heart disease (systolic BP, per 10 mm Hg: OR, 1.33 [95% CI, 1.24–1.41]; diastolic BP, per 5 mm Hg: OR, 1.20 [95% CI, 1.14–1.27]) and stroke (systolic BP, per 10 mm Hg: OR, 1.35 [95% CI, 1.24–1.48]; diastolic BP, per 5 mm Hg: OR, 1.20 [95% CI, 1.12–1.28]). Nonlinearity Mendelian randomization test demonstrated linear causal association of BP with these outcomes. Consistent estimates were observed in sensitivity analyses, suggesting robustness of the associations and minimal horizontal pleiotropy. The linear positive causal association of BP and CVD was consistent with previous findings that lower BP is better, thus consolidating clinical knowledge on hypertension management in CVD risk reduction.

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Genome-Wide Association Study of Response to Selenium Supplementation and Circulating Selenium Concentrations in Adults of European Descent

Journal of Nutrition ◽

10.1093/jn/nxaa355 ◽

2020 ◽

Author(s):

Ken Batai ◽

Mario J Trejo ◽

Yuliang Chen ◽

Lindsay N Kohler ◽

Peter Lance ◽

...

Keyword(s):

Genome Wide Association Study ◽

Association Studies ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

European Descent ◽

Significance Level ◽

Genome Wide ◽

A Genome ◽

Basal Plasma

ABSTRACT Background Selenium (Se) is a trace element that has been linked to many health conditions. Genome-wide association studies (GWAS) have identified variants for blood and toenail Se levels, but no GWAS has been conducted to date on responses to Se supplementation. Objectives A GWAS was performed to identify the single nucleotide polymorphisms (SNPs) associated with changes in Se concentrations after 1 year of supplementation. A GWAS of basal plasma Se concentrations at study entry was conducted to evaluate whether SNPs for Se responses overlap with SNPs for basal Se levels. Methods A total of 428 participants aged 40–80 years of European descent from the Selenium and Celecoxib Trial (Sel/Cel Trial) who received daily supplementation with 200 µg of selenized yeast were included for the GWAS of responses to supplementation. Plasma Se concentrations were measured from blood samples collected at the time of recruitment and after 1 year of supplementation. Linear regression analyses were performed to assess the relationship between each SNP and changes in Se concentrations. We further examined whether the identified SNPs overlapped with those related to basal Se concentrations. Results No SNP was significantly associated with changes in Se concentration at a genome-wide significance level. However, rs56856693, located upstream of the NEK6, was nominally associated with changes in Se concentrations after supplementation (P = 4.41 × 10−7), as were 2 additional SNPs, rs11960388 and rs6887869, located in the dimethylglycine dehydrogenase (DMGDH)/betaine-homocysteine S-methyltransferase (BHMT) region (P = 0.01). Alleles of 2 SNPs in the DMGDH/BHMT region associated with greater increases in Se concentrations after supplementation were also strongly associated with higher basal Se concentrations (P = 8.67 × 10−8). Conclusions This first GWAS of responses to Se supplementation in participants of European descent from the Sel/Cel Trial suggests that SNPs in the NEK6 and DMGDH/BHMT regions influence responses to supplementation.

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Relationship Between Serum Amino Acid Levels and Bone Mineral Density: A Mendelian Randomization Study

Frontiers in Endocrinology ◽

10.3389/fendo.2021.763538 ◽

2021 ◽

Vol 12 ◽

Author(s):

Zhiyong Cui ◽

Hui Feng ◽

Baichuan He ◽

Jinyao He ◽

Yun Tian

Keyword(s):

Bone Mineral Density ◽

Bone Mineral ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

Nucleotide Polymorphisms ◽

Mineral Density ◽

Global Test ◽

Inverse Variance ◽

Profile Score ◽

Total Body

BackgroundThis study aimed to explore the association between serum amino acids (AAs) levels and bone mineral density (BMD).MethodsWe performed a two-sample Mendelian randomization (MR) analysis to analyze the associations between the levels of eight AAs and BMD values by using summary-level genome-wide association study (GWAS) data. We applied the MR Steiger filtering method and MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) global test to check for and remove single nucleotide polymorphisms (SNPs) that were horizontally pleiotropic. The associations were estimated with the inverse variance weighted (IVW), MR-Egger, weighted median and MR Robust Adjusted Profile Score (MR.RAPS) methods.ResultsOur study found that genetically increased isoleucine (Ile) [IVW: effect = 0.1601, 95% confidence interval (CI) = 0.0604 ~ 0.2597, p = 0.0016] and valine (Val) levels (IVW: effect = 0.0953, 95% CI = 0.0251 ~ 0.1655, p = 0.0078) were positively associated with total body BMD (TB-BMD). The results also revealed that genetically increased tyrosine (Tyr) levels were negatively associated with TB-BMD (IVW: effect = -0.1091, 95% CI = -0.1863 ~ -0.0320, p = 0.0055).ConclusionsIn this study, associations between serum AA levels and BMD were established. These findings underscore the important role that serum AAs play in the development of osteoporosis and provide evidence that osteoporosis can be prevented and treated by the intake of certain AAs.

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