Educational Attainment Decreases the Risk of COVID-19 Severity in the European Population: A Two-Sample Mendelian Randomization Study

Observational studies have reported that the severity of COVID-19 depends not only on physical conditions but also on socioeconomic status, including educational level. Because educational attainment (EA), which measures the number of years of schooling, is moderately heritable, we investigated the causal association of EA on the risk of COVID-19 severity using the Mendelian randomization (MR) approach. A two-sample MR analysis was performed using publicly available summary-level data sets of genome-wide association studies (GWASs). A total of 235 single-nucleotide polymorphisms (SNPs) were extracted as instrumental variables for the exposure of EA from the Social Science Genetic Association Consortium GWAS summary data of 766,345 participants of European ancestry. The effect of each SNP on the outcome of COVID-19 severity risk was obtained from the GWAS summary data of 1,059,456 participants of European ancestry gathered from the COVID-19 Host Genetics Initiative. Using inverse variance weighted method, our MR study shows that EA was significantly associated with a lower risk of COVID-19 severity (odds ratio per one standard deviation increase in years of schooling, 0.540; 95% confidence interval, 0.376–0.777, P = 0.0009). A series of sensitivity analyses showed little evidence of bias. In conclusion, we show for the first time using a two-sample MR approach the associations between higher EA and the lower risk of COVID-19 severity in the European population. However, the genetic or epidemiological mechanisms underlying the association between EA and the risk of COVID-19 severity remain unknown, and further studies are warranted to validate the MR findings and investigate underlying mechanisms.

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Causal Relationship between Educational Attainment and the Risk of Rheumatoid Arthritis: A Mendelian Randomization Study

10.21203/rs.3.rs-134634/v1 ◽

2021 ◽

Author(s):

Guiwu Huang ◽

Jiahao Cai ◽

Wenchang Li ◽

Yanlin Zhong ◽

Weiming Liao ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Educational Attainment ◽

Instrumental Variables ◽

Mendelian Randomization ◽

Meta Analysis ◽

Sensitivity Analyses ◽

European Ancestry ◽

Genome Wide Association Studies ◽

Weighted Median ◽

Leave One Out

Abstract Background Educational attainment is moderately heritable and positively associated with the risk of rheumatoid arthritis. However, the causality from educational attainment on rheumatoid arthritis remained unknown. Here, we aimed to determine whether educational attainment is causally associated with rheumatoid arthritis (RA) by using a Mendelian randomization (MR) approach.Methods Summary statistics data for RA were obtained from an available, published meta-analysis of genome-wide association studies (GWAS) that included 14,361 RA cases and 43,923 controls of European ancestry. The instrumental variables for educational attainment were obtained from a GWAS meta-analysis that included over 1 million individuals (N = 1,131,881) of European ancestry. MR analyses were performed using the inverse-variance weighted (IVW), weighted median, and MR-Egger methods. Sensitivity analyses were performed to test the robustness of the association using the Cochran Q test, MR Egger intercept test, “leave-one-out” analysis and MR-PRESSO test.Results A total of 387 SNPs were employed as instrumental variables in our MR analysis. Genetically predicted higher educational attainment was associated with a significantly lower risk of RA using the IVW method (odds ratio [OR] = 0.42, 95% confidence interval [CI]: 0.34–0.52; p = 1.78×10−14). The weighted median and MR Egger methods yielded consistent results. The causality remained robust after discarding the outlier variants and SNPs associated with the confounding factors. "Leave-one-out" analysis confirmed the stability of our results. Additionally, the results demonstrated the absence of the horizontal pleiotropy.Conclusions The MR analysis supported a potential inverse causative relationship between educational attainment and the risk of RA.

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Growth Differentiation Factor 15 Is Associated With Alzheimer’s Disease Risk

Frontiers in Genetics ◽

10.3389/fgene.2021.700371 ◽

2021 ◽

Vol 12 ◽

Author(s):

Peng-Fei Wu ◽

Xing-Hao Zhang ◽

Ping Zhou ◽

Rui Yin ◽

Xiao-Ting Zhou ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mendelian Randomization ◽

Association Studies ◽

Sensitivity Analyses ◽

European Ancestry ◽

Reverse Direction ◽

Genome Wide Association Studies ◽

Growth Differentiation Factor 15 ◽

Differentiation Factor

BackgroundPrevious observational studies have suggested that associations exist between growth differentiation factor 15 (GDF-15) and neurodegenerative diseases. We aimed to investigate the causal relationships between GDF-15 and Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS).MethodsUsing summary-level datasets from genome-wide association studies of European ancestry, we performed a two-sample Mendelian randomization (MR) study. Genetic variants significantly associated (p < 5 × 10–8) with GDF-15 were selected as instrumental variables (n = 5). An inverse-variance weighted method was implemented as the primary MR approach, while weighted median, MR–Egger, leave-one-out analysis, and Cochran’s Q-test were conducted as sensitivity analyses. All analyses were performed using R 3.6.1 with relevant packages.ResultsMR provided evidence for the association of elevated GDF-15 levels with a higher risk of AD (odds ratio = 1.14; 95% confidence interval, 1.04–1.24; p = 0.004). In the reverse direction, Mendelian randomization suggested no causal effect of genetically proxied risk of AD on circulating GDF-15 (p = 0.450). The causal effects of GDF-15 on PD (p = 0.597) or ALS (p = 0.120) were not identified, and the MR results likewise did not support the association of genetic liability to PD or ALS with genetically predicted levels of GDF-15. No evident heterogeneity or horizontal pleiotropy was revealed by multiple sensitivity analyses.ConclusionWe highlighted the role of GDF-15 in AD as altogether a promising diagnostic marker and a therapeutic target.

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Association between premorbid body mass index and amyotrophic lateral sclerosis: causal inference through genetic approaches

10.1101/526186 ◽

2019 ◽

Cited By ~ 3

Author(s):

Ping Zeng ◽

Xinghao Yu ◽

Haibo Xu

Keyword(s):

Body Mass Index ◽

Amyotrophic Lateral Sclerosis ◽

Causal Relationship ◽

Body Mass ◽

European Population ◽

Sensitivity Analyses ◽

Genome Wide Association Studies ◽

Inverse Association ◽

Standard Deviation Increase ◽

Lateral Sclerosis

Background: Inverse association between premorbid body mass index (BMI) and amyotrophic lateral sclerosis (ALS) has been discovered in observational studies; however, whether this association is causal remains largely unknown. Methods: We employed a two-sample Mendelian randomization approach to evaluate the causal relationship of genetically increased BMI with the risk of ALS. The analyses were implemented using summary statistics obtained for the independent instruments identified from large-scale genome-wide association studies of BMI (up to ~770,000 individuals) and ALS (up to ~81,000 individuals). The causal relationship between BMI and ALS was estimated using inverse-variance weighted methods and was further validated through extensive complementary and sensitivity analyses. Findings: Using 1,031 instruments strongly related to BMI, the causal effect of per one standard deviation increase of BMI was estimated to be 1.04 (95% CI 0.97~1.11, p=0.275) in the European population. The null association between BMI and ALS discovered in the European population also held in the East Asian population and was robust against various modeling assumptions and outlier biases. Additionally, the Egger-regression and MR-PRESSO ruled out the possibility of horizontal pleiotropic effects of instruments. Interpretation: Our results do not support the causal role of genetically increased or decreased BMI on the risk of ALS.

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Causal Associations Between Educational Attainment and 14 Urological and Reproductive Health Outcomes: A Mendelian Randomization Study

Frontiers in Public Health ◽

10.3389/fpubh.2021.742952 ◽

2021 ◽

Vol 9 ◽

Author(s):

Menghua Wang ◽

Zhongyu Jian ◽

Xiaoshuai Gao ◽

Chi Yuan ◽

Xi Jin ◽

...

Keyword(s):

Reproductive Health ◽

Educational Attainment ◽

Health Outcomes ◽

Lower Risk ◽

Mendelian Randomization ◽

Association Studies ◽

Causal Effects ◽

Genome Wide Association Studies ◽

Bonferroni Correction ◽

The Impact

Background: The impact of educational attainment (EA) on multiple urological and reproductive health outcomes has been explored in observational studies. Here we used Mendelian randomization (MR) to investigate whether EA has causal effects on 14 urological and reproductive health outcomes.Methods: We obtained summary statistics for EA and 14 urological and reproductive health outcomes from genome-wide association studies (GWAS). MR analyses were applied to explore the potential causal association between EA and them. Inverse variance weighted was the primary analytical method.Results: Genetically predicted one standard deviation (SD) increase in EA was causally associated with a higher risk of prostate cancer [odds ratio (OR) 1.14, 95% confidence interval (CI) 1.05–1.25, P = 0.003] and a reduced risk of kidney stone (OR 0.73, 95% CI 0.62–0.87, P < 0.001) and cystitis (OR 0.76, 95% CI 0.67–0.86, P < 0.001) after Bonferroni correction. EA was also suggestively correlated with a lower risk of prostatitis (OR 0.76, 95% CI 0.59–0.98, P = 0.037) and incontinence (OR 0.64, 95% CI 0.47–0.87, P = 0.004). For the bioavailable testosterone levels and infertility, sex-specific associations were observed, with genetically determined increased EA being related to higher levels of testosterone in men (β 0.07, 95% CI 0.04–0.10, P < 0.001), lower levels of testosterone in women (β −0.13, 95% CI−0.16 to−0.11, P < 0.001), and a lower risk of infertility in women (OR 0.74, 95% CI 0.64–0.86, P < 0.001) but was not related to male infertility (OR 0.79, 95% CI 0.52–1.20, P = 0.269) after Bonferroni correction. For bladder cancer, kidney cancer, testicular cancer, benign prostatic hyperplasia, and erectile dysfunction, no causal effects were observed.Conclusions: EA plays a vital role in urological diseases, especially in non-oncological outcomes and reproductive health. These findings should be verified in further studies when GWAS data are sufficient.

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Causal association of adipokines with osteoarthritis: a Mendelian randomization study

Rheumatology ◽

10.1093/rheumatology/keaa719 ◽

2020 ◽

Author(s):

Jiayao Fan ◽

Jiahao Zhu ◽

Lingling Sun ◽

Yasong Li ◽

Tianle Wang ◽

...

Keyword(s):

Mendelian Randomization ◽

Association Studies ◽

Genome Wide Association ◽

Sensitivity Analyses ◽

European Ancestry ◽

Genome Wide Association Studies ◽

Knee Oa ◽

Genome Wide ◽

A Genome ◽

Weighted Median

Abstract Objective This two-sample Mendelian randomization study aimed to delve into the effects of genetically predicted adipokine levels on OA. Methods Summary statistic data for OA originated from a meta-analysis of a genome-wide association study with an overall 50 508 subjects of European ancestry. Publicly available summary data from four genome-wide association studies were exploited to respectively identify instrumental variables of adiponectin, leptin, resistin, chemerin and retinol-blinding protein 4. Subsequently, Mendelian randomization analyses were conducted with inverse variance weighted (IVW), weighted median and Mendelian randomization-Egger regression. Furthermore, sensitivity analyses were then conducted to assess the robustness of our results. Results The positive causality between genetically predicted leptin level and risk of total OA was indicated by IVW [odds ratio (OR): 2.40, 95% CI: 1.13–5.09] and weighted median (OR: 2.94, 95% CI: 1.23–6.99). In subgroup analyses, evidence of potential harmful effects of higher level of adiponectin (OR: 1.28, 95% CI: 1.01–1.61 using IVW), leptin (OR: 3.44, 95% CI: 1.18–10.03 using IVW) and resistin (OR: 1.18, 95% CI: 1.03–1.36 using IVW) on risk of knee OA were acquired. However, the mentioned effects on risk of hip OA were not statistically significant. Slight evidence was identified supporting causality of chemerin and retinol-blinding protein 4 for OA. The findings of this study were verified by the results from sensitivity analysis. Conclusions An association between genetically predicted leptin level and risk of total OA was identified. Furthermore, association of genetically predicted levels of adiponectin, leptin and resistin with risk of knee OA were reported.

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Association of genetically predicted blood sucrose with coronary heart disease and its risk factors in Mendelian randomization

Scientific Reports ◽

10.1038/s41598-020-78685-5 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Ting Zhang ◽

Shiu Lun Au Yeung ◽

C. Mary Schooling

Keyword(s):

Risk Factors ◽

Coronary Heart Disease ◽

Heart Disease ◽

Dental Caries ◽

Multiple Testing ◽

Mendelian Randomization ◽

Association Studies ◽

Sensitivity Analyses ◽

Genome Wide Association Studies ◽

Standard Deviation Increase

AbstractWe assessed the associations of genetically instrumented blood sucrose with risk of coronary heart disease (CHD) and its risk factors (i.e., type 2 diabetes, adiposity, blood pressure, lipids, and glycaemic traits), using two-sample Mendelian randomization. We used blood fructose as a validation exposure. Dental caries was a positive control outcome. We selected genetic variants strongly (P < 5 × 10–6) associated with blood sucrose or fructose as instrumental variables and applied them to summary statistics from the largest available genome-wide association studies of the outcomes. Inverse-variance weighting was used as main analysis. Sensitivity analyses included weighted median, MR-Egger and MR-PRESSO. Genetically higher blood sucrose was positively associated with the control outcome, dental caries (odds ratio [OR] 1.04 per log10 transformed effect size [median-normalized standard deviation] increase, 95% confidence interval [CI] 1.002–1.08, P = 0.04), but this association did not withstand allowing for multiple testing. The estimate for blood fructose was in the same direction. Genetically instrumented blood sucrose was not clearly associated with CHD (OR 1.01, 95% CI 0.997–1.02, P = 0.14), nor with its risk factors. Findings were similar for blood fructose. Our study found some evidence of the expected detrimental effect of sucrose on dental caries but no effect on CHD. Given a small effect on CHD cannot be excluded, further investigation with stronger genetic predictors is required.

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Rheumatoid arthritis decreases risk for Parkinson’s disease: a Mendelian randomization study

npj Parkinson s Disease ◽

10.1038/s41531-021-00166-x ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

ChunYu Li ◽

RuWei Ou ◽

HuiFang Shang

Keyword(s):

Rheumatoid Arthritis ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Genetic Correlation ◽

Mendelian Randomization ◽

Association Studies ◽

Sensitivity Analyses ◽

Genome Wide Association Studies ◽

Standard Deviation Increase ◽

Rheumatoid Arthritis Risk

AbstractEpidemiological and clinical studies have suggested comorbidity between rheumatoid arthritis and Parkinson’s disease (PD), but whether there exists a causal association and the effect direction of rheumatoid arthritis on PD is controversial and elusive. To evaluate the causal relationship, we first estimated the genetic correlation between rheumatoid arthritis and PD, and then performed a two-sample Mendelian randomization analysis based on summary statistics from large genome-wide association studies of rheumatoid arthritis (N = 47,580) and PD (N = 482,703). We identified negative and significant correlation between rheumatoid arthritis and PD (genetic correlation: −0.10, P = 0.0033). Meanwhile, one standard deviation increase in rheumatoid arthritis risk was associated with a lower risk of PD (OR: 0.904, 95% CI: 0.866–0.943, P: 2.95E–06). The result was robust under all sensitivity analyses. Our results provide evidence supporting a protective role of rheumatoid arthritis on PD. A deeper understanding of the inflammation and immune response is likely to elucidate the potential pathogenesis of PD and identify therapeutic targets for PD.

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Investigating the relationships between unfavourable habitual sleep and metabolomic traits: evidence from multi-cohort multivariable regression and Mendelian randomization analyses

BMC Medicine ◽

10.1186/s12916-021-01939-0 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Maxime M. Bos ◽

Neil J. Goulding ◽

Matthew A. Lee ◽

Amy Hofman ◽

Mariska Bot ◽

...

Keyword(s):

Sleep Duration ◽

Mendelian Randomization ◽

Disease Risk ◽

Association Studies ◽

Sensitivity Analyses ◽

European Ancestry ◽

Genome Wide Association Studies ◽

Multivariable Regression ◽

Artery Disease ◽

Insomnia Symptoms

Abstract Background Sleep traits are associated with cardiometabolic disease risk, with evidence from Mendelian randomization (MR) suggesting that insomnia symptoms and shorter sleep duration increase coronary artery disease risk. We combined adjusted multivariable regression (AMV) and MR analyses of phenotypes of unfavourable sleep on 113 metabolomic traits to investigate possible biochemical mechanisms linking sleep to cardiovascular disease. Methods We used AMV (N = 17,368) combined with two-sample MR (N = 38,618) to examine effects of self-reported insomnia symptoms, total habitual sleep duration, and chronotype on 113 metabolomic traits. The AMV analyses were conducted on data from 10 cohorts of mostly Europeans, adjusted for age, sex, and body mass index. For the MR analyses, we used summary results from published European-ancestry genome-wide association studies of self-reported sleep traits and of nuclear magnetic resonance (NMR) serum metabolites. We used the inverse-variance weighted (IVW) method and complemented this with sensitivity analyses to assess MR assumptions. Results We found consistent evidence from AMV and MR analyses for associations of usual vs. sometimes/rare/never insomnia symptoms with lower citrate (− 0.08 standard deviation (SD)[95% confidence interval (CI) − 0.12, − 0.03] in AMV and − 0.03SD [− 0.07, − 0.003] in MR), higher glycoprotein acetyls (0.08SD [95% CI 0.03, 0.12] in AMV and 0.06SD [0.03, 0.10) in MR]), lower total very large HDL particles (− 0.04SD [− 0.08, 0.00] in AMV and − 0.05SD [− 0.09, − 0.02] in MR), and lower phospholipids in very large HDL particles (− 0.04SD [− 0.08, 0.002] in AMV and − 0.05SD [− 0.08, − 0.02] in MR). Longer total sleep duration associated with higher creatinine concentrations using both methods (0.02SD per 1 h [0.01, 0.03] in AMV and 0.15SD [0.02, 0.29] in MR) and with isoleucine in MR analyses (0.22SD [0.08, 0.35]). No consistent evidence was observed for effects of chronotype on metabolomic measures. Conclusions Whilst our results suggested that unfavourable sleep traits may not cause widespread metabolic disruption, some notable effects were observed. The evidence for possible effects of insomnia symptoms on glycoprotein acetyls and citrate and longer total sleep duration on creatinine and isoleucine might explain some of the effects, found in MR analyses of these sleep traits on coronary heart disease, which warrant further investigation.

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Diet‐Derived Antioxidants Do Not Decrease Risk of Ischemic Stroke: A Mendelian Randomization Study in 1 Million People

Journal of the American Heart Association ◽

10.1161/jaha.121.022567 ◽

2021 ◽

Author(s):

Leon G. Martens ◽

Jiao Luo ◽

Ko Willems van Dijk ◽

J. Wouter Jukema ◽

Raymond Noordam ◽

...

Keyword(s):

Ischemic Stroke ◽

Lower Risk ◽

Mendelian Randomization ◽

Association Studies ◽

European Ancestry ◽

Blood Levels ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Blood Concentrations ◽

Vitamins E And C

Background Dietary intake and blood concentrations of vitamins E and C, lycopene, and carotenoids have been associated with a lower risk of incident (ischemic) stroke. However, causality cannot be inferred from these associations. Here, we investigated causality by analyzing the associations between genetically influenced antioxidant levels in blood and ischemic stroke using Mendelian randomization. Methods and Results For each circulating antioxidant (vitamins E and C, lycopene, β‐carotene, and retinol), which were assessed as either absolute blood levels and/or high‐throughput metabolite levels, independent genetic instrumental variables were selected from earlier genome‐wide association studies ( P <5×10 −8 ). We used summary statistics for single‐nucleotide polymorphisms–stroke associations from 3 European‐ancestry cohorts (cases/controls): MEGASTROKE (60 341/454 450), UK Biobank (2404/368 771), and the FinnGen study (8046/164 286). Mendelian randomization analyses were performed on each exposure per outcome cohort using inverse variance–weighted analyses and subsequently meta‐analyzed. In a combined sample of 1 058 298 individuals (70 791 cases), none of the genetically influenced absolute antioxidants or antioxidant metabolite concentrations were causally associated with a lower risk of ischemic stroke. For absolute antioxidants levels, the odds ratios (ORs) ranged between 0.94 (95% CI, 0.85–1.05) for vitamin C and 1.04 (95% CI, 0.99–1.08) for lycopene. For metabolites, ORs ranged between 1.01 (95% CI, 0.98–1.03) for retinol and 1.12 (95% CI, 0.88–1.42) for vitamin E. Conclusions This study did not provide evidence for a causal association between dietary‐derived antioxidant levels and ischemic stroke. Therefore, antioxidant supplements to increase circulating levels are unlikely to be of clinical benefit to prevent ischemic stroke.

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Association of Thyroid Function with Blood Pressure and Cardiovascular Disease: A Mendelian Randomization

Journal of Personalized Medicine ◽

10.3390/jpm11121306 ◽

2021 ◽

Vol 11 (12) ◽

pp. 1306

Author(s):

Alice Giontella ◽

Luca A. Lotta ◽

John D. Overton ◽

Aris Baras ◽

Andrea Sartorio ◽

...

Keyword(s):

Atrial Fibrillation ◽

Blood Pressure ◽

Thyroid Function ◽

Lower Risk ◽

Mendelian Randomization ◽

Association Studies ◽

Sensitivity Analyses ◽

Thyroid Peroxidase ◽

Genome Wide Association Studies ◽

Causal Association

Thyroid function has a widespread effect on the cardiometabolic system. However, the causal association between either subclinical hyper- or hypothyroidism and the thyroid hormones with blood pressure (BP) and cardiovascular diseases (CVD) is not clear. We aim to investigate this in a two-sample Mendelian randomization (MR) study. Single nucleotide polymorphisms (SNPs) associated with thyroid-stimulating hormone (TSH), free tetraiodothyronine (FT4), hyper- and hypothyroidism, and anti-thyroid peroxidase antibodies (TPOAb), from genome-wide association studies (GWAS), were selected as MR instrumental variables. SNPs–outcome (BP, CVD) associations were evaluated in a large-scale cohort, the Malmö Diet and Cancer Study (n = 29,298). Causal estimates were computed by inverse-variance weighted (IVW), weighted median, and MR-Egger approaches. Genetically increased levels of TSH were associated with decreased systolic BP and with a lower risk of atrial fibrillation. Hyperthyroidism and TPOAb were associated with a lower risk of atrial fibrillation. Our data support a causal association between genetically decreased levels of TSH and both atrial fibrillation and systolic BP. The lack of significance after Bonferroni correction and the sensitivity analyses suggesting pleiotropy, should prompt us to be cautious in their interpretation. Nevertheless, these findings offer mechanistic insight into the etiology of CVD. Further work into the genes involved in thyroid functions and their relation to cardiovascular outcomes may highlight pathways for targeted intervention.

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