Evaluating the Causal Association Between Educational Attainment and Asthma Using a Mendelian Randomization Design

Asthma is a common chronic respiratory disease. In the past 10 years, genome-wide association study (GWAS) has been widely used to identify the common asthma genetic variants. Importantly, these publicly available asthma GWAS datasets provide important data support to investigate the causal association of kinds of risk factors with asthma by a Mendelian randomization (MR) design. It is known that socioeconomic status is associated with asthma. However, it remains unclear about the causal association between socioeconomic status and asthma. Here, we selected 162 independent educational attainment genetic variants as the potential instruments to evaluate the causal association between educational attainment and asthma using large-scale GWAS datasets of educational attainment (n = 405,072) and asthma (n = 30,810). We conducted a pleiotropy analysis using the MR-Egger intercept test and the MR pleiotropy residual sum and outlier (MR-PRESSO) test. We performed an MR analysis using inverse-variance weighted, weighted median, MR-Egger, and MR-PRESSO. The main analysis method inverse-variance weighted indicated that each 1 standard deviation increase in educational attainment (3.6 years) could reduce 35% asthma risk [odds ratio (OR) = 0.65, 95% confidence interval (CI) 0.51–0.85, P = 0.001]. Importantly, evidence from other MR methods further supported this finding, including weighted median (OR = 0.55, 95% CI 0.38–0.80, P = 0.001), MR-Egger (OR = 0.48, 95% CI 0.16–1.46, P = 0.198), and MR-PRESSO (OR = 0.65, 95% CI 0.51–0.85, P = 0.0015). Meanwhile, we provide evidence to support that educational attainment protects against asthma risk dependently on cognitive performance using multivariable MR analysis. In summary, we highlight the protective role of educational attainment against asthma. Our findings may have public health applications and deserve further investigation.

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Genetically increased serum calcium levels reduce Alzheimer’s disease risk

10.1101/255059 ◽

2018 ◽

Cited By ~ 3

Author(s):

Qinghua Jiang ◽

Yang Hu ◽

Shuilin Jin ◽

Guiyou Liu

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Genetic Association ◽

Serum Calcium ◽

Genetic Variants ◽

Large Scale ◽

Mendelian Randomization ◽

European Descent ◽

Gwas Dataset ◽

Weighted Median

AbstractIMPORTANCE Alzheimer’s disease (AD) is the leading cause of disability in the elderly. It has been a long time about the calcium hypothesis of AD on the basis of emerging evidence since 1994. However, most studies focused on the association between calcium homeostasis and AD, and concerned the intracellular calcium concentration. Only few studies reported reduced serum calcium levels in AD. Until now, it remains unclear whether serum calcium levels are genetically associated with AD risk.OBJECTIVE To evaluate the genetic association between increased serum calcium levels and AD riskDESIGN, SETTING, AND PARTICIPANTS We performed a Mendelian randomization study to investigate the association of increased serum calcium with AD risk using the genetic variants from the large-scale serum calcium genome-wide association study (GWAS) dataset (N=61,079 individuals of European descent) and the large-scale AD GWAS dataset (N=54,162 individuals including 17,008 AD cases and 37,154 controls of European descent). Inverse-variance weighted meta-analysis (IVW) was used to provide a combined estimate of the genetic association. Meanwhile, we selected the weighted median regression and MR-Egger regression as the complementary analysis methods to examine the robustness of the IVW estimate.EXPOSURES Genetic predisposition to increased serum calcium levelsMAIN OUTCOMES AND MEASURES The risk of AD.RESULTS We selected 6 independent genetic variants influencing serum calcium levels as the instrumental variables. IVW analysis showed that a genetically increased serum calcium level (per 1 standard deviation (SD) increase 0.5-mg/dL) was significantly associated with a reduced AD risk (OR=0.56, 95% CI: 0.34-0.94, P=5.00E-03). Meanwhile, both the weighted median estimate (OR=0.60, 95% CI: 0.34-1.06, P=0.08) and MR-Egger estimate (OR=0.66, 95% CI: 0.26-1.67, P=0.381) were consistent with the IVW estimate in terms of direction and magnitude.CONCLUSIONS AND RELEVANCE We provided evidence that genetically increased serum calcium levels could reduce the risk of AD. Meanwhile, randomized controlled study should be further conducted to assess the effect of serum calcium levels on AD risk, and further clarify whether diet calcium intake or calcium supplement, or both could reduce the risk of AD.Key PointsQuestion Is there a genetic relationship between elevated serum calcium levels and the risk of Alzheimer’s disease?Findings This Mendelian randomization study showed that the genetically increased serum calcium levels were associated with the reduced risk of Alzheimer’s disease.Meaning These findings provide evidence that genetically increased serum calcium levels could reduce the risk of Alzheimer’s disease.

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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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Mendelian randomization study updates the effect of 25-hydroxyvitamin D levels on the risk of multiple sclerosis

Journal of Translational Medicine ◽

10.1186/s12967-021-03205-6 ◽

2022 ◽

Vol 20 (1) ◽

Author(s):

Renxi Wang

Keyword(s):

Multiple Sclerosis ◽

Large Scale ◽

Mendelian Randomization ◽

European Ancestry ◽

Causal Association ◽

Serum 25Ohd ◽

Hydroxyvitamin D ◽

Simple Mode ◽

Weighted Median ◽

25 Hydroxyvitamin D

Abstract Background Observational studies and previous Mendelian randomization (MR) studies have shown that genetically low 25-hydroxyvitamin D (25OHD) levels are associated with a high susceptibility to multiple sclerosis (MS). The present MR study aims to update the causal estimates for the effects of 25OHD levels on MS risk. Methods To date, the largest genome-wide association study (GWAS) for serum 25OHD (n = 401,460) and MS (14,498 MS cases and 24,091 controls) was used to assess the effect of serum 25OHD levels on MS. All participants were of European ancestry. The MR-egger_intercept test and Cochran’s Q statistic were used to determine the pleiotropy and the heterogeneity, respectively. MR-egger, weighted median, inverse variance weighted (multiplicative random effects), simple mode, and weighted mode methods were used to evaluate the causal association of serum 25OHD levels with MS. Finally, the effect of a single 25OHD SNP (single nucleotide polymorphism) on MS was used to test the SNP bias. Results One hundred and fifteen newly identified serum 25OHD genetic variants were extracted from a large-scale serum 25OHD GWAS dataset. The 20 most effective and independent 25OHD genetic instrumental variables were extracted from the MS GWAS summary statistics. Pleiotropy analysis suggested no significant pleiotropic variant among the 20 selected 25OHD genetic instrument variants in MS GWAS datasets. As serum levels of 25OHD based on genetic changes increased, the risk of MS decreased using MR-egger (Beta = − 0.940, p = 0.001; OR = 0.391), weighted median (Beta = − 0.835, p = 0.000; OR = 0.434), IVW (Beta = − 0.781, p = 0.000; OR = 0.458), simple mode (Beta = − 1.484, p = 0.016; OR = 0.227), and weighted mode (Beta = − 0.913, p = 0.000; OR = 0.401). Our results were robust, with no obvious bias based on investigating the single 25OHD SNP on MS. Conclusions Our analysis suggested a causal association between genetically increased serum 25OHD levels and reduced MS in the European population.

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P0770IMPAIRED FASTING GLUCOSE AND CHRONIC KIDNEY DISEASE: A MENDELIAN RANDOMIZATION STUDY

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p0770 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Hyunjin Noh ◽

Hyoungnae Kim ◽

Su Yeon Park ◽

Dohui Hwang ◽

Kyoungin Choi

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Genetic Variants ◽

Mendelian Randomization ◽

Fasting Glucose ◽

Association Studies ◽

Genetic Risk Score ◽

Genome Wide Association Studies ◽

Standard Deviation Increase ◽

Inverse Variance

Abstract Background and Aims Diabetes mellitus is a risk factor of chronic kidney disease (CKD); however, the relationship between fasting glucose and CKD remains controversial in non-diabetic population. Method This study included 6,354 participants without diabetes and CKD from the KoreanGenome Epidemiology Study. The genetic risk score (GRS9) was calculated using nine genetic variants associated with fasting glucose in previous genome wide association studies. Incident CKD was defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 or proteinuria (≥1+). The causal relationship between fasting glucose and CKD was evaluated using Mendelian randomization (MR) approach. Results The GRS9 was strongly associated with fasting glucose (β, 1.01; P < 0.001). During a median follow-up of 11.6 years, 531 (8.4%) CKD events occurred. After adjusting for confounding factors, fasting glucose was not associated with incident CKD (odds ratio [OR], 0.991; 95% confidence interval [CI], 0.980–1.003; P =0.139). In the MR analysis, GRS9 was not associated with CKD development (OR per 1 standard deviation increase, 1.179; 95% CI, 0.819–1.696; P = 0.376). Further evaluation with various other MR methods using inverse-variance weighted, MR-Egger, and weighted median methods for multiple genetic variants and strict CKD criteria (decrease in the eGFR of ≥ 30% to a value of < 60 mL/min/1.73m2) found no significant relationship between GRS9 and incident CKD. Conclusion Impaired fasting glucose was not causally associated with CKD development in nondiabetic population.

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An Updated Mendelian Randomization Analysis of the Association Between Serum Calcium Levels and the Risk of Alzheimer’s Disease

Frontiers in Genetics ◽

10.3389/fgene.2021.731391 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yuchen Shi ◽

Ruifei Liu ◽

Ying Guo ◽

Qiwei Li ◽

Haichun Zhou ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Serum Calcium ◽

Large Scale ◽

Mendelian Randomization ◽

Causal Association ◽

Cognitively Normal ◽

Gwas Dataset ◽

Weighted Median ◽

Normal Controls

It has been a long time that the relationship between serum calcium levels and Alzheimer’s disease (AD) remains unclear. Until recently, observational studies have evaluated the association between serum calcium levels and the risk of AD, however, reported inconsistent findings. Meanwhile, a Mendelian randomization (MR) study had been conducted to test the causal association between serum calcium levels and AD risk, however, only selected 6 serum calcium SNPs as the instrumental variables. Hence, these findings should be further verified using additional more genetic variants and large-scale genome-wide association study (GWAS) dataset to increase the statistical power. Here, we conduct an updated MR analysis of the causal association between serum calcium levels and the risk of AD using a two-stage design. In discovery stage, we conducted a MR analysis using 14 SNPs from serum calcium GWAS dataset (N = 61,079), and AD GWAS dataset (N = 63,926, 21,982 cases, 41,944 cognitively normal controls). All four MR methods including IVW, weighted median, MR-Egger, and MR-PRESSO showed a reduced trend of AD risk with the increased serum calcium levels. In the replication stage, we performed a MR analysis using 166 SNPs from serum calcium GWAS dataset (N = 305,349), and AD GWAS dataset (N = 63,926, 21,982 cases, 41,944 cognitively normal controls). Only the weighted median indicated that genetically increased serum calcium level was associated with the reduced risk of AD. Hence, additional studies are required to investigate these findings.

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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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Polycystic Ovary Syndrome and Risk of Five Common Psychiatric Disorders Among European Women: A Two-Sample Mendelian Randomization Study

Frontiers in Genetics ◽

10.3389/fgene.2021.689897 ◽

2021 ◽

Vol 12 ◽

Author(s):

Luyang Jin ◽

Jia'en Yu ◽

Yuxiao Chen ◽

Haiyan Pang ◽

Jianzhong Sheng ◽

...

Keyword(s):

Polycystic Ovary Syndrome ◽

Genetic Variants ◽

Mendelian Randomization ◽

Polycystic Ovary ◽

Causal Effects ◽

Ovary Syndrome ◽

Inverse Variance ◽

Simulation Extrapolation ◽

Weighted Median ◽

European Populations

Background: Observational studies have implied an association between polycystic ovary syndrome (PCOS) and psychiatric disorders. Here we examined whether PCOS might contribute causally to such disorders, focusing on anxiety disorder (AD), bipolar disorder (BIP), major depression disorder (MDD), obsessive compulsive disorder (OCD), and schizophrenia (SCZ).Methods: Causality was explored using two-sample Mendelian randomization (MR) with genetic variants as instrumental variables. The genetic variants were from summary data of genome-wide association studies in European populations. First, potential causal effects of PCOS on each psychiatric disorder were evaluated, and then potential reverse causality was also assessed once PCOS was found to be causally associated with any psychiatric disorder. Causal effects were explored using inverse variance weighting, MR-Egger analysis, simulation extrapolation, and weighted median analysis.Results: Genetically predicted PCOS was positively associated with OCD based on inverse variance weighting (OR 1.339, 95% CI 1.083–1.657, p = 0.007), simulation extrapolation (OR 1.382, 95% CI 1.149–1.662, p = 0.009) and weighted median analysis (OR 1.493, 95% CI 1.145–1.946, p = 0.003). However, genetically predicted OCD was not associated with PCOS. Genetically predicted PCOS did not exert causal effects on AD, BIP, MDD, or SCZ.Conclusions: In European populations, PCOS may be a causal factor in OCD, but not AD, BIP, MDD, or SCZ.

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Effect of plasma vitamin C levels on Parkinson’s disease and age at onset: a Mendelian randomization study

Journal of Translational Medicine ◽

10.1186/s12967-021-02892-5 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Haijie Liu ◽

Yan Zhang ◽

Haihua Zhang ◽

Longcai Wang ◽

Tao Wang ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Vitamin C ◽

Large Scale ◽

Mendelian Randomization ◽

Age At Onset ◽

Causal Link ◽

Plasma Vitamin ◽

Causal Association ◽

Weighted Median

Abstract Background Until now, epidemiological evidence regarding the association between vitamin C intake (both diet and supplements) and Parkinson’s disease (PD) remains inconsistent. Hence, it is necessary to establish the causal link between vitamin C levels and PD, and further develop effective therapies or prevention. Methods We selected 11 newly identified plasma vitamin C genetic variants from a large-scale plasma vitamin C GWAS dataset (n = 52,018) as the effective instrumental variables, and extracted their corresponding GWAS summary statistics from PD (33,674 PD cases and 449,056 controls) and PD age at onset (AAO) (n = 28,568). We then performed a Mendelian randomization (MR) study to evaluate the causal association of plasma vitamin C levels with PD and PD AAO using inverse-variance weighted (IVW), the weighted median, MR-Egger, and MR-PRESSO test. Results We did not observe any significant association between genetically increased vitamin C levels and PD. Interestingly, we found a reduced trend of PD AAO (1.134 years) with 1 SD genetically increased vitamin C levels using IVW (beta = − 1.134, 95% CI: [− 2.515, 0.248], P = 0.108). Importantly, this trend was further successfully verified using both weighted median and MR-Egger. Each 1 SD genetically increased vitamin C levels could reduce PD AAO 1.75 and 2.592 years using weighted median (beta = − 1.750, 95% CI: [− 3.396, − 0.105], P = 0.037) and MR-Egger (beta = − 2.592, 95% CI: [− 4.623, − 0.560], P = 0.012). Conclusions We demonstrated the causal association between genetically increased plasma vitamin C levels and reduced PD AAO in people of European descent. Randomized controlled trials are required to clarify whether diet intake or supplement, or both could reduce the AAO of PD.

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A Mendelian randomization analysis of the relationship between cardioembolic risk factors and ischemic stroke

Scientific Reports ◽

10.1038/s41598-021-93979-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Danyang Tian ◽

Linjing Zhang ◽

Zhenhuang Zhuang ◽

Tao Huang ◽

Dongsheng Fan

Keyword(s):

Risk Factors ◽

Ischemic Stroke ◽

Mendelian Randomization ◽

P Wave ◽

Cardioembolic Stroke ◽

Large Artery ◽

Weighted Analysis ◽

Inverse Variance ◽

Weighted Median ◽

Genetically Determined

AbstractObservational studies have shown that several risk factors are associated with cardioembolic stroke. However, whether such associations reflect causality remains unknown. We aimed to determine whether established and provisional cardioembolic risk factors are causally associated with cardioembolic stroke. Genetic instruments for atrial fibrillation (AF), myocardial infarction (MI), electrocardiogram (ECG) indices and N-terminal pro-brain natriuretic peptide (NT-pro BNP) were obtained from large genetic consortiums. Summarized data of ischemic stroke and its subtypes were extracted from the MEGASTROKE consortium. Causal estimates were calculated by applying inverse-variance weighted analysis, weighted median analysis, simple median analysis and Mendelian randomization (MR)-Egger regression. Genetically predicted AF was significantly associated with higher odds of ischemic stroke (odds ratio (OR): 1.20, 95% confidence intervals (CI): 1.16–1.24, P = 6.53 × 10–30) and cardioembolic stroke (OR: 1.95, 95% CI: 1.85–2.06, P = 8.81 × 10–125). Suggestive associations were found between genetically determined resting heart rate and higher odds of ischemic stroke (OR: 1.01, 95% CI: 1.00–1.02, P = 0.005), large-artery atherosclerotic stroke (OR: 1.02, 95% CI: 1.00–1.04, P = 0.026) and cardioembolic stroke (OR: 1.02, 95% CI: 1.00–1.04, P = 0.028). There was no causal association of P‐wave terminal force in the precordial lead V1 (PTFVI), P-wave duration (PWD), NT-pro BNP or PR interval with ischemic stroke or any subtype.

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Circulating Alpha-Tocopherol Levels, Bone Mineral Density, and Fracture: Mendelian Randomization Study

Nutrients ◽

10.3390/nu13061940 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1940

Author(s):

Karl Michaëlsson ◽

Susanna C. Larsson

Keyword(s):

Bone Mineral Density ◽

Confidence Interval ◽

Bone Mineral ◽

Genetic Variants ◽

Mendelian Randomization ◽

Alpha Tocopherol ◽

European Ancestry ◽

Mineral Density ◽

Standard Deviation Increase ◽

A Genome

Recent cohort studies indicate a potential role of the antioxidant α-tocopherol in reducing bone loss and risk of fractures, especially hip fractures. We performed a Mendelian randomization investigation of the associations of circulating α-tocopherol with estimated bone mineral density (eBMD) using heel ultrasound and fractures, identified from hospital records or by self-reports and excluding minor fractures. Circulating α-tocopherol was instrumented by three genetic variants associated with α-tocopherol levels at p < 5 × 10−8 in a genome-wide association meta-analysis of 7781 participants of European ancestry. Summary-level data for the genetic associations with eBMD in 426,824 individuals and with fracture (53,184 cases and 373,611 non-cases) were acquired from the UK Biobank. Two of the three genetic variants were strongly associated with eBMD. In inverse-variance weighted analysis, a genetically predicted one-standard-deviation increase of circulating α-tocopherol was associated with 0.07 (95% confidence interval, 0.05 to 0.09) g/cm2 increase in BMD, which corresponds to a >10% higher BMD. Genetically predicted circulating α-tocopherol was not associated with odds of any fracture (odds ratio 0.97, 95% confidence interval, 0.91 to 1.05). In conclusion, our results strongly strengthen a causal link between increased circulating α-tocopherol and greater BMD. Both an intervention study in those with a low dietary intake of α-tocopherol is warranted and a Mendelian randomization study with fragility fractures as an outcome.

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