Circulating adiponectin levels and systemic lupus erythematosus: a two-sample Mendelian randomization study

Abstract Objectives Several studies have reported increased serum/plasma adiponectin levels in SLE patients. This study was performed to estimate the causal effects of circulating adiponectin levels on SLE. Methods We selected nine independent single-nucleotide polymorphisms that were associated with circulating adiponectin levels (P < 5 × 10−8) as instrumental variables from a published genome-wide association study (GWAS) meta-analysis. The corresponding effects between instrumental variables and outcome (SLE) were obtained from an SLE GWAS analysis, including 7219 cases with 15 991 controls of European ancestry. Two-sample Mendelian randomization (MR) analyses with inverse-variance weighted, MR-Egger regression, weighted median and weight mode methods were used to evaluate the causal effects. Results The results of inverse-variance weighted methods showed no significantly causal associations of genetically predicted circulating adiponectin levels and the risk for SLE, with an odds ratio (OR) of 1.38 (95% CI 0.91, 1.35; P = 0.130). MR-Egger [OR 1.62 (95% CI 0.85, 1.54), P = 0.195], weighted median [OR 1.37 (95% CI 0.82, 1.35), P = 0.235) and weighted mode methods [OR 1.39 (95% CI 0.86, 1.38), P = 0.219] also supported no significant associations of circulating adiponectin levels and the risk for SLE. Furthermore, MR analyses in using SLE-associated single-nucleotide polymorphisms as an instrumental variable showed no associations of genetically predicted risk of SLE with circulating adiponectin levels. Conclusion Our study did not find evidence for a causal relationship between circulating adiponectin levels and the risk of SLE or of a causal effect of SLE on circulating adiponectin levels.

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Elucidation of a Causal Relationship Between Platelet Count and Hypertension: A Bi-Directional Mendelian Randomization Study

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.743075 ◽

2021 ◽

Vol 8 ◽

Author(s):

Po-Chun Chiu ◽

Amrita Chattopadhyay ◽

Meng-Chun Wu ◽

Tzu-Hung Hsiao ◽

Ching-Heng Lin ◽

...

Keyword(s):

Platelet Count ◽

Causal Relationship ◽

Mendelian Randomization ◽

Causal Effect ◽

Sensitivity Analyses ◽

Exact Nature ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Inverse Variance ◽

Weighted Median

Hypertension has been reported as a major risk factor for diseases such as cardiovascular disease, and associations between platelet activation and risk for hypertension are well-established. However, the exact nature of causality between them remains unclear. In this study, a bi-directional Mendelian randomization (MR) analysis was conducted on 15,996 healthy Taiwanese individuals aged between 30 and 70 years from the Taiwan Biobank, recorded between 2008 and 2015. The inverse variance weighted (IVW) method was applied to determine the causal relationship between platelet count and hypertension with single nucleotide polymorphisms as instrumental variables (IVs). Furthermore, to check for pleiotropy and validity of the IVs, sensitivity analyses were performed using the MR-Egger, weighted median and simple median methods. This study provided evidence in support of a positive causal effect of platelet count on the risk of hypertension (odds ratio: 1.149, 95% confidence interval: 1.131–1.578, P < 0.05), using the weighted median method. A significant causal effect of platelet count on hypertension was observed using the IVW method. No pleiotropy was observed. The causal effect of hypertension on platelet count was found to be non-significant. Therefore, the findings from this study provide evidence that higher platelet count may have a significant causal effect on the elevated risk of hypertension for the general population of Taiwan.

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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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Association between depression and sleep apnoea: a Mendelian randomisation study

ERJ Open Research ◽

10.1183/23120541.00394-2021 ◽

2021 ◽

pp. 00394-2021

Author(s):

Gui Chen ◽

Junyang Xie ◽

Weixing Liu ◽

Tianhao Liang ◽

Xiao Liao ◽

...

Keyword(s):

Causal Effect ◽

Sleep Apnoea ◽

Mendelian Randomisation ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Outlier Test ◽

Inverse Variance ◽

Close Relationship ◽

Weighted Median ◽

Summary Data

BackgroundStudies have reported a close relationship between depression and sleep apnoea, yet it is unknown whether these are causally related. Thus, we aimed to determine whether depression is associated with the aetiology of sleep apnoea.MethodsWe used publicly available genetic summary data from two large consortia, the Psychiatric Genomics Consortium, with data from 36 single-nucleotide polymorphisms (SNPs) closely associated with major depressive disorder (MDD) and UK Biobank, including 456 736 patients with sleep apnoea and 766 964 controls. For Mendelian randomisation (MR) analysis, we used the inverse-variance weighted method, weighted median method, MR-Egger regression, MR pleiotropy residual sum, and outlier test to retrieve summary data. Analyses were performed using the “TwoSampleMR” package in R.ResultsOf the 36 SNPs associated with MDD, we found statistically significant evidence of a potential causal effect of MDD on the risk of sleep apnoea (odds ratio 1.004, 95% confidence interval: 1.001–1.006, p=0.001). Similar results were obtained using the MR-Egger and weighted median methods. Additionally, we found no heterogeneity or pleiotropy.ConclusionsOur findings suggest that depression slightly increases the risk of sleep apnoea. Further investigation of the potential biological mechanisms is necessary.

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Pediatric and Adult Obesity Concern Female Health: A Mendelian Randomization Study

10.21203/rs.3.rs-390994/v1 ◽

2021 ◽

Author(s):

yishang yan ◽

Zihao Qu ◽

Ping-ping Lv ◽

He-Feng Huang

Keyword(s):

Mendelian Randomization ◽

Later Life ◽

Nucleotide Polymorphisms ◽

Adult Obesity ◽

Gynecological Cancers ◽

Single Nucleotide ◽

Genetic Groups ◽

Inverse Variance ◽

Children Obesity ◽

Weighted Median

Abstract Purpose: Adulthood and childhood obesity are associated with female reproductive endocrinology and gynecological cancers. However, the causality of such association is yet to be identified. Independent of inverse bias and confounding, mendelian randomization is like a random control trial where genetic groups are settled during meiosis, which could be effective to examine the causality. Methods: We carried out several Mendelian randomization trials based on combined genetic scores of 75 adult-associated and 15 child-associated BMI single nucleotide polymorphisms (SNPs), diseases databases of several gynecological cancers and reproductive diseases from UK Biobank with 194,153 participants, using traditional inverse-variance weighted (IVW) method, Weighted Median (WM) approach, MR-Egger regression and updated MR-PRESSO analysis. Results: Elevated adult-associated BMI (effect:1.003;95%CI:1.001,1.004) and child-associated BMI (effect:1.003;95%CI:1.001,1.004) genetic scores were related to higher risk of PCOS incidence by using traditional IVW method. Random IVW method showed a negative causal association between the child-associated BMI and subsequent endometriosis attack(effect:0.995;95%CI:0.991,0.999). Conclusions: Consistent with observational consequences, our findings suggested that childhood and adulthood obesity may play roles in the development of PCOS, and children obesity can elevate the possibility of PCOS but decrease the incidence of endometriosis in later life. More researches need to be conducted for further validation and potential mechanisms.

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The Impact of Homocysteine on the Risk of Hormone-Related Cancers: A Mendelian Randomization Study

Frontiers in Nutrition ◽

10.3389/fnut.2021.645371 ◽

2021 ◽

Vol 8 ◽

Author(s):

Qian He ◽

Ze Yang ◽

Yandi Sun ◽

Zihao Qu ◽

Xueyao Jia ◽

...

Keyword(s):

Breast Cancer ◽

Single Nucleotide Polymorphisms ◽

Mendelian Randomization ◽

Meta Analysis ◽

Plasma Homocysteine ◽

European Ancestry ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Genome Wide ◽

The Impact

Background: Aberrant homocysteine level is associated with metabolic disorders and DNA damage, which may be involved in the carcinogenesis of hormone-related cancers, but clinical results of observational studies are controversial. In this study, we investigated the causal relationships between plasma homocysteine and breast cancer (BRCA), prostate cancer (PrCa), and renal cell carcinoma (RCC) using Mendelian randomization (MR) analyses.Design and Methods: To investigate the putative causal associations between homocysteine and the aforementioned three types of cancers, a two-sample MR study was employed for the study. The primary strategy for summary data analyses was the inverse-variance-weighted (IVW) approach. In our study, the single-nucleotide polymorphisms (SNPs) excluded confounding factors through Linkage Disequilibrium (LD). Phenoscanner tests were the instrumental variants (IVs), homocysteine was the exposure, and BRCA, PrCa, and RCC were the outcomes. Single-nucleotide polymorphisms associated with homocysteine were extracted from a large genome-wide association study (GWAS) meta-analysis of European participants (n = 44,147). Summary Statistics of BRCA were obtained from the latest and largest GWAS meta-analysis comprising of 82 studies from Breast Cancer Association Consortium (BCAC) studies, including women of European ancestry (133,384 cases and 113,789 controls); we obtained summary-level data from the GWAS meta-analysis of PrCa comprising 79,148 cases and 61,106 controls of European ancestry, and the dataset of RCC was a sex-specific GWAS meta-analysis comprising of two kidney cancer genome-wide scans for men (3,227 cases and 4,916 controls) and women (1,992 cases and 3,095 controls) of European ancestry. The MR-Egger and weight median analyses were applied for the pleiotropy test.Results: The results showed null associations between plasma homocysteine levels and overall BRCA (effect = 0.97, 95% CI: 0.90–1.06, P = 0.543), overall PrCa (effect = 1.01, 95% CI: 0.93–1.11, P = 0.774), RCC in men (effect = 0.99, 95% CI: 0.73–1.34, P = 0.929), and RCC in women (effect = 0.89, 95% CI: 0.61–1.31, P = 0.563).Conclusions: We found no putative causal associations between homocysteine and risk of BRCA, PrCa, and RCC.

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Causal Association between Periodontitis and Parkinson’s Disease: A Bidirectional Mendelian Randomization Study

Genes ◽

10.3390/genes12050772 ◽

2021 ◽

Vol 12 (5) ◽

pp. 772

Author(s):

João Botelho ◽

Vanessa Machado ◽

José João Mendes ◽

Paulo Mascarenhas

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Instrumental Variables ◽

Mendelian Randomization ◽

Association Studies ◽

European Ancestry ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Genetic Liability ◽

Bidirectional Association

The latest evidence revealed a possible association between periodontitis and Parkinson’s disease (PD). We explored the causal relationship of this bidirectional association through two-sample Mendelian randomization (MR) in European ancestry populations. To this end, we used openly accessible data of genome-wide association studies (GWAS) on periodontitis and PD. As instrumental variables for periodontitis, seventeen single-nucleotide polymorphisms (SNPs) from a GWAS of periodontitis (1817 periodontitis cases vs. 2215 controls) and eight non-overlapping SNPs of periodontitis from an additional GWAS for validation purposes. Instrumental variables to explore for the reverse causation included forty-five SNPs from a GWAS of PD (20,184 cases and 397,324 controls). Multiple approaches of MR were carried-out. There was no evidence of genetic liability of periodontitis being associated with a higher risk of PD (B = −0.0003, Standard Error [SE] 0.0003, p = 0.26). The eight independent SNPs (B = −0.0000, SE 0.0001, p = 0.99) validated this outcome. We also found no association of genetically primed PD towards periodontitis (B = −0.0001, SE 0.0001, p = 0.19). These MR study findings do not support a bidirectional causal genetic liability between periodontitis and PD. Further GWAS studies are needed to confirm the consistency of these results.

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Causal associations of obesity with chronic kidney disease and arterial stiffness: a Mendelian randomization study

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgab633 ◽

2021 ◽

Author(s):

Chaojie Ye ◽

Lijie Kong ◽

Zhiyun Zhao ◽

Mian Li ◽

Shuangyuan Wang ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Standard Deviation ◽

Kidney Disease ◽

Single Nucleotide Polymorphisms ◽

Arterial Stiffness ◽

Genetic Risk ◽

Mendelian Randomization ◽

Genetic Risk Score ◽

Nucleotide Polymorphisms ◽

Single Nucleotide

Abstract Purpose Observational studies have associated obesity with chronic kidney disease (CKD) and arterial stiffness, but the causality remains unclear. We aimed to investigate the causality of obesity with CKD and arterial stiffness using Mendelian randomization (MR) analysis. Methods We genotyped 14 body mass index (BMI)-associated variants validated in East Asians in 11384 Chinese adults. A genetic risk score based on the 14 variants and the 14 individual single nucleotide polymorphisms were respectively used as instrumental variables (IVs). CKD was defined as estimated glomerular filtration rate <60 mL/min/1.73 m 2. Arterial stiffness was defined as brachial-ankle pulse wave velocity >1550 cm/s. Results Using the genetic risk score as the IV, we demonstrated causal relations of each 1-standard deviation increment in BMI with CKD (odds ratio [OR]: 2.36; 95% confidence interval [CI]: 1.11-5.00) and arterial stiffness (OR: 1.71; 95% CI: 1.22-2.39). Using the 14 single nucleotide polymorphisms individually as IVs, each 1-standard deviation increment in BMI casually associated with CKD (OR: 2.58; 95% CI: 1.39-4.79) and arterial stiffness (OR: 1.87; 95% CI: 1.24-2.81) in the inverse-variance weighted analysis, and MR-Egger regression revealed no evidence of horizontal pleiotropy (Both P for intercept≥0.34). The causality between obesity and CKD was validated in two-sample MR analysis among Europeans (681275 of Genetic Investigation of ANthropometric Traits and 133413 of CKD Genetics). Conclusions This study provided novel insights into causality of obesity with CKD and arterial stiffness, highlighting the importance of weight management for primary prevention and control of subclinical vascular diseases.

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Assessing the Causality Factors in the Association between (Abdominal) Obesity and Physical Activity among the Newfoundland Population–-A Mendelian Randomization Analysis

Genetics & Epigenetics ◽

10.4137/geg.s38289 ◽

2016 ◽

Vol 8 ◽

pp. GEG.S38289 ◽

Cited By ~ 2

Author(s):

Frank Barning ◽

Taraneh Abarin

Keyword(s):

Physical Activity ◽

Newfoundland And Labrador ◽

Mendelian Randomization ◽

Causal Effect ◽

Intervention Strategies ◽

Nucleotide Polymorphisms ◽

Fto Gene ◽

Single Nucleotide ◽

Similar Association ◽

Randomization Analysis

A total of 1,263 adults from Newfoundland and Labrador were studied in the research. Body mass index (BMI) and percent trunk fat (PTF) were analyzed as biomarkers for obesity. The Mendelian randomization (MR) approach with two single-nucleotide polymorphisms in the fat-mass and obesity (FTO) gene as instruments was employed to assess the causal effect. In both genders, increasing physical activity significantly reduced BMI and PTF when adjusted for age and the FTO gene. The effect of physical activity was stronger on PTF than BMI. Direct observational analyses showed significant increase in BMI/PTF when physical activity decreased. A similar association in MR analyses was not significant. The association between physical activity and BMI/PTF could be due to reversed causality or common confounding factors. Our study provides insights into the causal contributions of obesity to physical activity in adults. Health intervention strategies to increase physical activity among adults should include some other plans such as improving diet for reducing obesity.

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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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