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

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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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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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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Mendelian randomization analysis of Circulating adiponectin levels on prostate cancer

10.21203/rs.3.rs-319125/v1 ◽

2021 ◽

Author(s):

Liangliang Ren ◽

Chenhao Yu ◽

Zhenwei Zhou ◽

Gonghui Li

Keyword(s):

Prostate Cancer ◽

Protective Effect ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

Meta Analysis ◽

Causal Effects ◽

Nucleotide Polymorphisms ◽

Genetic Associations ◽

Mendelian Randomization Analysis ◽

Randomization Analysis

Abstract Background: Previous observational studies showed a conflict with the correlation between circulating adiponectin levels and prostate cancer. Methods: In this study, we employed Mendelian randomization analysis to identify the causal effects between them. 14 single nucleotide polymorphisms were screened from the largest-scale genome-wide association study meta-analysis of adiponectin in a multi-ethnic population. The SNP outcome effects were obtained from Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome and Japanese Encyclopedia of Genetic Associations by Riken. Inverse variance weighted model with random-effects was the main effect estimation in our study, alongside weighted median, MR-Egger, and weighted mode models.Results: The results showed no significant causal estimate but a potential protective effect of adiponectin on prostate cancer. In addition, two other research of adiponectin repeated the analysis to avoid the bias of human species showing the similar results. Conclusion: Our study did not provide significant evidence to support the causal effects of circulating adiponectin levels on prostate cancer, but most of our results showed a potential protective effect requiring larger-scale MR analysis to confirm.

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

Genes ◽

10.3390/genes12040498 ◽

2021 ◽

Vol 12 (4) ◽

pp. 498

Author(s):

Yandi Sun ◽

Jingjia Li ◽

Zihao Qu ◽

Ze Yang ◽

Xueyao Jia ◽

...

Keyword(s):

Genome Wide Association Study ◽

Mendelian Randomization ◽

Sensitivity Analyses ◽

Nucleotide Polymorphisms ◽

Serum Urea ◽

Urea Level ◽

Genome Wide ◽

Inverse Variance ◽

Weighted Median ◽

First Time

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

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

Rheumatology ◽

10.1093/rheumatology/keaa506 ◽

2020 ◽

Author(s):

Yi-Lin Dan ◽

Peng Wang ◽

Zhongle Cheng ◽

Qian Wu ◽

Xue-Rong Wang ◽

...

Keyword(s):

Single Nucleotide Polymorphisms ◽

Instrumental Variables ◽

Mendelian Randomization ◽

Causal Effect ◽

Causal Effects ◽

European Ancestry ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Inverse Variance ◽

Weighted Median

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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GP.01 Childhood obesity and multiple sclerosis susceptibility: a Mendelian randomization study

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/cjn.2019.77 ◽

2019 ◽

Vol 46 (s1) ◽

pp. S6 ◽

Cited By ~ 1

Author(s):

A Harroud ◽

RE Mitchell ◽

JA Morris ◽

V Forgetta ◽

SJ Sawcer ◽

...

Keyword(s):

Multiple Sclerosis ◽

Childhood Obesity ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

Sensitivity Analyses ◽

Significant Heterogeneity ◽

Genetic Associations ◽

Standard Deviation Increase ◽

A Genome ◽

The Individual

Background: Observational studies have reported an association between childhood obesity and a higher risk of multiple sclerosis (MS). However, the difficulties to fully account for confounding and long recall periods make causal inference from these studies challenging. The objective of this study was to assess the contribution of childhood obesity to the development of MS through Mendelian randomization, which uses genetic associations to minimize the risk of confounding. Methods: We selected 23 independent genetic variants strongly associated with childhood body mass index (BMI) in a genome-wide association study (GWAS) which included 47,541 children. The corresponding effects of these variants on risk of MS were obtained from a GWAS of 14,802 MS cases and 26,703 controls. Standard two-sample Mendelian randomization methods were performed, with additional sensitivity analyses to assess the likelihood of bias from genetic pleiotropy. Results: The inverse-variance weighted MR analysis revealed that one standard deviation increase in childhood BMI increased odds of MS by 26% (odds ratio=1.26, 95% confidence interval 1.10-1.45, p=0.001). There was no significant heterogeneity across the individual estimates. Sensitivity analyses were consistent with the main findings and provided no evidence of pleiotropy. Conclusions: This study provides genetic support of a role for increased childhood BMI in the development of MS.

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Matrix Metalloproteinases in Relation to Bone Mineral Density: A Two-Sample Mendelian Randomization Study

Frontiers in Genetics ◽

10.3389/fgene.2021.754795 ◽

2021 ◽

Vol 12 ◽

Author(s):

Xin Lv ◽

Pengfei Wu ◽

Shipeng Xiao ◽

Wan Zhang ◽

Yawei Li ◽

...

Keyword(s):

Bone Mineral Density ◽

Lumbar Spine ◽

Matrix Metalloproteinases ◽

Femoral Neck ◽

Bone Mineral ◽

Mendelian Randomization ◽

Causal Effects ◽

Sensitivity Analyses ◽

Mineral Density ◽

Inverse Variance

Background: We aimed at investigating causal associations between matrix metalloproteinases (MMPs) and bone mineral density (BMD) by the Mendelian randomization (MR) analysis.Methods: From genome-wide association studies of European ancestry, we selected instrumental variables for MMP-1, MMP-3, MMP-7, MMP-8, MMP-10, and MMP-12. Accordingly, we retrieved summary statistics of three site-specific BMD, namely, forearm, femoral neck, and lumbar spine. We conducted an inverse variance weighted MR as the primary method to compute overall effects from multiple instruments, while additional MR approaches and sensitivity analyses were implemented. Bonferroni-adjusted significance threshold was set at p < 0.05/18 = 0.003.Results: Totally, there was no evidence for causal effects of genetically-predicted levels of MMPs on BMD measurement at three common sites. MR results indicated that there were no causal associations of circulating MMPs with forearm BMD (all p ≥ 0.023) by the inverse variance weighted method. Similarly, there were no causal effects of MMPs on femoral neck BMD (all p ≥ 0.120) and MR results did not support causal relationships between MMPs and lumbar spine BMD (all p ≥ 0.017). Multiple sensitivity analyses suggested the robustness of MR results, which were less likely to be biased by unbalanced pleiotropy or evident heterogeneity.Conclusion: We found no evidence for the causal relationship between MMPs and BMD in the European population.

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Mendelian randomization analysis of the association between human blood cell traits and uterine polyps

Scientific Reports ◽

10.1038/s41598-021-84851-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Shuliu Sun ◽

Yan Liu ◽

Lanlan Li ◽

Minjie Jiao ◽

Yufen Jiang ◽

...

Keyword(s):

Human Blood ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

Random Effect ◽

Sensitivity Analyses ◽

Endometrial Polyps ◽

Inverse Variance ◽

Weighted Median ◽

The Uk ◽

Uterine Polyps

AbstractHuman blood cells (HBCs) play essential roles in multiple biological processes but their roles in development of uterine polyps are unknown. Here we implemented a Mendelian randomization (MR) analysis to investigate the effects of 36 HBC traits on endometrial polyps (EPs) and cervical polyps (CPs). The random-effect inverse-variance weighted method was adopted as standard MR analysis and three additional MR methods (MR-Egger, weighted median, and MR-PRESSO) were used for sensitivity analyses. Genetic instruments of HBC traits was extracted from a large genome-wide association study of 173,480 individuals, while data for EPs and CPs were obtained from the UK Biobank. All samples were Europeans. Using genetic variants as instrumental variables, our study found that both eosinophil count (OR 0.85, 95% CI 0.79–0.93, P = 1.06 × 10−4) and eosinophil percentage of white cells (OR 0.84, 95% CI 0.77–0.91, P = 2.43 × 10−5) were associated with decreased risk of EPs. The results were robust in sensitivity analyses and no evidences of horizontal pleiotropy were observed. While we found no significant associations between HBC traits and CPs. Our findings suggested eosinophils might play important roles in the pathogenesis of EPs. Besides, out study provided novel insight into detecting uterine polyps biomarkers using genetic epidemiology approaches.

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Body mass index and height and risk of cutaneous melanoma: Mendelian randomization analyses

International Journal of Epidemiology ◽

10.1093/ije/dyaa009 ◽

2020 ◽

Vol 49 (4) ◽

pp. 1236-1245 ◽

Cited By ~ 2

Author(s):

Jean Claude Dusingize ◽

Catherine M Olsen ◽

Jiyuan An ◽

Nirmala Pandeya ◽

Matthew H Law ◽

...

Keyword(s):

Body Mass Index ◽

Body Mass ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

Meta Analysis ◽

Positive Association ◽

Sensitivity Analyses ◽

Nucleotide Polymorphisms ◽

Melanoma Risk ◽

Lifestyle Risk Factors

Abstract Background Height and body mass index (BMI) have both been positively associated with melanoma risk, although findings for BMI have been less consistent than height. It remains unclear, however, whether these associations reflect causality or are due to residual confounding by environmental and lifestyle risk factors. We re-evaluated these associations using a two-sample Mendelian randomization (MR) approach. Methods We identified single nucleotide polymorphisms (SNPs) for BMI and height from separate genome-wide association study (GWAS) meta-analyses. We obtained melanoma SNPs from the most recent melanoma GWAS meta-analysis comprising 12 874 cases and 23 203 controls. We used the inverse variance-weighted estimator to derive separate causal risk estimates across all SNP instruments for BMI and height. Results Based on the combined estimate derived from 730 SNPs for BMI, we found no evidence of an association between genetically predicted BMI and melanoma [odds ratio (OR) per one standard deviation (1 SD) (4.6 kg/m2) increase in BMI 1.00, 95% confidence interval (CI): 0.91–1.11]. In contrast, we observed a positive association between genetically-predicted height (derived from a pooled estimate of 3290 SNPs) and melanoma risk [OR 1.08, 95% CI: 1.02–1.13, per 1 SD (9.27 cm) increase in height]. Sensitivity analyses using two alternative MR methods yielded similar results. Conclusions These findings provide no evidence for a causal association between higher BMI and melanoma, but support the notion that height is causally associated with melanoma risk. Mechanisms through which height influences melanoma risk remain unclear, and it remains possible that the effect could be mediated through diverse pathways including growth factors and even socioeconomic status.

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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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