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

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.

scholarly journals Mendelian randomization to evaluate the effect of plasma vitamin C levels on the risk of Alzheimer’s disease

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Haijie Liu ◽  
Yan Zhang ◽  
Yang Hu ◽  
Haihua Zhang ◽  
Tao Wang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Vitamin C ◽  
Cognitive Performance ◽  
Large Scale ◽  
Mendelian Randomization ◽  
Plasma Vitamin ◽  
Causal Association ◽  
Uk Biobank ◽  
Gwas Dataset

Abstract Objective Until now, observational studies have explored the impact of vitamin C intake on Alzheimer’s disease (AD) risk, however, reported ambiguous findings. To develop effective therapies or prevention, the causal link between vitamin C levels and AD should be established. Methods Here, we selected 11 plasma vitamin C genetic variants from a large-scale plasma vitamin C GWAS dataset (N = 52,018) as the potential instrumental variables. We extracted their corresponding summary statistics from large-scale IGAP clinically diagnosed AD GWAS dataset (N = 63,926) and UK Biobank AD proxy phenotype GWAS dataset (N = 314,278), as well as two UK Biobank subgroups including the maternal AD group (27,696 cases of maternal AD and 260,980 controls) and paternal AD group (14,338 cases of paternal AD and 245,941 controls). We then performed a Mendelian randomization (MR) study to evaluate the causal association between plasma vitamin C levels and the risk of AD and AD proxy phenotype. Meanwhile, we further verified these findings using a large-scale cognitive performance GWAS dataset (N = 257,841). Results In IGAP, we found no significant causal association between plasma vitamin C levels and the risk of AD. In UK Biobank, we found that per 1 SD increase in plasma vitamin C levels (about 20.2 μmol/l) was significantly associated with the reduced risk of AD proxy phenotype (OR = 0.93, 95% CI 0.88–0.98, P = 7.00E−03). A subgroup MR analysis in UK Biobank indicated that per 1 SD increase in plasma vitamin C levels could significantly reduce the risk of AD proxy phenotype in the maternal AD group (OR = 0.89, 95% CI 0.84–0.94, P = 7.29E−05), but not in the paternal AD group (OR = 1.02, 95% CI 0.92–1.12, P = 7.59E−01). The leave-one-out permutation further showed that the SLC23A1 rs33972313 variant largely changed the precision of the overall MR estimates in all these four GWAS datasets. Meanwhile, we did not observe any significant causal effect of plasma vitamin C levels on the cognitive performance. Conclusion We demonstrated that there may be no causal association between plasma vitamin C levels and the risk of AD in people of European descent. The insistent findings in clinically diagnosed AD and AD proxy phenotype may be caused by the phenotypic heterogeneity.

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

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.

scholarly journals Finding genetically-supported drug targets for Parkinson’s disease using Mendelian randomization of the druggable genome

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Catherine S. Storm ◽  
Demis A. Kia ◽  
Mona M. Almramhi ◽  
Sara Bandres-Ciga ◽  
Chris Finan ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Drug Targets ◽  
Molecular Mechanisms ◽  
Mendelian Randomization ◽  
Disease Risk ◽  
Target Identification ◽  
Causal Effect ◽  
Age At Onset ◽  
Drug Repurposing

AbstractParkinson’s disease is a neurodegenerative movement disorder that currently has no disease-modifying treatment, partly owing to inefficiencies in drug target identification and validation. We use Mendelian randomization to investigate over 3,000 genes that encode druggable proteins and predict their efficacy as drug targets for Parkinson’s disease. We use expression and protein quantitative trait loci to mimic exposure to medications, and we examine the causal effect on Parkinson’s disease risk (in two large cohorts), age at onset and progression. We propose 23 drug-targeting mechanisms for Parkinson’s disease, including four possible drug repurposing opportunities and two drugs which may increase Parkinson’s disease risk. Of these, we put forward six drug targets with the strongest Mendelian randomization evidence. There is remarkably little overlap between our drug targets to reduce Parkinson’s disease risk versus progression, suggesting different molecular mechanisms. Drugs with genetic support are considerably more likely to succeed in clinical trials, and we provide compelling genetic evidence and an analysis pipeline to prioritise Parkinson’s disease drug development.

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

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.

scholarly journals Predicting the efficacy of exenatide in Parkinson’s disease using genetics – a Mendelian randomization study

2020 ◽  
Author(s):  
Catherine S. Storm ◽  
Demis A. Kia ◽  
Mona Almramhi ◽  
Dilan Athauda ◽  
Stephen Burgess ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Type 2 Diabetes Mellitus ◽  
Brain Tissue ◽  
Mendelian Randomization ◽  
Disease Risk ◽  
Age At Onset

AbstractBackgroundExenatide is a glucagon-like peptide 1 receptor (GLP1R) agonist used in type 2 diabetes mellitus that has shown promise for Parkinson’s disease in a phase II clinical trial. Drugs with genetic evidence are more likely to be successful in clinical trials. In this study we investigated whether the genetic technique Mendelian randomization (MR) can “rediscover” the effects of exenatide on diabetes and weight, and predict its efficacy for Parkinson’s disease.MethodsWe used genetic variants associated with increased expression of GLP1R in blood to proxy exenatide, as well as variants associated with expression of DPP4, TLR4 and 15 genes thought to act downstream of GLP1R or mimicking alternative actions of GLP-1 in blood and brain tissue. Using an MR approach, we predict the effect of exenatide on type 2 diabetes risk, body mass index (BMI), Parkinson’s disease risk and several Parkinson’s disease progression markers.ResultsWe found that genetically-raised GLP1R expression in blood was associated with lower BMI and possibly type 2 diabetes mellitus risk, but not Parkinson’s disease risk, age at onset or progression. Reduced DPP4 expression in brain tissue was significantly associated with increased Parkinson’s disease risk.ConclusionsWe demonstrate the usefulness of MR using expression data in predicting the efficacy of a drug and exploring its mechanism of action. Our data suggest that GLP-1 mimetics like exenatide, if ultimately proven to be effective in Parkinson’s disease, will be through a mechanism that is independent of GLP1R in blood.

scholarly journals The Parkinson’s Disease GWAS Locus Browser

2020 ◽  
Author(s):  
Francis P. Grenn ◽  
Jonggeol J. Kim ◽  
Mary B. Makarious ◽  
Hirotaka Iwaki ◽  
Anastasia Illarionova ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Large Scale ◽  
Association Studies ◽  
Age At Onset ◽  
Genome Wide Association Studies ◽  
Functional Studies ◽  
Risk Variants ◽  
Genome Wide

AbstractParkinson’s disease (PD) is a neurodegenerative disease with an often complex genetic component identifiable by genome-wide association studies (GWAS). The most recent large scale PD GWASes have identified more than 90 independent risk variants for PD risk and progression across 80 loci. One major challenge in current genomics is identifying the causal gene(s) and variant(s) from each GWAS locus. Here we present a GWAS locus browser application that combines data from multiple databases to aid in the prioritization of genes associated with PD GWAS loci. We included 92 independent genome-wide significant signals from multiple recent PD GWAS studies including the PD risk GWAS, age-at-onset GWAS and progression GWAS. We gathered data for all 2336 genes within 1Mb up and downstream of each variant to allow users to assess which gene(s) are most associated with the variant of interest based on a set of self-ranked criteria. Our aim is that the information contained in this browser (https://pdgenetics.shinyapps.io/GWASBrowser/) will assist the PD research community with the prioritization of genes for follow-up functional studies and as potential therapeutic targets.

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

2021 ◽  
Vol 12 ◽  
Author(s):  
Yunxia Li ◽  
Wenhao Chen ◽  
Shiyao Tian ◽  
Shuyue Xia ◽  
Biao Yang
Keyword(s):  
Socioeconomic Status ◽  
Educational Attainment ◽  
Genetic Variants ◽  
Large Scale ◽  
Mendelian Randomization ◽  
Causal Association ◽  
Standard Deviation Increase ◽  
Asthma Risk ◽  
Inverse Variance ◽  
Weighted Median

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.

scholarly journals Analysis of PTRHD1 common and rare variants in European patients with Parkinson’s disease

2020 ◽  
Author(s):  
Yuri L. Sosero ◽  
Sara Bandres-Ciga ◽  
Ziv Gan-Or ◽  
Lynne Krohn
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Large Scale ◽  
Genome Wide Association Study ◽  
Rare Variants ◽  
Age At Onset ◽  
European Population ◽  
European Ancestry ◽  
Genome Wide ◽  
Meta Analyses

AbstractThree family studies identified three different variants in the peptidyl-tRNA hydrolase domain containing 1 gene (PTRHD1) in patients affected by syndromic parkinsonism. In the current study, our objective was to investigate whether PTRHD1 variants are associated with Parkinson’s disease (PD) risk and age at onset (AAO). To evaluate the association between PTRHD1 and PD risk, we analyzed whole genome sequencing (WGS) data of 1,647 PD cases and 1,050 healthy controls, as well as genome-wide imputed genotyping data on 14,671 PD cases and 17,667 controls, all of European ancestry. Furthermore, we examined the association of PTRHD1 with PD risk and AAO using summary statistics data from the most recent PD genome-wide association study (GWAS) meta-analyses. Our results show no association between PTRHD1 and PD risk or AAO. We conclude that PTRHD1 does not play a major role in PD in the European population. Further large-scale studies including subjects with different ancestry and family trios might further clarify the relationship of this gene with PD and atypical parkinsonism.

scholarly journals Assessment of LIN28A variants in Parkinson’s disease

2020 ◽  
Author(s):  
Monica Diez-Fairen ◽  
Mary B. Makarious ◽  
Sara Bandres-Ciga ◽  
Cornelis Blauwendraat
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Large Scale ◽  
Disease Risk ◽  
Age At Onset ◽  
European Ancestry ◽  
Whole Genome Sequencing Data ◽  
Sequencing Data ◽  
Common Genetic Variants

AbstractParkinson’s disease (PD) is a complex neurodegenerative disease with a strong genetic component in which both rare and common genetic variants contribute to disease risk, onset and progression. Despite that several genes have been associated with familial forms of disease, validation of novel genes associated with PD remains extremely challenging. Recently, a heterozygous loss-of-function variant in LIN28A was associated with PD pathogenesis in the Asian population. Here, we comprehensively assess the role of LIN28A variants in PD susceptibility using individual-level genotyping data from 14,671 PD cases and 17,667 controls, as well as whole-genome sequencing data from 1,647 PD patients and 1,050 controls. Additionally, we further assessed the summary statistics from the most recent GWAS meta-analyses to date for PD risk and age at onset. After evaluating these data, we did not find evidence to support a role for LIN28A as a major causal gene for PD. However, additional large-scale familial and case-control studies in non-European ancestry populations are necessary to further evaluate the role of LIN28A in PD etiology.

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