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

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.

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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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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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The impact of plasma vitamin C levels on the risk of cardiovascular diseases and Alzheimer's disease: a Mendelian randomization study

Clinical Nutrition ◽

10.1016/j.clnu.2021.08.020 ◽

2021 ◽

Author(s):

Lu Chen ◽

Xingang Sun ◽

Zhen Wang ◽

Yunlong Lu ◽

Miao Chen ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cardiovascular Diseases ◽

Vitamin C ◽

Mendelian Randomization ◽

Plasma Vitamin ◽

The Impact

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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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Evidence of a Causal Association Between Cancer and Alzheimer’s Disease: a Mendelian Randomization Analysis

Scientific Reports ◽

10.1038/s41598-019-49795-6 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 5

Author(s):

Sahba Seddighi ◽

Alexander L. Houck ◽

James B. Rowe ◽

Paul D. P. Pharoah

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mendelian Randomization ◽

Observational Evidence ◽

Inverse Association ◽

Causal Association ◽

Lower Odds ◽

Genetic Predictors ◽

Log Odds ◽

Randomization Analysis

Abstract While limited observational evidence suggests that cancer survivors have a decreased risk of developing Alzheimer’s disease (AD), and vice versa, it is not clear whether this relationship is causal. Using a Mendelian randomization approach that provides evidence of causality, we found that genetically predicted lung cancer (OR 0.91, 95% CI 0.84–0.99, p = 0.019), leukemia (OR 0.98, 95% CI 0.96–0.995, p = 0.012), and breast cancer (OR 0.94, 95% CI 0.89–0.99, p = 0.028) were associated with 9.0%, 2.4%, and 5.9% lower odds of AD, respectively, per 1-unit higher log odds of cancer. When genetic predictors of all cancers were pooled, cancer was associated with 2.5% lower odds of AD (OR 0.98, 95% CI 0.96–0.988, p = 0.00027) per 1-unit higher log odds of cancer. Finally, genetically predicted smoking-related cancers showed a more robust inverse association with AD than non-smoking related cancers (OR 0.95, 95% CI 0.92–0.98, p = 0.0026, vs. OR 0.98, 95% CI 0.97–0.995, p = 0.0091).

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Examination of the causal association between lung function and Alzheimer’s Disease: a Mendelian Randomization study

10.1183/13993003.congress-2019.pa4402 ◽

2019 ◽

Author(s):

Daniel Higbee ◽

Raquell Granell ◽

George Davey Smith ◽

John Henderson ◽

James Dodd

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Lung Function ◽

Mendelian Randomization ◽

Causal Association

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Evidence for a causal association between milk intake and cardiometabolic disease outcomes using a two-sample Mendelian Randomization analysis in up to 1,904,220 individuals

International Journal of Obesity ◽

10.1038/s41366-021-00841-2 ◽

2021 ◽

Author(s):

Karani Santhanakrishnan Vimaleswaran ◽

Ang Zhou ◽

Alana Cavadino ◽

Elina Hyppönen

Keyword(s):

Large Scale ◽

Mendelian Randomization ◽

Meta Analysis ◽

Density Lipoprotein ◽

Milk Intake ◽

Milk Consumption ◽

Causal Association ◽

Uk Biobank ◽

Meta Analyses ◽

Mr Study

Abstract Background High milk intake has been associated with cardio-metabolic risk. We conducted a Mendelian Randomization (MR) study to obtain evidence for the causal relationship between milk consumption and cardio-metabolic traits using the lactase persistence (LCT-13910 C > T, rs4988235) variant as an instrumental variable. Methods We tested the association of LCT genotype with milk consumption (for validation) and with cardio-metabolic traits (for a possible causal association) in a meta-analysis of the data from three large-scale population-based studies (1958 British Birth Cohort, Health and Retirement study, and UK Biobank) with up to 417,236 participants and using summary statistics from consortia meta-analyses on intermediate traits (N = 123,665–697,307) and extended to cover disease endpoints (N = 86,995–149,821). Results In the UK Biobank, carriers of ‘T’ allele of LCT variant were more likely to consume milk (P = 7.02 × 10−14). In meta-analysis including UK Biobank, the 1958BC, the HRS, and consortia-based studies, under an additive model, ‘T’ allele was associated with higher body mass index (BMI) (Pmeta-analysis = 4.68 × 10−12) and lower total cholesterol (TC) (P = 2.40 × 10−36), low-density lipoprotein cholesterol (LDL-C) (P = 2.08 × 10−26) and high-density lipoprotein cholesterol (HDL-C) (P = 9.40 × 10−13). In consortia meta-analyses, ‘T’ allele was associated with a lower risk of coronary artery disease (OR:0.86, 95% CI:0.75–0.99) but not with type 2 diabetes (OR:1.06, 95% CI:0.97–1.16). Furthermore, the two-sample MR analysis showed a causal association between genetically instrumented milk intake and higher BMI (P = 3.60 × 10−5) and body fat (total body fat, leg fat, arm fat and trunk fat; P < 1.37 × 10−6) and lower LDL-C (P = 3.60 × 10−6), TC (P = 1.90 × 10−6) and HDL-C (P = 3.00 × 10−5). Conclusions Our large-scale MR study provides genetic evidence for the association of milk consumption with higher BMI but lower serum cholesterol levels. These data suggest no need to limit milk intakes with respect to cardiovascular disease risk, with the suggested benefits requiring confirmation in further studies.

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Association between alcohol consumption and Alzheimer’s disease: A Mendelian randomization Study

10.1101/190165 ◽

2017 ◽

Author(s):

Shea J. Andrews ◽

Alison Goate ◽

Kaarin J. Anstey

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Alcohol Consumption ◽

Alcohol Dependence ◽

Alcohol Intake ◽

Mendelian Randomization ◽

Age Of Onset ◽

Moderate Alcohol Consumption ◽

Causal Association ◽

Study Designs

AbstractINTRODUCTIONObservational studies have suggested that light-moderate alcohol consumptions decreases the risk of Alzheimer’s disease, but it is unclear if this association is causal.METHODSTwo-sample Mendelian randomization (MR) analysis was used to examine whether alcohol consumption, alcohol dependence or Alcohol Use Disorder Identification Test (AUDIT) scores were causally associated with the risk of Late Onset Alzheimer’s disease (LOAD) or Alzheimer’s disease age of onset survival (AAOS). Additionally, γ-glutamyltransferase levels were included as a positive control.RESULTSThere was no evidence of a causal association between alcohol consumption, alcohol dependence or AUDIT and LOAD. Alcohol consumption was associated with an earlier AAOS and increased γ-glutamyltransferase blood concentrations. Alcohol dependence was associated with a delayed AAOS.DISCUSSIONMR found robust evidence of a causal association between alcohol consumption and an earlier AAOS, but not alcohol intake and LOAD risk. The protective effect of alcohol dependence is potentially due to survivor bias.Research in ContextSystematic ReviewThe authors reviewed the literature using online databases (e.g. PubMed). Previous research links light-moderate alcohol consumption to a decreased risk of Alzheimer’s disease (AD), however, prior studies based on observational study designs may be biased due to unmeasured confounders influencing both alcohol consumption and AD risk.InterpretationWe used a two-sample Mendelian randomization (MR) approach to evaluated the causal relationship between alcohol intake and AD. MR uses genetic variants as proxies for environmental exposures to provide an estimate of the causal association between an intermediate exposure and a disease outcome. MR found evidence of a causal association between alcohol consumption and an earlier AD age of onset, suggesting that light-moderate alcohol consumption does not reduce risk of Alzheimer’s disease.Future DirectionsFuture studies should use alterative study designs and account for additional confounders when evaluating the causal relationship between alcohol consumption and AD.HighlightsWe evaluated causal relationships between alcohol intake and Alzheimer’s diseaseAlcohol consumption is causally associated with an earlier Alzheimer’s age of onsetNo evidence of causal assocations between alcohol intake and Alzheimer’s risk

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Identification of functionally connected multi-omic biomarkers for Alzheimer’s Disease using modularity-constrained Lasso

10.1101/789693 ◽

2019 ◽

Author(s):

Linhui Xie ◽

Pradeep Varathan ◽

Kwangsik Nho ◽

Andrew J. Saykin ◽

Paul Salama ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Performance ◽

Large Scale ◽

Association Studies ◽

Interaction Network ◽

Real Data ◽

Genome Wide Association Studies ◽

Penalty Term ◽

Genome Wide

AbstractIn the past decade, a large number of genetic biomarkers have been discovered through large-scale genome wide association studies (GWASs) in Alzheimer’s disease (AD), such as APOE, TOMM40 and CLU. Despite this significant progress, existing genetic findings are largely passengers not directly involved in the driver events, which presents challenges for replication and translation into targetable mechanisms. In this paper, leveraging the protein interaction network, we proposed a modularity-constrained Lasso model to jointly analyze the genotype, gene expression and protein expression data. With a prior network capturing the functional relationship between SNPs, genes and proteins, the newly introduced penalty term maximizes the global modularity of the subnetwork involving selected markers and encourages the selection of multi-omic markers with dense functional connectivity, instead of individual markers. We applied this new model to the real data in ROS/MAP cohort for discovery of biomarkers related to cognitive performance. A functionally connected subnetwork involving 276 multi-omic biomarkers, including SNPs, genes and proteins, were identified to bear predictive power. Within this subnetwork, multiple trans-omic paths from SNPs to genes and then proteins were observed, suggesting that cognitive performance can be potentially affected by the genetic mutations due to their cascade effect on the expression of downstream genes and proteins.

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