Circulating Vitamin D Levels and Alzheimer’s Disease: A Mendelian Randomization Study in the IGAP and UK Biobank

Wang, Longcai; Qiao, Yanchun; Zhang, Haihua; Zhang, Yan; Hua, Jiao; Jin, Shuilin; Liu, Guiyou

doi:10.3233/jad-190713

Cited by 31 publications

(18 citation statements)

References 39 publications

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“…Using the summary results of these 14 genetic variants in both serum calcium levels and IS GWAS datasets, we first conducted a pleiotropy analysis using two statistical methods including the MR-Egger intercept test and the MR pleiotropy residual sum and outlier (MR-PRESSO) test (Verbanck et al, 2018). Both methods have been widely used in recent MR studies (Liu et al, 2018;Larsson et al, 2019;He et al, 2020;Wang et al, 2020). The statistical significance for evidence of pleiotropy is P < 0.05.…”

Section: Pleiotropy Analysismentioning

confidence: 99%

Integrated Genetics and Micronutrient Data to Inform the Causal Association Between Serum Calcium Levels and Ischemic Stroke

Meng

Huang

Tao

et al. 2020

Front. Cell Dev. Biol.Has correction 2020-12-18 Has erratum 2020-12-18

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There has been an increased interest for observational studies or randomized controlled trials exploring the impact of calcium intake on cardiovascular diseases (CVD) including coronary artery disease (CAD) and ischemic stroke (IS). However, a direct relationship between total calcium intake and CVD has not been well established and remains controversial. Mendelian randomization (MR) studies have been performed to evaluate the causal association between serum calcium levels and CAD risk and found that increased serum calcium levels could increase the risk of CAD. However, MR analysis found no significant association between genetically higher serum calcium levels and IS as well as its subtypes. Hence, three MR studies reported inconsistent effects of serum calcium levels on CAD and IS. Here, we performed an updated MR study to investigate the association of serum calcium levels with the risk of IS using large-scale genome-wide association study (GWAS) datasets. We selected 14 independent genetic variants as the potential instrumental variables from a large-scale serum calcium GWAS dataset and extracted summary statistics corresponding to the 14 serum calcium genetic variants from the MEGASTROKE Consortium IS GWAS dataset. Interestingly, we found a significant association between serum calcium levels and IS risk using the robust inverse-variance weighted (IVW) and penalized robust IVW methods, with β = 0.243 and P = 0.002. Importantly, the MR results from the robust MR-Egger and penalized robust MR-Egger methods further supported the causal association between serum calcium levels and IS risk, with β = 0.256 and P = 0.005. Meanwhile, the estimates from other MR methods are also consistent with the above findings.

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Section: Pleiotropy Analysismentioning

confidence: 99%

Integrated Genetics and Micronutrient Data to Inform the Causal Association Between Serum Calcium Levels and Ischemic Stroke

Meng

Huang

Tao

et al. 2020

Front. Cell Dev. Biol.Has correction 2020-12-18 Has erratum 2020-12-18

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“…1, a flow chart about our MR study design. The second and third assumptions are collectively known as independence from pleiotropy, as described in recent studies [16][17][18].…”

Section: Methodsmentioning

confidence: 99%

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

Liu

Zhang

et al. 2021

J Transl Med

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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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“…Hence, we used the GWAS datasets from the exposure (serum calcium) and the outcome (AD) to estimate the effect of exposure on outcome ( He et al, 2020 ). MR analysis has three assumptions, which have been widely described ( Liu et al, 2018 ; Anderson et al, 2020 ; He et al, 2020 ; Wang L. et al, 2020 ; Zhang et al, 2020 ; Ou et al, 2021 ; Sproviero et al, 2021 ). Ethical approvals were provided in the original articles ( Lambert et al, 2013 ; Young et al, 2021 ).…”

Section: Methodsmentioning

confidence: 99%

“…AD cases were autopsy-confirmed or clinically confirmed using the NINCDS-ADRDA criteria or DSM-IV guidelines ( Kunkle et al, 2019 ). The IGAP AD GWAS summary statistics have been widely used in recent MR analysis ( Liu et al, 2018 ; Anderson et al, 2020 ; He et al, 2020 ; Wang L. et al, 2020 ; Zhang et al, 2020 ; Ou et al, 2021 ; Sproviero et al, 2021 ).…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2021

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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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Circulating Vitamin D Levels and Alzheimer’s Disease: A Mendelian Randomization Study in the IGAP and UK Biobank

Cited by 31 publications

References 39 publications

Integrated Genetics and Micronutrient Data to Inform the Causal Association Between Serum Calcium Levels and Ischemic Stroke

Integrated Genetics and Micronutrient Data to Inform the Causal Association Between Serum Calcium Levels and Ischemic Stroke

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

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

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