Genetically increased serum calcium levels reduce Alzheimer’s disease risk

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

Genes & Nutrition ◽

10.1186/s12263-021-00700-9 ◽

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.

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Life Course Adiposity and Alzheimer’s Disease: A Mendelian Randomization Study

Journal of Alzheimer s Disease ◽

10.3233/jad-210345 ◽

2021 ◽

pp. 1-10

Author(s):

Xian Li ◽

Yan Tian ◽

Yu-Xiang Yang ◽

Ya-Hui Ma ◽

Xue-Ning Shen ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Life Course ◽

Mendelian Randomization ◽

Association Studies ◽

Meta Analysis ◽

Genome Wide Association Studies ◽

Fat Percentage ◽

Regression Methods ◽

Weighted Median

Background: Several studies showed that life course adiposity was associated with Alzheimer’s disease (AD). However, the underlying causality remains unclear. Objective: We aimed to examine the causal relationship between life course adiposity and AD using Mendelian randomization (MR) analysis. Methods: Instrumental variants were obtained from large genome-wide association studies (GWAS) for life course adiposity, including birth weight (BW), childhood body mass index (BMI), adult BMI, waist circumference (WC), waist-to-hip ratio (WHR), and body fat percentage (BFP). A meta-analysis of GWAS for AD including 71,880 cases and 383,378 controls was used in this study. MR analyses were performed using inverse variance weighted (IVW), weighted median, and MR-Egger regression methods. We calculated odds ratios (ORs) per genetically predicted standard deviation (1-SD) unit increase in each trait for AD. Results: Genetically predicted 1-SD increase in adult BMI was significantly associated with higher risk of AD (IVW: OR = 1.03, 95% confidence interval [CI] = 1.01–1.05, p = 2.7×10–3) after Bonferroni correction. The weighted median method indicated a significant association between BW and AD (OR = 0.94, 95% CI = 0.90–0.98, p = 1.8×10–3). We also found suggestive associations of AD with WC (IVW: OR = 1.03, 95% CI = 1.00–1.07, p = 0.048) and WHR (weighted median: OR = 1.04, 95% CI = 1.00–1.07, p = 0.029). No association was detected of AD with childhood BMI and BFP. Conclusion: Our study demonstrated that lower BW and higher adult BMI had causal effects on increased AD risk.

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Impact of Serum Calcium Levels on Alzheimer’s Disease: A Mendelian Randomization Study

Journal of Alzheimer s Disease ◽

10.3233/jad-191249 ◽

2020 ◽

pp. 1-12 ◽

Cited By ~ 1

Author(s):

Yating He ◽

Haihua Zhang ◽

Tao Wang ◽

Zhifa Han ◽

Qing-bin Ni ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Serum Calcium ◽

Mendelian Randomization

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Manifestations of Alzheimer’s Disease Genetic Risk in the Blood: A Cross-Sectional Multi-Omic Analysis in Healthy Adults Aged 18-90+

10.21203/rs.3.rs-1108842/v1 ◽

2021 ◽

Author(s):

Laura M Heath ◽

John C. Earls ◽

Andrew T. Magis ◽

Sergey A. Kornilov ◽

Jennifer C. Lovejoy ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Genetic Variants ◽

Genetic Risk ◽

Large Scale ◽

Late Onset ◽

Early Adulthood ◽

Whole Genome Sequencing Data ◽

Significant Finding ◽

Functional Interpretation

Abstract Background: Genetics play an important role in late-onset Alzheimer’s Disease (AD) etiology and dozens of genetic variants have been implicated in AD risk through large-scale GWAS meta-analyses. However, the precise mechanistic effects of most of these variants have yet to be determined. Deeply phenotyped cohort data can reveal physiological changes associated with genetic risk for AD across an age spectrum that may provide clues to the biology of the disease.Methods: We utilized over 2000 high-quality quantitative measurements obtained from blood of 2831 cognitively normal adult clients of a consumer-based scientific wellness company, each with CLIA-certified whole-genome sequencing data. Measurements included: clinical laboratory blood tests, targeted chip-based proteomics, and metabolomics. We performed a phenome-wide association study utilizing this diverse blood marker data and 25 known AD genetic variants, adjusting for sex, age, vendor (for clinical labs), and the first four genetic principal components; sex-SNP interactions were also assessed.Results: We observed statistically significant SNP-analyte associations for five genetic variants after correction for multiple testing (for SNPs in or near NYAP1, ABCA7, INPP5D, and APOE), with effects detectable from early adulthood. The ABCA7 SNP and the APOE2 and APOE4 encoding alleles were associated with lipid variability, as seen in previous studies; in addition, six novel proteins were associated with the e2 allele. The most statistically significant finding was between the NYAP1 variant and PILRA and PILRB protein levels, supporting previous functional genomic studies in the identification of a putative causal variant within the PILRA gene. Sex modified the effects of four genetic variants, with multiple interrelated immune-modulating effects associated with the PICALM variant. In post-hoc analysis, sex-stratified GWAS results from an independent AD case-control meta-analysis supported sex-specific disease effects of the PICALM variant, highlighting the importance of sex as a biological variable.Conclusions: Known AD genetic variation influenced lipid metabolism and immune response systems in a population of non-AD individuals, with associations observed from early adulthood onward. Further research is needed to determine whether and how these effects are implicated in early-stage biological pathways to AD. These analyses aim to complement ongoing work on the functional interpretation of AD-associated genetic variants.

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Association between Alzheimer's disease and COVID-19: A bidirectional Mendelian randomization

10.1101/2020.07.27.20163212 ◽

2020 ◽

Author(s):

Di Liu ◽

Xiaoyu Zhang ◽

Weijie Cao ◽

Jie Zhang ◽

Manshu Song ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Confidence Interval ◽

Genetic Variants ◽

Odds Ratio ◽

Observational Studies ◽

Mendelian Randomization ◽

Biological Pathways ◽

Bidirectional Regulation ◽

Increased Risk

Background In observational studies, Alzheimer's disease (AD) has been associated with an increased risk of Coronavirus disease 2019 (COVID-19), and the prognosis of COVID-19 can affect nervous systems. However, the causality between these conditions remains to be determined. Methods This study sought to investigate the bidirectional causal relations of AD with COVID-19 using two-sample Mendelian randomization (MR) analysis. Results We found that genetically predicted AD was significantly associated with higher risk of severe COVID-19 (odds ratio [OR], 3.329; 95% confidence interval [CI], 1.139-9.725; P=0.028). It's interesting that genetically predicted severe COVID-19 was also significantly associated with higher risk of AD (OR, 1.004; 95% CI, 1.001-1.007; P=0.018). In addition, the two strong genetic variants associated with severe COVID-19 was associated with higher AD risk (OR, 1.018; 95% CI, 1.003-1.034; P=0.018). There is no evidence to support that genetically predicted AD was significantly associated with COVID-19 susceptibility, and vice versa. No obvious pleiotropy bias and heterogeneity were observed. Conclusion Overall, AD may causally affect severe COVID-19, and vice versa, performing bidirectional regulation through independent biological pathways.

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PLCG2 rs72824905 Variant Reduces the Risk of Alzheimer’s Disease and Multiple Sclerosis

Journal of Alzheimer s Disease ◽

10.3233/jad-201140 ◽

2021 ◽

pp. 1-7

Author(s):

Fan Chen ◽

Yan Zhang ◽

Longcai Wang ◽

Tao Wang ◽

Zhifa Han ◽

...

Keyword(s):

Multiple Sclerosis ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Association Study ◽

Genetic Association ◽

Genetic Association Study ◽

Large Scale

We aimed to evaluate the association of PLCG2 rs72824905 variant with Alzheimer’s disease (AD) and multiple sclerosis (MS) using large-scale genetic association study datasets. We selected 50,024 AD cases and 467,330 controls, and 32,367 MS cases and 36,012 controls. We found moderate heterogeneity of rs72824905 in different studies. We found significant association between rs72824905 G allele and reduced AD risk (OR = 0.66, 95% CI 0.59–0.74, p = 5.91E-14). Importantly, rs72824905 G allele could also significantly reduce the risk of MS with OR = 0.94, p = 3.63E-05. Hence, the effects of rs72824905 on AD and MS are consistent.

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

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2020.590903 ◽

2020 ◽

Vol 8 ◽

Author(s):

Qiang Meng ◽

Lu Huang ◽

Kai Tao ◽

Yong Liu ◽

Jiangpeng Jing ◽

...

Keyword(s):

Ischemic Stroke ◽

Serum Calcium ◽

Calcium Intake ◽

Genetic Variants ◽

Large Scale ◽

Genome Wide Association Study ◽

Mr Studies ◽

Causal Association ◽

Gwas Dataset ◽

The Impact

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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Manifestations of genetic risk for Alzheimer’s Disease in the blood: a cross-sectional multi-omic analysis in healthy adults aged 18-90+

10.1101/2021.03.26.437267 ◽

2021 ◽

Author(s):

Laura Heath ◽

John C. Earls ◽

Andrew T. Magis ◽

Sergey A. Kornilov ◽

Jennifer C. Lovejoy ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Association Study ◽

Genetic Variants ◽

Genetic Risk ◽

Multiple Testing ◽

Large Scale ◽

Genome Wide Association Study ◽

Cross Sectional ◽

Risk Variants

AbstractDeeply phenotyped cohort data can elucidate differences associated with genetic risk for common complex diseases across an age spectrum. Previous work has identified genetic variants associated with Alzheimer’s disease (AD) risk from large-scale genome-wide association study meta-analyses. To explore effects of known AD-risk variants, we performed a phenome-wide association study on ~2000 clinical, proteomic, and metabolic blood-based analytes obtained from 2,831 cognitively normal adult clients of a consumer-based scientific wellness company. Results uncovered statistically significant SNP-analyte associations for five genetic variants after correction for multiple testing (for SNPs in or near NYAP1, ABCA7, INPP5D, and APOE). These effects were detectable from early adulthood. Sex modified the effects of four genetic variants, with multiple interrelated immune-modulating effects associated with the PICALM variant. Sex-stratified GWAS results from an independent AD case-control meta-analysis supported sexspecific disease effects of the PICALM variant, highlighting the importance of sex as a biological variable. These analyses support evidence from previous functional genomics studies in the identification of a causal variant within the PILRA gene. Taken together, this study highlights clues to the earliest effects of AD genetic risk variants in individuals where disease symptoms have not (yet) arisen.

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Impact of serum calcium levels on local and total body bone mineral density: A Mendelian randomization study and an age stratum analysis

10.1101/737585 ◽

2019 ◽

Author(s):

Jing-yi Sun ◽

Haihua Zhang ◽

Yan Zhang ◽

Longcai Wang ◽

Jin Rok Oh ◽

...

Keyword(s):

Bone Mineral Density ◽

Lumbar Spine ◽

Femoral Neck ◽

Bone Mineral ◽

Serum Calcium ◽

Large Scale ◽

Mendelian Randomization ◽

Mineral Density ◽

Gwas Dataset ◽

Total Body

AbstractObjectivesUntil recently, randomized controlled trials and meta-analyses have not demonstrated convincing conclusions regarding the association of calcium intake with bone mineral density (BMD). Until now, it remains unclear whether high serum calcium levels are causally associated with BMD. This study aimed to investigate the genetic association between serum calcium levels and BMD using a large-scale serum calcium GWAS dataset and four large-scale BMD GWAS datasets in individuals of European descent.MethodsWe performed a Mendelian randomization study to investigate the association of increased serum calcium levels with BMD using a large-scale serum calcium genome-wide association study (GWAS) dataset (including up to 61,079 individuals) and four large-scale BMD GWAS datasets (including minimum 4,180 individuals and maximum 142,487 individuals) regarding the total body, forearm, femoral neck, lumbar spine, and heel BMD. Here, we selected three Mendelian randomization methods including inverse-variance weighted meta-analysis (IVW), weighted median, and MR-Egger.ResultsIn specific site analysis, we found that increased serum calcium levels could reduce BMD at forearm (OR=0.59, 95% CI: 0.36-0.95, P=0.029) and lumbar spine (OR=0.65, 95% CI: 0.49-0.86, P=0.002). We did not identify any suggestive association of genetically increased serum calcium levels with BMD of total body, femoral neck, and heel BMD. In specific age stratum analysis, we found that genetically increased serum calcium levels were statistically significantly associated with reduced total body BMD in age stratum 60 or more years (OR=0.58, 95% CI: 0.41-0.82, P=0.002).ConclusionsWe provide genetic evidence that increased serum calcium levels could not improve BMD in the general population. The elevated serum calcium levels in generally healthy populations, especially adults older than 60 years, may even reduce the BMD, and further cause osteoporosis.

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