Genetic determinants of low vitamin B12 levels in Alzheimer's disease risk

Taliun, Sarah A. Gagliano

doi:10.1016/j.dadm.2019.04.007

Cited by 3 publications

(2 citation statements)

References 22 publications

(29 reference statements)

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“…Suggestive evidence has indicated that increased vitamin B12 levels may marginally increase fasting glucose while reducing beta-cell function in the pancreas 19 . However, no explicit associations have been identified between vitamin B12 levels and coronary artery disease, type 2 diabetes, measures of obesity, or Alzheimer’s disease 19, 20 . Recently, a phenome-wide study based on the UK Biobank confirmed the association between increased vitamin B12 levels and reduced odds of pernicious anemia 21 .…”

Section: Introductionmentioning

confidence: 99%

Estimating effects of serum vitamin B12 levels on psychiatric disorders and cognitive impairment: a Mendelian randomization study

Lu,

Paterson

2024

Preprint

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Vitamin B12 deficiency can lead to pernicious anemia, various neuropsychiatric diseases, and cognitive decline. However, it is unclear whether increasing vitamin B12 levels can help to prevent the onset of psychiatric disorders and cognitive impairment in the general population. Leveraging large-scale genome-wide association studies (GWASs), we conducted Mendelian randomization (MR) analyses to estimate the potential effects of serum vitamin B12 levels on eight psychiatric disorders, as well as educational attainment and cognitive performance. We performed sensitivity analyses by excluding genetic instruments that demonstrated potential horizontal pleiotropy. We conducted additional MR analyses utilizing within-sibship studies for depressive symptoms, educational attainment, and cognitive performance to mitigate bias due to potential residual confounding in GWASs. As a positive control, we confirmed that a one standard deviation increase in genetically increased vitamin B12 levels was strongly associated with a decreased odds of developing pernicious anemia (odds ratio, OR = 0.24; 95% confidence interval, CI: 0.15-0.40; p-value = 2.1x10-8). In contrast, MR estimates of vitamin B12 effects on all eight psychiatric disorders, educational attainment and cognitive performance largely overlapped with the null. In particular, based on the three most well-powered GWASs, a one standard deviation increase in genetically predicted vitamin B12 levels was associated with an OR of 1.01 for depression (95% CI: 0.97-1.04; p-value = 0.74), a 7.7x10-3standard deviation increase in educational attainment (95% CI: -1.0x10-2-2.5x10-2; p-value = 0.39) and a 1.3x10-2standard deviation increase in cognitive performance (95% CI: -8.8x10-3-3.5x10-2; p-value = 0.24). No significant associations between genetically predicted vitamin B12 levels and any of the outcomes were identified in sensitivity analyses excluding pleiotropic genetic instruments or MR analyses based on within-sibship studies. In summary, our findings suggest that increasing serum vitamin B12 levels may not protect against the investigated psychiatric disorders or cognitive impairment in the general population.

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Section: Introductionmentioning

confidence: 99%

Estimating effects of serum vitamin B12 levels on psychiatric disorders and cognitive impairment: a Mendelian randomization study

Lu,

Paterson

2024

Preprint

View full text Add to dashboard Cite

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“…Hence, it is necessary to improve the causal inference through other study designs and overcome the methodological limitations of observational studies [ 11 ]. Interestingly, Mendelian randomization (MR) design has been widely used to determine the causal inferences in AD, such as vitamin D levels and AD, vitamin E levels and AD, and vitamin B12 levels and AD [ 11 – 16 ]. Meanwhile, Williams and colleagues recently conducted a MR analysis to evaluate the causal association of four circulating antioxidants including circulating ascorbate (vitamin C), β-carotene, retinol (vitamin A), and urate with the risk of AD [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

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

Liu

Zhang

et al. 2021

Genes Nutr

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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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A Comprehensive Fuzzy Ontology-Based Decision Support System for Alzheimer’s Disease Diagnosis

et al. 2021

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The World Health Organization (WHO) indicates that the proportion of the elderly will soon include nearly a quarter of the world population. Ensuring that health systems are prepared to deal with this phenomenal rate of aging and associated diseases generates many challenges. Among these challenges is facing Alzheimer's Disease (AD) that may occur at some point in the elderly life and may harm societies. AD is considered a neurological, psychological, mental, and health setback. The Clinical Decision Support System (CDSS) can improve patient care and support many medical functions, such as diagnosing diseases that can reduce preventable harm. This research's main objective is to design, implement, and evaluate the Alzheimer's Disease Diagnosis Ontology (ADDO). It is a comprehensive semantic knowledge base toward the development of fuzzy ontology-based CDSS for AD diagnosis. ADDO can serve as a core component of CDSS, which provides representation, annotation, and access to aspects related to AD's study and diagnosis. Toward the management of this objective, ADDO is based on the essentials of the Open Biomedical Ontology (OBO) and follows the Basic Formal Ontology (BFO) and the Ontology for General Medical Sciences (OGMS) principles. ADDO focuses on representing the patient characteristics, complications, drugs, diagnosis examination tests, and key aspects of their periodic visits in a standard way. The possibility of semantic interoperability is taken into account by integrating ADDO and a heterogeneous AD dataset. We used ADNI as a case study to mapping a set of real instances. To manage the medical domain's uncertainty, ADDO is extended to fuzzy ontology to accommodate the medical linguistic variables and enhance diagnosis results' efficiency. ADDO is constructed using Protégé 5.5.0 software and evaluated using the HermiT reasoner and SPARQL semantic queries. ADDO currently includes 7060 concepts, 99 properties, 46274 axioms, and 30708 annotations. As a result, ADDO is consistent and more reliable in managing most AD aspects than other existing AD ontologies.INDEX TERMS Fuzzy ontology, Clinical decision support system, Alzheimer's disease, knowledge based, Mild cognitive impairment, Ontology representation. I. INTRODUCTIONA LZHEIMER'S Disease (AD) is classified as a neurological disorder. It is associated with progressive damage to parts of the brain that are essential in forming memo-ries and carrying out cognitive functions [1]. AD results in the death of neurons cells on a massive scale and significantly shrinking brain tissue [2]. This negatively affects basic body functions, such as vision, swallowing, walking, and

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Genetic determinants of low vitamin B12 levels in Alzheimer's disease risk

Cited by 3 publications

References 22 publications

Estimating effects of serum vitamin B12 levels on psychiatric disorders and cognitive impairment: a Mendelian randomization study

Estimating effects of serum vitamin B12 levels on psychiatric disorders and cognitive impairment: a Mendelian randomization study

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

A Comprehensive Fuzzy Ontology-Based Decision Support System for Alzheimer’s Disease Diagnosis

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