Impact of Vitamin D Binding Protein Levels on Alzheimer’s Disease: A Mendelian Randomization Study

Article type: Research Article

Authors: Zhang, Haihua^{a; b} | Wang, Tao^{c; d} | Han, Zhifa^{e; f; g} | Wang, Longcai^h | Zhang, Yanⁱ | Wang, Lijun^{j; *} | Liu, Guiyou^{a; b; k; *}

Affiliations: [a] National Engineering Laboratory of Internet Medical Diagnosis and Treatment Technology, Xuanwu Hospital, Capital Medical University, Beijing, China | [b] Beijing Institute for Brain Disorders, Capital Medical University, Beijing, China | [c] Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China | [d] Chinese Institute for Brain Research, Beijing, China | [e] School of Medicine, School of Pharmaceutical Sciences, THU-PKU Center for Life Sciences, Tsinghua University, Beijing, China | [f] State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, China | [g] Department of Pathophysiology, Peking Union Medical College, Beijing, China | [h] Department of Anesthesiology, The Affiliated Hospital of Weifang Medical University, Weifang, China | [i] Department of Pathology, The Affiliated Hospital of Weifang Medical University, Weifang, China | [j] Department of Encephalopathy, Shenzhen Hospital of Guangzhou University of Chinese Medicine (Futian), Shenzhen, China | [k] Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China

Correspondence: [*] Correspondence to: Guiyou Liu, Department of Neurology, Xuanwu Hospital, Capital Medical University, Room 1037, Donghuajinzuo, Guanganmennei Street, XiCheng District, Beijing 100053, China. E-mail: [email protected]. and Lijun Wang, Department of Encephalopathy, Shenzhen Hospital of Guangzhou University of Chinese Medicine (Futian), Shenzhen 518000, China. E-mail: [email protected].

Abstract: Until now, observational studies, randomized controlled trials (RCTs), and Mendelian randomization (MR) studies have explored the impact of vitamin D on Alzheimer’s disease (AD), and reported inconsistent findings. In MR studies, the sensitivity analysis by removing GC rs2282679 variant highlighted no association of 25OHD levels with AD risk, which indicates that vitamin D-binding protein (DBP) encoded by GC may have distinct effects on AD risk. Here, we aim to clarify this assumption. We selected the GC rs2282679 variant associated with DBP levels (p = 3.30E-76) as the instrumental variable, and extracted the summary statistics of rs2282679 variant in multiple AD GWAS datasets from IGAP, Complex Trait Genetics (CTG) lab, and UK Biobank. We then performed a MR study to investigate the causal association between DBP levels and AD. In IGAP, MR analysis showed that the genetically DBP levels (per 1 standard deviation (SD) increase 50 mg/L) were significantly associated with reduced AD risk (OR = 0.63, 95% CI: 0.45-0.89, p = 0.009). Importantly, the estimates from two sensitivity analyses were consistent with the main estimate in terms of direction and magnitude. Meanwhile, we found no causal association between DBP levels and other four AD phenotypes in CTG lab and UK Biobank. In summary, we highlight the role of DBP levels in AD risk, and provide strong support evidence that DBP may be the therapeutic agent for the treatment of AD. Meanwhile, our findings clarify the assumption that DBP may drive the observed relationship between 25OHD levels and AD.

Keywords: Alzheimer’s disease, genome-wide association study, Mendelian randomization, vitamin D, vitamin D-binding protein

DOI: 10.3233/JAD-191051

Journal: Journal of Alzheimer's Disease, vol. 74, no. 3, pp. 991-998, 2020