Assessment of the Causal Effect of IgG N-Glycosylation Level on Risk of Dementia: A 2-Sample Mendelian Randomization Study

Article type: Research Article

Authors: Zhang, Xiaoyu^{a; b} | Cong, Ruyi^c | Geng, Tao^{d; e} | Zhang, Jinxia^b | Liu, Di^{f; b} | Tian, Qiuyue^b | Meng, Xiaoni^b | Song, Manshu^g | Wu, Lijuan^b | Zheng, Deqiang^b | Wang, Wei^{b; h} | Wang, Baoguo^{a; *} | Wang, Youxin^{b; g; *}

Affiliations: [a] Department of Anesthesiology, Sanbo Brain Hospital, Capital Medical University, Beijing, China | [b] Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, Beijing, China | [c] School of Public Health, Shandong First Medical University & Shandong Academy of Medical Sciences, Tai’an, China | [d] Geriatric Department, Emergency General Hospital, Beijing, China | [e] Department of Medicine & Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong | [f] Centre for Biomedical Information Technology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, China | [g] School of Medical and Health Sciences, Edith Cowan University, Perth, Australia | [h] Centre for Precision Health, Edith Cowan University, Perth, Australia

Correspondence: [*] Correspondence to: Baoguo Wang, MS, Professor, Department of Anesthesiology, Sanbo Brain Hospital, Capital Medical University, No. 50 Xiang Shan Yi-Ke-Song, Haidian District, Beijing, 100095, China. Tel./Fax: +86 1062856765; E-mail: wangbg@ccmu.edu.cn.; Youxin Wang, PhD, Professor, School of Public Health, Capital Medical University, No.10 Xitoutiao, Youanmenwai Street, Fengtai District, Beijing, 100069, China. Tel./Fax: +86 1083911497; E-mail: wangy@ccmu.edu.cn.

Abstract: Background:Previous prospective studies highlighted aberrant immunoglobulin G (IgG) N-glycosylation as a risk factor for dementia [such as Alzheimer’s disease (AD) and vascular dementia (VaD)]. It is unclear whether this association is causal or explained by confounding or reverse causation. Objective:The aim is to examine the association of genetically predicted IgG N-glycosylation with dementia using 2-sample Mendelian randomization (MR). Methods:Independent genetic variants for IgG N-glycosylation traits were selected as instrument variables from published genome-wide association studies (GWAS) among individuals of European ancestry. We extracted their corresponding summary statistics from large-scale clinically diagnosed AD GWAS dataset and FinnGen biobank VaD GWAS dataset. The inverse variance weighted (IVW) was performed to calculate the effect estimates. Meanwhile, multiple sensitivity analyses were used to assess horizontal pleiotropy and outliers. Results:There were no associations of genetically predicted IgG N-glycosylation traits with the risk of AD and VaD using the IVW method (all Bonferroni corrected p > 0.0013). These estimates of four additional sensitivity analyses methods were consistent with the IVW estimates in terms of direction and magnitude. Additionally, the MR-PRESSO global test and the intercept of MR-Egger regression indicated no evidence of horizontal pleiotropy. Meanwhile, the heterogeneity test showed no significant heterogeneity using the Cochran Q statistic. The leave-one-out sensitivity analyses also did not detect any significant change. Conclusion:Our MR study did not support evidence for the hypothesis that IgG N-glycosylation level may be causally associated with the risk of dementia.

Keywords: Alzheimer’s disease, IgG N-glycosylation, mendelian randomization, vascular dementia

DOI: 10.3233/JAD-220074

Journal: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1435-1441, 2022