Causal associations of specific immunoglobulin G N-glycosylation subtypes with osteoporosis: A two-sample Mendelian randomization
Yu Zhao1
, Yimiao Zhu2, Wei Zhang1, Lijun Wang1, Chenyan Yan1, Chaoyun Yuan3, Lijuan Wang4
1Department of Endocrinology, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Geriatric Medicine Center, Hangzhou, China
2Department of Gastroenterology, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Center for General Practice Medicine, Hangzhou, China
3Information Center, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, China
4Department of Rheumatology and Immunology, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Center for General Practice Medicine, Hangzhou, China
Keywords: Causal association, genome-wide association study, immunoglobulin G N-glycosylation, instrumental variables, Mendelian randomization, osteoporosis.
Abstract
Objectives: This study aims to examine whether genetically predicted immunoglobulin G (IgG) N-glycosylation patterns (IGPs) affect osteoporosis risk using a two-sample Mendelian randomization (MR) method.
Materials and methods: In a collaborative effort involving the Medical Research Council (MRC) Human Genetics Unit and the FinnGen consortium, we conducted genome-wide association studies (GWAS) to explore the relationship between 77 IGPs (8,090 samples) and osteoporosis (438,872 samples). Utilizing the inverse-variance weighted (IVW) method as our primary analytical tool, we delved into these complex genetic associations. To further substantiate our findings, we employed additional complementary methods such as MR-Egger, weighted median, and weighted mode. Sensitivity analyses, including MR-Pleiotropy RESidual Sum and Outlier (MR-PRESSO), MR-Egger, Cochran’s Q, and leave-one-out methods, were used to test the core MR assumptions and validate the robustness of the results. This multi-faceted approach allowed us to detect underlying causal relationships with greater confidence.
Results: The IGP4 exhibited a protective effect against osteoporosis with an odds ratio (OR) of 0.77 (95% confidence interval [CI]: 0.63-0.95, p=0.012). In contrast, IGP45 demonstrated a modest risk increase with an OR of 1.10 (95% CI: 1.01-1.19, p=0.021). Similarly, the results of the present MR study suggest that IGP56 also showed a protective trend, with an OR of 0.86 (95% CI: 0.78-0.96, p=0.006). To confirm our findings, we conducted rigorous sensitivity analyses utilizing MR-PRESSO, MR-Egger, Cochran’s Q, and leave-one-out methods. These analyses revealed no evidence of heterogeneity or horizontal pleiotropy, thereby reinforcing the robustness and reliability of our findings.
Conclusion: Our study results indicate that IgG45 contributes positively to osteoporosis, whereas IgG4 and IgG56 exhibit a negative correlation. Nonetheless, additional research is crucial to understand their mechanisms and devise broader preventive strategies for osteoporosis.
Citation: Zhao Y, Zhu Y, Zhang W, Wang L, Yan C, Yuan C, et al. Causal associations of specific immunoglobulin G N-glycosylation subtypes with osteoporosis: A two-sample Mendelian randomization. Jt Dis Relat Surg 2026;37(1):i-xii. doi: 10.52312/jdrs.2026.2361,