Xinlei Yang,1,* Guojun Wei,2,* Yu Fan,3 Han Gao,4 Shengxin Bao,5 Xiaobo Sun,6 Jiming Sun,7 Yiran Du8 

1Tumor Treatment Center, Affiliated Hospital of Beihua University, Jilin City, Jilin, People’s Republic of China; 2Oncology Department 5, The Second People’s Hospital of Jilin City, Jilin City, Jilin, People’s Republic of China; 3Pain Management Department, Qian Gorlos Mongolian Autonomous County Hospital, Songyuan, Jilin, People’s Republic of China; 4Department of General surgery, Qian Gorlos Mongolian Autonomous County Hospital, Songyuan, Jilin, People’s Republic of China; 5Tonghua City Hospital of Chinese medicine, Tonghua, Jilin, People’s Republic of China; 6Outpatient Department, Affiliated Hospital of Beihua University, Jilin City, Jilin, People’s Republic of China; 7Department of Functional Neurosurgery, Shanghai Eber Hospital, Shanghai, People’s Republic of China; 8Department of Neurovascular Surgery Group3, Jilin Central Hospital, Jilin City, Jilin, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Yiran Du, Department of Neurovascular Surgery Group3, Jilin Central Hospital, No. 4 Nanjing Street, Chuanying District, Jilin City, Jilin, 132011, People’s Republic of China, Tel + 86 15144239616, Email duyr2024yr@163.com Jiming Sun, Department of Functional Neurosurgery, Shanghai Eber Hospital, Building 50, No. 2380, Xinsiping Road, Fengxian District, Shanghai, 201412, People’s Republic of China, Email sunjm55jm@21cn.com

Objective: To investigate the potential causal relationship between DNA methylation GrimAge acceleration (GAA) and brain tumor incidence using a two-sample Mendelian randomization (MR) approach.
Methods: We leveraged publicly available genome-wide association study (GWAS) summary data for GAA (34,467 participants) and brain tumor incidence (491,542 participants). Twenty-six single nucleotide polymorphisms (SNPs) served as instrumental variables for GAA. Inverse variance weighted (IVW) was the primary method, complemented by MR-Egger, weighted median, simple mode, and weighted mode. Sensitivity analyses tested heterogeneity and pleiotropy.
Results: The IVW analysis indicated no significant causal effect of GAA on brain tumor risk (β = − 0.006, p = 0.908). Other MR methods concurred. Sensitivity checks, including heterogeneity and MR-Egger intercept tests, supported these null findings.
Conclusion: Our results do not support a causal association between GrimAge acceleration and brain tumor incidence. Accelerated epigenetic aging, as measured by GAA, may not be a direct driver of brain tumor risk. Further investigations should explore other epigenetic or genetic factors implicated in brain tumor etiology.

Keywords: DNA methylation, GrimAge acceleration, brain tumor, Mendelian randomization, causal inference, epigenetics, cancer risk