Journal of Shandong University (Health Sciences) ›› 2026, Vol. 64 ›› Issue (9): 50-59.doi: 10.6040/j.issn.1671-7554.0.2025.1060

• Clinical Medicine • Previous Articles    

Causal effects of aspirin on phenome-wide diseases: a drug target Mendelian randomization study

ZHANG Xiumei, CHEN Changhai, YUAN Zhongshang, WANG Shukang   

  1. 1. Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong, China;
    2. National Institute of Health and Medical Big Data, Jinan 250003, Shandong, China
  • Published:2026-09-09

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Abstract: Objective To systematically investigate the causal effects of genetically proxied aspirin exposure on a broad range of phenotypes using drug-target Mendelian randomization(MR)and polygenic score analysis. Methods Exposure data were obtained from the eQTLGen consortium(31,684 healthy European individuals). Cis-expression quantitative trait loci(cis-eQTL)significantly associated with aspirin target genes were selected as instrumental variables(IVs). Outcome data were derived from the FinnGen study R12 release(500,348 Finnish participants, 2,502 disease endpoints), with 1,265 diseases(case count ≥1,000)included for analysis. The inverse variance weighted(IVW)method was used as the primary MR analysis, complemented by weighted median, MR-Egger regression, simple mode, and weighted mode methods for verification. Heterogeneity and pleiotropy were assessed using Cochrans Q test, MR-Egger intercept test, and leave-one-out analysis. A polygenic score was constructed based on nine aspirin-related genes and tested for associations with disease outcomes in the UK Biobank cohort(402,700 participants). Results A total of 27 SNPs were selected as instrumental variables. After multiple testing correction, the IVW analysis showed that genetically proxied aspirin exposure was significantly causally associated with 34 diseases, among which 13 associations were supported by at least three complementary MR methods(replication evidence). Specifically, reduced risks were observed for fetal growth restriction(OR=0.471, 95%CI: 0.348-0.636, P<0.001), other embolism and thrombosis(OR=0.665, 95%CI: 0.495-0.894, P=0.007), unspecified rheumatic disease(OR=0.651, 95% CI: 0.489-0.867, P=0.003), benign neoplasm of the small intestine(OR=0.449, 95%CI: 0.251-0.802, P=0.003), and senile cataract(OR=0.840, 95%CI: 0.760-0.929, P=0.001).In contrast, increased risks were observed for chronic ulcerative ileocolitis(OR=2.427, 95%CI: 1.363-4.320, P=0.003)and Crohns disease of the large intestine(OR=1.843, 95%CI: 1.156-2.938, P=0.003). Polygenic risk score analysis further indicated a negative association between aspirin use and the risk of senile cataract(OR=0.985, 95% CI: 0.974-0.996, P=0.007). Conclusion Aspirin exhibits pleiotropic effects across multiple disease systems, with protective effects against thromboembolism, fetal growth restriction, rheumatic diseases, and benign small intestinal tumors, but potential risks for inflammatory bowel diseases. This study provides genetic evidence to inform clinical application and drug repurposing of aspirin.

Key words: Aspirin, Phenome-wide Diseases, Drug target Mendelian randomization, Causal association

CLC Number: 

  • R969.4
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