Mendelian randomization and transcriptomic analysis reveal a positive cause-and-effect relationship between Alzheimer's disease and colorectal cancer

Wei Du; Xueming Xia; Qiheng Gou; Yan Qiu

doi:10.1016/j.tranon.2024.102169

Mendelian randomization and transcriptomic analysis reveal a positive cause-and-effect relationship between Alzheimer's disease and colorectal cancer

Transl Oncol. 2024 Nov 27:51:102169. doi: 10.1016/j.tranon.2024.102169. Online ahead of print.

Authors

Wei Du¹, Xueming Xia², Qiheng Gou², Yan Qiu³

Affiliations

¹ Department of Biotherapy, West China Hospital and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
² Department of Head and Neck Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China.
³ Department of Pathology, West China Hospital, Sichuan University, Chengdu, China. Electronic address: yanqiu@scu.edu.cn.

PMID: 39608211
DOI: 10.1016/j.tranon.2024.102169

Abstract

Background: This study addresses the complex multifactorial causes of Alzheimer's disease (AD) and colorectal cancer (CRC), two significant public health issues. Despite previous research, the precise relationship between AD and CRC remains unclear. This study aimed to explore the potential causal relationship between AD and CRC using Mendelian randomization (MR) and to identify risk genes through colocalization and transcriptomic analyses.

Method: The study used a two-sample Mendelian randomization (MR) approach to investigate the causal effect of AD on CRC. Genome-wide association study (GWAS) summary statistics for AD and CRC were utilized. Colocalization analysis was conducted to identify risk genes associated with AD, which were then validated through transcriptomic analysis in CRC samples. The study used GWAS data from a cohort of European patients and applied several MR methods, including MR Egger, weighted median, and inverse-variance weighted approaches, to ensure robust findings.

Results: The MR analysis revealed a significant positive causal relationship between AD and CRC, indicating that an increased genetic predisposition to AD is associated with a elevated risk of developing CRC. The colocalization analysis identified COLEC11 as a significant risk gene for AD, which also showed a strong positive correlation with clinical features and survival outcomes in CRC. Elevated COLEC11 expression was linked to advanced clinical stages, increased tumor mutational burden, microsatellite instability, and poorer overall survival in CRC patients.

Conclusions: This study provides evidence of a causal relationship between AD and CRC, suggesting that shared genetic and inflammatory pathways may underlie both conditions. The identification of COLEC11 as a potential link between AD and CRC offers new avenues for research and therapeutic interventions. These findings contribute to a deeper understanding of the interplay between neurodegenerative and oncologic diseases, highlighting the importance of exploring common pathogenic mechanisms.

Keywords: Alzheimer's disease; Colorectal cancer; Mendelian randomization; Transcriptomic analysis.