Mendelian randomization and genetic pleiotropy analysis for the connection between inflammatory bowel disease and Alzheimer's disease

Yuxuan Wu; Yu Yan; Jike Qi; Yuxin Liu; Ting Wang; Hao Chen; Xinying Guan; Chu Zheng; Ping Zeng

doi:10.1016/j.pnpbp.2024.111203

Mendelian randomization and genetic pleiotropy analysis for the connection between inflammatory bowel disease and Alzheimer's disease

Prog Neuropsychopharmacol Biol Psychiatry. 2024 Nov 21:111203. doi: 10.1016/j.pnpbp.2024.111203. Online ahead of print.

Authors

Yuxuan Wu¹, Yu Yan¹, Jike Qi¹, Yuxin Liu¹, Ting Wang¹, Hao Chen², Xinying Guan³, Chu Zheng⁴, Ping Zeng⁵

Affiliations

¹ Department of Biostatistics, School of Public Health, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China.
² Department of Neurology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou 221004, China.
³ Department of Neurology, Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang, Jiangsu 222002, China.
⁴ Department of Biostatistics, School of Public Health, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China; Jiangsu Engineering Research Center of Biological Data Mining and Healthcare Transformation, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China. Electronic address: zhengchufory@xzhmu.edu.cn.
⁵ Department of Biostatistics, School of Public Health, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China; Jiangsu Engineering Research Center of Biological Data Mining and Healthcare Transformation, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China. Electronic address: zpstat@xzhmu.edu.cn.

PMID: 39579960
DOI: 10.1016/j.pnpbp.2024.111203

Abstract

Background: The gut-microbiome-brain axis (GMBA) implies the connection between inflammatory bowel disease (IBD) and Alzheimer's disease (AD). We aimed to comprehensively explore the relation between IBD (and its subtypes) and AD, early-onset AD (EOAD) and late-onset AD (LOAD) from a genetic pleiotropy perspective.

Methods: Relying on summary statistics (N = 472,868 for AD, 185,204 for EOAD, 191,061 for LOAD, 59,957 for IBD, 45,975 for CD, and 40,266 for UC), we first performed Mendelian Randomization to examine the causal association between IBD and AD by leveraging vertical pleiotropy. Then, we estimated global and local genetic correlations, followed by cross-trait association analysis to identify SNPs and genes with horizontal pleiotropy. Particularly, we utilized multi-trait colocalization analysis to assess the role of microbes in the common genetic etiology underlying the two types of diseases. Finally, we conducted functional enrichment analysis for pleiotropic genes.

Results: We discovered suggestively causal relations between IBD (and its subtypes) and EOAD (OR_IBD = 1.06 [1.01-1.11], OR_CD = 1.05 [1.01-1.10], OR_UC = 1.08 [1.01-1.15]) as well as between UC and LOAD (OR = 1.04 [1.01-1.08]), and discovered 44 local regions showing suggestively significant genetic correlations between IBD (and its subtypes) and AD (and EODA and LOAD). We further detected substantial genetic overlap, as characterized by 182 CE-associated, 3 EOAD-associated and 51 LOAD-associated pleiotropic SNPs as well as 291 pleiotropic genes. Pleiotropic genes more likely enriched in the GMBA-relevant tissues such as brain, intestine and esophagus. Moreover, we identified three microorganisms related to these disease pairs, including the Catenibacterium, Clostridia, and Prevotella species.

Conclusion: The suggestively causal associations and shared genetic basis between IBD and its subtypes with AD, EOAD and LOAD may commonly drive their co-occurrence, and gut microbes might partly explain the shared genetic etiology. Further studies are warranted to elaborate the possibly biological mechanisms underlying the two types of diseases.

Keywords: Alzheimer's disease; Gut-microbiome-brain axis; Inflammatory bowel disease; Mendelian randomization; Summary statistics; Vertical and horizontal pleiotropy.