Mendelian randomization study of causal link from gut microbiota to colorectal cancer

Abstract

Recent studies have shown the relevance of gut microbiota in the occurrence and development of colorectal cancer (CRC), but the causal relationship remains unclear in the human population. The present study aims to assess the causal relationship from the gut microbiota to CRC and to identify specific causal microbe taxa via genome-wide association study (GWAS) summary statistics based two-sample Mendelian randomization (MR) analyses. Microbiome GWAS (MGWAS) in the TwinsUK 1,126 twin pairs was used as discovery exposure sample, and MGWAS in 1,812 northern German participants was used as replication exposure sample. GWAS of CRC in 387,156 participants from the UK Biobank (UKB) was used as the outcome sample. Bacteria were grouped into taxa features at both family and genus levels. In the discovery sample, a total of 30 bacteria features including 15 families and 15 genera were analyzed. Five features, including 2 families (Verrucomicrobiaceae and Enterobacteriaceae) and 3 genera (Akkermansia, Blautia, and Ruminococcus), were nominally significant. In the replication sample, the genus Blautia (discovery beta=-0.01, P = 0.04) was successfully replicated (replication beta=-0.18, P = 0.01) with consistent effect direction. Our findings identified genus Blautia that was causally associated with CRC, thus offering novel insights into the microbiota-mediated CRC development mechanism.

Keywords: Causal relationship; Colorectal cancer; Gut microbiota; Mendelian randomization; genus Blautia.

Fig. 1

A flowchart of MR analysis in the discovery and replication. The MR analysis workflow and the main results were displayed in this figure

Fig. 2

Forest plots of the 4 MR tests at the genus Blautia. Effect size, pleiotropy, and heterogeneity significance were displayed for each test, if applicable

Fig. 3

Scatter plot of the 4 MR tests at the genus Blautia. SNP effects were plotted into lines for the IVW test (grep solid line), MR-Egger regression (black solid line), weighted median estimator (grep dashed line), and MR-PRESSO (black dashed line). The slope of the line corresponded to the causal estimation

Fig. 4

Forest plot of causal effects (A) and MR leave-one-out sensitivity analysis (B) for genus Blautia on colorectal cancer. A The causal effect of genus Blautia on colorectal cancer was estimated using each SNP singly using the Wald ratio, and using all SNPs using the MR Egger and IVW methods. B Leave-one-out sensitivity analysis represents the MR analysis excluding the particular SNP using the IVW test