Mendelian randomization study of inflammatory bowel disease and bone mineral density

Abstract

Background: Recently, the association between inflammatory bowel disease (including ulcerative colitis and Crohn's disease) and BMD has attracted great interest in the research community. However, the results of the published epidemiological observational studies on the relationship between inflammatory bowel disease and BMD are still inconclusive. Here, we performed a two-sample Mendelian randomization analysis to investigate the causal link between inflammatory bowel disease and level of BMD using publically available GWAS summary statistics.

Methods: A series of quality control steps were taken in our analysis to select eligible instrumental SNPs which were strongly associated with exposure. To make the conclusions more robust and reliable, we utilized several robust analytical methods (inverse-variance weighting, MR-PRESSO method, mode-based estimate method, weighted median, MR-Egger regression, and MR.RAPS method) that are based on different assumptions of two-sample MR analysis. The MR-Egger intercept test, Cochran's Q test, and "leave-one-out" sensitivity analysis were performed to evaluate the horizontal pleiotropy, heterogeneities, and stability of these genetic variants on BMD. Outlier variants identified by the MR-PRESSO outlier test were removed step-by-step to reduce heterogeneity and the effect of horizontal pleiotropy.

Results: Our two-sample Mendelian randomization analysis with two groups of exposure GWAS summary statistics and four groups of outcome GWAS summary statistics suggested a definitively causal effect of genetically predicted ulcerative colitis on TB-BMD and FA-BMD but not on FN-BMD or LS-BMD (after Bonferroni correction), and we merely determined a causal effect of Crohn's disease on FN-BMD but not on the others, which was somewhat inconsistent with many published observational researches. The causal effect of inflammatory bowel disease on TB-BMD was significant and robust but not on FA-BMD, FN-BMD, and LS-BMD, which might result from the cumulative effect of ulcerative colitis and Crohn's disease on BMDs.

Conclusions: Our Mendelian randomization analysis supported the causal effect of ulcerative colitis on TB-BMD and FA-BMD. As to Crohn's disease, only the definitively causal effect of it on decreased FN-BMD was observed. Updated MR analysis is warranted to confirm our findings when a more advanced method to get less biased estimates and better precision or GWAS summary data with more ulcerative colitis and Crohn's disease patients was available.

Keywords: Bone mineral density; Crohn’s disease; Inflammatory bowel disease; Osteoporosis; Two-sample Mendelian randomization; Ulcerative colitis.

Fig. 1

Flow chart about the analytical methods and how the MR analysis was performed step-by-step

Fig. 2

Scatter plots for MR analyses of the causal effect of IBD on BMDs in initial practice. a TB-BMD. b FN-BMD. c LS-BMD. d FA-BMD. Analyses were conducted using the conventional IVW, MBE, WMM, MR-Egger, and MR.RAPS methods. The slope of each line corresponding to the estimated MR effect per method

Fig. 3

Scatter plots for MR analyses of the causal effect of IBD on BMDs in replicative practice. a TB-BMD. b FN-BMD. c LS-BMD. d FA-BMD. Analyses were conducted using the conventional IVW, MBE, WMM, MR-Egger, and MR.RAPS methods. The slope of each line corresponding to the estimated MR effect per method

Fig. 4

Scatter plots for MR analyses of the causal effect of UC on BMDs in initial practice. a TB-BMD. b FN-BMD. c LS-BMD. d FA-BMD. Analyses were conducted using the conventional IVW, MBE, WMM, MR-Egger, and MR.RAPS methods. The slope of each line corresponding to the estimated MR effect per method

Fig. 5

Scatter plots for MR analyses of the causal effect of UC on BMDs in replicative practice. a TB-BMD. b FN-BMD. c LS-BMD. d FA-BMD. Analyses were conducted using the conventional IVW, MBE, WMM, MR-Egger, and MR.RAPS methods. The slope of each line corresponding to the estimated MR effect per method

Fig. 6

Scatter plots for MR analyses of the causal effect of CD on BMDs in initial practice. a TB-BMD. b FN-BMD. c LS-BMD. d FA-BMD. Analyses were conducted using the conventional IVW, MBE, WMM, MR-Egger, and MR.RAPS methods. The slope of each line corresponding to the estimated MR effect per method

Fig. 7

Scatter plots for MR analyses of the causal effect of CD on BMDs in replicative practice. a TB-BMD. b FN-BMD. c LS-BMD. d FA-BMD. Analyses were conducted using the conventional IVW, MBE, WMM, MR-Egger, and MR.RAPS methods. The slope of each line corresponding to the estimated MR effect per method