Mendelian randomisation shows diverticular disease and irritable bowel syndrome increase the risk of haemorrhoidal disease

Recently in Gut, Zhu and colleagues1 investigated causality of genetic risk effects across three genetically correlated conditions: haemorrhoidal disease (HEM), diverticular disease (DIV) and IBS. Using genome-wide association study (GWAS) summary statistics from our previous HEM GWAS2 and other studies,3-5 they conducted unidirectional two-sample Mendelian randomisation (MR) and concluded € HEM might not be a trigger for developing diverticular disease or IBS, providing novel insights into a modest genetic correlation in conditions. Simultaneously, the observed causal (protective, ed.) effects of HEM on diverticular disease and IBS requires further exploration'. Although we did not originally make any claims of causality from the observed genetic correlations, the findings of Zhu et al are surprising and not in line with previous results,2 hence we set out to investigate further the relationship between HEM, DIV and IBS. Here, we briefly report an analysis that differs from Zhu et al in that: (1) we used best practice two-sample MR analysis,6 (2) causality was studied bi-directionally (testing HEM both as exposure (cause) and outcome (effect) versus DIV and IBS risk) and (3) summary statistics from the largest, recent GWAS meta-analysis including >53 000 IBS cases were used to test genetic risk effects of HEM relative to IBS (online supplemental material).7 By these means, we obtained results different from Zhu et al and new evidence of causative effects of DIV and (to a lesser extent) IBS towards the risk of HEM. Figure 1, online supplemental figure S1 and S2 illustrate the outcome of our analyses, outlined below.