Network Mendelian randomisation analysis deciphers protein pathways linking type 2 diabetes and gastrointestinal disease.

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The molecular mechanisms underlying the association between type 2 diabetes (T2D) and gastrointestinal (GI) disease are unclear. To identify protein pathways, we conducted a two-stage network Mendelian randomisation (MR) study. Genetic instruments for T2D were obtained from a large-scale summary-level genome-wide meta-analysis. Genetic associations with blood protein levels were obtained from three genome-wide association studies on plasma proteins (i.e. the deCODE study as the discovery and the UKB-PPP and Fenland studies as the replication). Summary-level data on 10 GI diseases were derived from genome-wide meta-analysis of the UK Biobank and FinnGen. MR and colocalisation analyses were performed. Pathways were constructed according to the directionality of total and indirect effects, and corresponding proportional mediation was estimated. Druggability assessments were conducted across four databases to prioritise protein mediators. Genetic liability to T2D was associated with 69 proteins in the discovery protein dataset after multiple testing corrections. All associations were replicated at the nominal significance level. Among T2D-associated proteins, genetically predicted levels of nine proteins were associated with at least one of the GI diseases. Genetically predicted levels of SULT2A1 (odds ratio = 1.98, 95% CI 1.80-2.18), and ADH1B (odds ratio = 2.05, 95% CI 1.43-2.94) were associated with cholelithiasis and cirrhosis respectively. SULT2A1 and cholelithiasis (PH4 = 0.996) and ADH1B and cirrhosis (PH4 = 0.931) have strong colocalisation support, accounting for the mediation proportion of 72.8% (95% CI 45.7-99.9) and 42.9% (95% CI 15.5-70.4) respectively. The study identified some proteins mediating T2D-GI disease associations, which provided biological insights into the underlying pathways.