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

Jiawei Geng; Xixian Ruan; Xing Wu; Xuejie Chen; Tian Fu; Dipender Gill; Stephen Burgess; Jie Chen; Jonas F Ludvigsson; Susanna C Larsson; Xue Li; Zhongyan Du; Shuai Yuan

doi:10.1111/dom.16087

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

Diabetes Obes Metab. 2025 Feb;27(2):866-875. doi: 10.1111/dom.16087. Epub 2024 Nov 26.

Authors

Jiawei Geng^{1

2}, Xixian Ruan³, Xing Wu³, Xuejie Chen³, Tian Fu³, Dipender Gill⁴, Stephen Burgess^{5

6}, Jie Chen^{1

2

3}, Jonas F Ludvigsson^{7

8

9}, Susanna C Larsson^{10

11}, Xue Li², Zhongyan Du^{1

12

13}, Shuai Yuan^{10

14}

Affiliations

¹ Zhejiang Key Laboratory of Blood-Stasis-Toxin Syndrome, Zhejiang Chinese Medical University, Hangzhou, China.
² Department of Big Data in Health Science School of Public Health, Center of Clinical Big Data and Analytics of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
³ Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha, China.
⁴ Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
⁵ MRC Biostatistics Unit, University of Cambridge, Cambridge, UK.
⁶ Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁷ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
⁸ Department of Pediatrics, Orebro University Hospital, Orebro, Sweden.
⁹ Department of Medicine, Celiac Disease Center at Columbia University Medical Center, New York, New York, USA.
¹⁰ Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
¹¹ Unit of Medical Epidemiology, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
¹² Zhejiang Engineering Research Center for 'Preventive Treatment' Smart Health of Traditional Chinese Medicine, Zhejiang Chinese Medical University, Hangzhou, China.
¹³ School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China.
¹⁴ Department of Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Abstract

Aims: 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.

Materials and methods: 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.

Results: 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.

Conclusions: The study identified some proteins mediating T2D-GI disease associations, which provided biological insights into the underlying pathways.

Keywords: Mendelian randomisation; drug target; gastrointestinal diseases; protein biomarker; type 2 diabetes.

Abstract

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