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Abstract
Background The Global Burden of Diseases study indicates that digestive system disorders are identified as high morbidity and high burden diseases.The human proteome serves as a primary source of therapeutic targets for disease treatment, with its genetic association analysis (pQTL) enabling the systematic evaluation of the causal consequences of plasma protein level variations on digestive system disorders.
Methods We conducted Mendelian randomization (MR) analyses on 47 digestive system disorders using data from the FinnGen study cohort, followed by validation using the UK Biobank. Co-localization and mediation MR analyses were employed to explore causal proteins of the disease. Molecular dynamics simulations were used to investigate potential protein-mediator interactions and their impact on the disease.
Results FinnGen results revealed significant associations of 12 proteins with 5 diseases, of which four proteins displayed risk alterations confirmed by UKB (p FDR < 0.05), associating with three diseases: celiac disease, cholelithiasis, and diverticular disease.Co-localization analysis identified shared genetic traits of 3 genes with the diseases (H4 ABF > 0.8). Finally, by selecting effective cis-pQTL SNP loci of causal proteins at the GWAS level, Mediation exploration was conducted using a twostep MR approach.We identified that 25-hydroxyvitamin D levels partially mediate the increased risk of cholelithiasis following the upregulation of SULT2A1 protein expression, with a mediation proportion of 21% (UKB) and 11% (FinnGen). In addition, Deoxycholic acid 25-sulfate levels partially mediate the increased risk of cholelithiasis following the upregulation of SULT2A1 protein expression, with a mediation proportion of 13.89% (UKB) and 12.83% (FinnGen).
Conclusions This study provides MR evidence supporting a causal relationship between plasma proteins and various digestive system disorders. Additionally, the negative correlation between SULT2A1 and 25- hydroxyvitamin D, along with the positive correlation with deoxycholic acid 25-sulfate levels, may potentially lead to cholelithiasis.