Identification of shared genetic architecture between non-alcoholic fatty liver disease and type 2 diabetes: A genome-wide analysis

Abstract

BackgroundThe incidence of complications of non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D) has been increasing.MethodIn order to identify the shared genetic architecture of the two disease phenotypes of NAFLD and T2D, a European population-based GWAS summary and a cross-trait meta-analysis was used to identify significant shared genes for NAFLD and T2D. The enrichment of shared genes was then determined through the use of functional enrichment analysis to investigate the relationship between genes and phenotypes. Additionally, differential gene expression analysis was performed, significant differentially expressed genes in NAFLD and T2D were identified, genes that overlapped between those that were differentially expressed and cross-trait results were reported, and enrichment analysis was performed on the core genes that had been obtained in this way. Finally, the application of a bidirectional Mendelian randomization (MR) approach determined the causal link between NAFLD and T2D.ResultA total of 115 genes were discovered to be shared between NAFLD and T2D in the GWAS analysis. The enrichment analysis of these genes showed that some were involved in the processes such as the decomposition and metabolism of lipids, phospholipids, and glycerophospholipids. Additionally, through the use of differential gene expression analysis, 15 core genes were confirmed to be linked to both T2D and NAFLD. They were correlated with carcinoma cells and inflammation. Furthermore, the bidirectional MR identified a positive causal relationship between NAFLD and T2D.ConclusionOur study determined the genetic structure shared between NAFLD and T2D, offering a new reference for the genetic pathogenesis and mechanism of NAFLD and T2D comorbidities.

Associations between type 2 diabetes mellitus and chronic liver diseases: evidence from a Mendelian randomization study in Europeans and East Asians

“…Epidemiological data has revealed that the age-adjusted risk of NAFLD is approximately 5.36 times greater in individuals with T2DM as opposed to the general non-diabetic population (45). Prior MR studies also presented evidence supporting correlations between genetic predisposition to T2DM and an escalated risk of NAFLD, particularly within European populations (46). These findings align with our MR analysis, albeit our study was conducted on a larger sample size.…”

Association between diabetes mellitus and primary biliary cholangitis: a two-sample Mendelian randomization study

“…proposed the concept of Hepatic Diabetes (HD) in 1967, pointing out that patients with chronic liver disease are more likely to have impaired glucose tolerance and complicated diabetes ( 22 ). Although some researchers have studied the relationship between DM and liver disease, the majority of studies have solely focused on non-alcoholic fatty liver disease ( 23 , 24 ), and little information is available on the potential relationship between DM and PBC risk. Meanwhile, previous findings in the literature were limited to observing correlations, and reverse causality may not be avoided.…”

The relationship between sex hormone‐binding protein and non‐alcoholic fatty liver disease using Mendelian randomisation

“…[16][17][18] Tan et al carried out the MR study to demonstrate a positive causal correlation between T2D and NAFLD. 19 Ruth et al also demonstrated a negative correlation between SHBG levels in serum and the risk of T2D using MR analysis, suggesting that a decrease in SHBG levels in serum would elevate the risk of developing T2D. 20 Based on this, we employed a two-sample MR approach to explore the causal relationship between SHBG and NAFLD.…”

“…Previously published MR studies have reported that free thyroid hormone levels, vitamin D levels and plasma phospholipid arachidonic acid levels in serum are all causally associated with the risk of NAFLD 16–18 . Tan et al carried out the MR study to demonstrate a positive causal correlation between T2D and NAFLD 19 . Ruth et al also demonstrated a negative correlation between SHBG levels in serum and the risk of T2D using MR analysis, suggesting that a decrease in SHBG levels in serum would elevate the risk of developing T2D 20 .…”