Genome-wide and Mendelian randomisation studies of liver MRI yield insights into the pathogenesis of steatohepatitis

Abstract

Background & aims: MRI-based corrected T1 (cT1) is a non-invasive method to grade the severity of steatohepatitis and liver fibrosis. We aimed to identify genetic variants influencing liver cT1 and use genetics to understand mechanisms underlying liver fibroinflammatory disease and its link with other metabolic traits and diseases.

Methods: First, we performed a genome-wide association study (GWAS) in 14,440 Europeans, with liver cT1 measures, from the UK Biobank. Second, we explored the effects of the cT1 variants on liver blood tests, and a range of metabolic traits and diseases. Third, we used Mendelian randomisation to test the causal effects of 24 predominantly metabolic traits on liver cT1 measures.

Results: We identified 6 independent genetic variants associated with liver cT1 that reached the GWAS significance threshold (p <5×10^-8). Four of the variants (rs759359281 in SLC30A10, rs13107325 in SLC39A8, rs58542926 in TM6SF2, rs738409 in PNPLA3) were also associated with elevated aminotransferases and had variable effects on liver fat and other metabolic traits. Insulin resistance, type 2 diabetes, non-alcoholic fatty liver and body mass index were causally associated with elevated cT1, whilst favourable adiposity (instrumented by variants associated with higher adiposity but lower risk of cardiometabolic disease and lower liver fat) was found to be protective.

Conclusion: The association between 2 metal ion transporters and cT1 indicates an important new mechanism in steatohepatitis. Future studies are needed to determine whether interventions targeting the identified transporters might prevent liver disease in at-risk individuals.

Lay summary: We estimated levels of liver inflammation and scarring based on magnetic resonance imaging of 14,440 UK Biobank participants. We performed a genetic study and identified variations in 6 genes associated with levels of liver inflammation and scarring. Participants with variations in 4 of these genes also had higher levels of markers of liver cell injury in blood samples, further validating their role in liver health. Two identified genes are involved in the transport of metal ions in our body. Further investigation of these variations may lead to better detection, assessment, and/or treatment of liver inflammation and scarring.

Keywords: Fibrosis; Genome-wide association study; Magnetic resonance imaging; Metabolic syndrome; Steatohepatitis; Transaminases; cT1.

Graphical abstract

Fig. 1

GWAS of liver cT1 in the UK Biobank. (A) Liver MRI scans of cT1. Three selected cases of liver MRI scans showing, from left to right, progressively elevated cT1 values (671 ms, 777 ms, 917 ms), reproduced by kind permission of UK Biobank©. (B) Manhattan plot illustrating GWAS of liver cT1 measurements in 14,440 UK Biobank individuals (~12 million imputed variants). The x-axis is the chromosomal position and y-axis is the significance of association for each variant in log10(p values). Grey line indicates genome-wide significance level. For the GWAS, a linear mixed model was used. Levels of significance: p <5×10⁻⁸_. cT1, corrected T1; GWAS, genome-wide association study. (This figure appears in color on the web.)

Fig. 2

Forest plot of the associations of liver cT1 variants with liver and metabolic phenotypes. Effects are in SD for continuous traits and log(OR) for disease outcomes per copy of the risk allele. A linear mixed model was used for genetic associations. Levels of significance: p <0.05. ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CAD, coronary artery disease; cT1, corrected T1; GGT, gamma-glutamyltransferase; HDL-C, HDL-cholesterol; LDL-C, LDL cholesterol; OR, odds ratio; T2DM, type 2 diabetes.

Fig. 3

LD regression analysis. Fig. demonstrating the significant genetic correlations (rg) between cT1 and metabolic traits following correction for multiple testing (levels of significance: p false discovery rate <0.05) among more than 120 traits. The colours correspond to significance of correlation (t test); red: p <1×10⁻⁸; orange: 1×10⁻⁶ <p <1×10⁻⁵; blue: 1×10⁻⁵ <p <1×10⁻⁴; green: 1×10⁻⁴ <p <1×10⁻³; yellow: 0.001 <p <0.01. Higher cT1 is positively genetically correlated with VLDL, type 2 diabetes, coronary artery disease, and inversely correlated with HDL. cT1, corrected T1; HOMA-IR, homeostatic model assessment of insulin resistance, HOMA-B, homeostatic model assessment of β cell function; LD, linkage disequilibrium. (This figure appears in color on the web.)

Fig. 4

Mendelian randomisation investigating the effect of 24 predominantly metabolic traits on liver cT1. We used 2-sample Mendelian randomisation analysis to investigate the causal effects of metabolic traits on liver cT1. For full results, including sensitivity analyses, please see Table S4. The inverse variance weighted test was used as the main analysis. Levels of significance: p <0.05. 2hGlu, 2 hour glucose tolerance test; cT1, corrected T1; NAFLD, non-alcoholic fatty liver disease; WHR_BMI, waist hip ratio adjusted for BMI.