Exploring the Causality Between Hypothyroidism and Non-alcoholic Fatty Liver: A Mendelian Randomization Study

Abstract

The etiology of non-alcoholic fatty liver disease (NAFLD) involves complex interaction of genetic and environmental factors. A large number of observational studies have shown that hypothyroidism contributes to a high risk of NAFLD. However, the exact causality is still unknown. Due to the progress of genome-wide association study (GWAS) and the discovery of Mendelian randomization (MR), it is possible to explore the causality between the two diseases. In this study, in order to research into the influence of intermediate phenotypes on outcome, nine independent genetic variants of hypothyroidism obtained from the GWAS were used as instrumental variables (IVs) to perform MR analysis on NAFLD. Since there was no heterogeneity between IVs (P = 0.70), a fixed-effects model was used. The correlation between hypothyroidism and NAFLD was evaluated by using inverse-variance weighted (IVW) method and weighted median method. Then the sensitivity test was analyzed. The results showed that there was a high OR (1.7578; 95%CI 1.1897–2.5970; P = 0.0046) and a low intercept (−0.095; P = 0.431). None of the genetic variants drove the overall result (P < 0.01). Simply, we proved for the first time that the risk of NAFLD increases significantly on patients with hypothyroidism. Furthermore, we explained possible causes of NAFLD caused by hypothyroidism.

Integration of Multiple-Omics Data to Analyze the Population-Specific Differences for Coronary Artery Disease

“…In order to identify genes that showed pleiotropic/causal association with CAD, we integrated summary-level data from independent GWAS and eQTLs to perform summary data-based Mendelian randomization (SMR) [ 13 ]. SMR was based on the framework of Mendelian randomization (MR), which could determine whether gene expression (exposure) was related to traits (outcome) [ 13 , 31 , 32 ]. Therefore, the effect of gene expression ( x ) on trait ( y ) can be expressed as the ratio of the least-square estimates of y and x on a genetic variant ( z ), respectively, namely, …”

Association Between Thyroid Hormone Levels and Advanced Liver Fibrosis in Patients with Type 2 Diabetes Mellitus and Non-Alcoholic Fatty Liver Disease

“…Previous studies reported that serum thyroid hormone levels were inversely correlated with the occurrence of NAFLD, 9 and a recent Mendelian randomization study revealed the causal relationship between hypothyroidism and NAFLD firstly. 10 In addition, it was found that low TH levels increased the occurrence and progression of liver fibrosis. 11 , 12 However, there are a limited number of studies on the relationship between TH levels and advanced liver fibrosis in patients with NAFLD and T2DM.…”

Rheumatoid Arthritis and Cardio-Cerebrovascular Disease: A Mendelian Randomization Study

“…Two-sample MR requires that the samples of exposure and outcome be independent, which greatly expands the application range of MR ( Hemani et al, 2018 ). Details of MR analysis have been described in previous reports ( Davey Smith and Hemani, 2014 ; Bowden et al, 2015 , 2016 ; Yavorska and Burgess, 2017 ; Cheng et al, 2018 , 2019b ; Hemani et al, 2018 ; Hu et al, 2020 , 2021 ; Qiu et al, 2021 ). Herein, we first aligned alleles on the forward strand and harmonized SNP effects of exposure and outcome ( Ong et al, 2021 ).…”

“…Unlike IVW, MR-Egger allows horizontal pleiotropy between IVs and exposure and outcome, and the weighted median allows a more powerful variant to have a greater impact on the overall result (Bowden et al, 2017;Hartwig et al, 2017;Qiu et al, 2021).…”

“…Mendelian randomization (MR) could estimate causality without bias, which has been used in previous studies to explore the association between phenotypes ( Jansen et al, 2014 ; Smith et al, 2017 ; Hemani et al, 2018 ; Cheng et al, 2019b , 2021 ; Zhuang et al, 2019 ; Qiu et al, 2021 ). Causality between multiple metabolic characteristics, nutrient elements, and common diseases with cardiovascular disease have been demonstrated ( Ference et al, 2017 ; Larsson et al, 2017 , 2020 ; Yeung et al, 2018 ; Rosoff et al, 2020 ; Arvanitis et al, 2021 ).…”