Mendelian randomisation highlights hypothyroidism as a causal determinant of idiopathic pulmonary fibrosis

Abstract

Background: Although the association between hypothyroidism and idiopathic pulmonary fibrosis (IPF) is found in observational studies, it remains uncertain whether hypothyroidism causally influences IPF.

Methods: Two-sample Mendelian randomisation (MR) was conducted with hypothyroidism genome-wide association study (GWAS) data in the UK Biobank from 289,307 individuals (18,740 cases and 270,567 controls) and the largest GWAS summary statistics of IPF from 11,259 individuals (2,668 cases and 8,591 controls). Findings were verified using an independent validation dataset, as well as through different MR methods with different model assumptions. A multivariable MR based on Bayesian model averaging was further performed to evaluate whether hypothyroidism, even given several other comorbidities of IPF, remained to be the true causal one of IPF.

Findings: A positive causal effect of hypothyroidism on IPF was revealed (MR inverse-variance weighted [MR-IVW], odds ratio [OR]=1.125, 95% confidence interval [CI] 1.028-1.231; P=0.011), which was further verified in an independent validation set (MR-IVW, OR=1.229, 95% CI 1.054-1.432; P=0.008). The results were consistent from a variety of MR methods. Bidirectional analyses also indicated no reverse causation. Multivariable MR analysis showed hypothyroidism had the strongest marginal evidence (marginal inclusion probability=0.397, false discovery rate=0.025) compared with other comorbidities of IPF.

Interpretation: Our results illustrate the significant causal effect of hypothyroidism on IPF, which holds even given several other comorbidities of IPF. These findings may have an important insight into pathogenesis and possible future therapies of IPF.

Funding: National Natural Science Foundation of China, the Natural Science Foundation of Shandong Province and the Young Scholars Program of Shandong University.

Keywords: GWAS summary statistics; Hypothyroidism; Idiopathic pulmonary fibrosis; Mendelian randomisation.

Fig. 1

Study design. (a) The causal diagram for standard Mendelian randomisation (MR) analysis, which involves instrumental variable (IV) and requires three assumptions. (b) Illustrative diagram of IV assumptions made in multivariable MR model. IPF, idiopathic pulmonary fibrosis; MR, Mendelian randomisation.

Fig. 2

The causal effect estimates from various Mendelian randomisation methods. The odds ratios of hypothyroidism on IPF are displayed as blue solid box. The 95% confidence intervals are shown as horizontal blue lines. MR, Mendelian randomisation; MR-IVW, MR inverse-variance weighted; MR-RAPS, Robust Adjusted Profile Score; MR-PRESSO, Mendelian Randomisation Pleiotropy RESidual Sum and Outlier; OR, odds ratio; 95%CI, The 95% confidence intervals.

Fig. 3

Diagnostic plots for the two-sample Mendelian randomisation analysis. (a) Funnel plot for individual causal effect estimate. (b) Forest plot for leave-one-out analysis, with each point denoting the causal effect by IVW after removing the specific SNP on the left side. IVW, inverse variance weighted method.

Fig. 4

Model diagnostics in multivariable MR based on BMA. The predicted associations with IPF based on the model including hypothyroidism (x-axis) are plotted against the observed associations with IPF (y-axis). This is the top model when keeping outliers and influential genetic variants in the analysis. (a) Cook's distance for the influential points; (b) the q-statistic for outliers. Any genetic variant with q value larger than threshold (q-statistic = 13.246) or Cook's distance larger than the median of the relevant F-distribution (Cd = 0.457) is marked by a label indicating the gene region. IPF, idiopathic pulmonary fibrosis.