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

Yanan Zhang; Meng Zhao; Ping Guo; Yanjun Wang; Lu Liu; Jinghua Zhao; Ling Gao; Zhongshang Yuan; Fuzhong Xue; Jiajun Zhao

doi:10.1016/j.ebiom.2021.103669

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

EBioMedicine. 2021 Nov:73:103669. doi: 10.1016/j.ebiom.2021.103669. Epub 2021 Nov 5.

Authors

Yanan Zhang¹, Meng Zhao², Ping Guo¹, Yanjun Wang¹, Lu Liu¹, Jinghua Zhao³, Ling Gao², Zhongshang Yuan⁴, Fuzhong Xue⁵, Jiajun Zhao⁶

Affiliations

¹ Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China; Institute for Medical Dataology, Shandong University, Jinan, Shandong, 250003, China.
² Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China; Department of Endocrinology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250021, China.
³ Cardiovasucular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
⁴ Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China; Institute for Medical Dataology, Shandong University, Jinan, Shandong, 250003, China. Electronic address: yuanzhongshang@sdu.edu.cn.
⁵ Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China; Institute for Medical Dataology, Shandong University, Jinan, Shandong, 250003, China. Electronic address: xuefzh@sdu.edu.cn.
⁶ Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China; Department of Endocrinology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250021, China. Electronic address: jjzhao@sdu.edu.cn.

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.

MeSH terms

Alleles
Genetic Predisposition to Disease*
Genome-Wide Association Study
Humans
Hypothyroidism / complications*
Hypothyroidism / genetics*
Idiopathic Pulmonary Fibrosis / etiology*
Idiopathic Pulmonary Fibrosis / metabolism
Idiopathic Pulmonary Fibrosis / pathology
Mendelian Randomization Analysis
Polymorphism, Single Nucleotide
Reproducibility of Results
Risk Factors