Association Between Telomere Length and Thyrotoxicosis: Insights from a Two-sample Mendelian Randomization Study

Summary

This protocol describes a two-sample Mendelian randomization pipeline assessing whether telomere length causally affects thyrotoxicosis risk using public genetic summary data. It covers instrument selection, harmonization, primary estimation, sensitivity analyses, and reproducible R code with figure-ready outputs to support transparent reporting.

Abstract

Thyrotoxicosis is an endocrine disorder characterized by excess thyroid hormones, yet its etiologic links to systemic aging biology remain incompletely defined. Telomere length (TL) reflects cellular senescence and genome stability and has been implicated in multiple complex diseases. We conducted a two-sample Mendelian randomization (MR) study to evaluate the causal effect of genetically predicted TL on the risk of thyrotoxicosis. Genetic instruments for TL were derived from a large genome-wide association study (GWAS) of European ancestry (n > 470,000). Thyrotoxicosis summary statistics were obtained from the latest FinnGen release (≈4,000 cases and >210,000 controls). Primary inverse-variance-weighted analyses indicated that longer genetically proxied TL is associated with a lower risk of thyrotoxicosis, and the direction and magnitude of the effect were consistent across complementary estimators (MR-Egger, weighted median/maximum likelihood, MR-PRESSO, and MR-RAPS). Sensitivity analyses showed no evidence of directional pleiotropy, and Cochran's Q was used to assess heterogeneity. A Steiger directionality test supported the causal flow from TL to thyrotoxicosis.

To our knowledge, this work is among the first MR analyses to assess the causal relationship between overall thyrotoxicosis risk and TL using contemporary GWAS resources, extending prior evidence focused on hyperthyroidism-related phenotypes. These findings suggest that cellular aging processes indexed by TL may contribute to thyrotoxicosis susceptibility and motivate future longitudinal and mechanistic studies on telomere biology in thyroid dysfunction.

Introduction

Thyrotoxicosis is a common endocrine condition characterized by excess circulating thyroid hormones. Typical manifestations include weight loss, tachycardia, irritability, anxiety, and tremor, with severe cases predisposing to arrhythmias, heart failure, and bone loss¹. Although clinical features and therapeutic strategies are relatively well established, the biological mechanisms that shape inter-individual susceptibility and progression remain incompletely defined. Etiologies range from autoimmune hyperfunction (e.g., Graves' disease) to toxic nodules, thyroiditis, exogenous hormone exposure, drug reactions, and tumor-related causes

Protocol

This study applies a two-sample Mendelian randomization (MR) design to evaluate whether genetically proxied telomere length (TL) causally influences the risk of thyrotoxicosis. Only de-identified, publicly available GWAS summary statistics were used, and no individual-level data were accessed. The Institutional Review Board of Qingdao Municipal Hospital determined that the analysis is exempt from further review because it relies exclusively on public summary data. All contributing genome-wide association studies obtained informed consent and ethical approvals as part of their original protocols. The analysis is structured to minimize confounding and reverse causation ....

Results

Instrument characteristics and assumption checks
From the telomere-length GWAS, 129 genome-wide significant, LD-independent instruments (p < 5×10^-8; r² < 0.001; 10,000 kb window) were retained. Per-SNP F-statistics exceeded the conventional threshold for the large majority of variants, indicating limited risk of weak-instrument bias. Harmonization removed ambiguous palindromic variants and aligned alleles so that exposure and outcome effects referred to the same effect all.......

Discussion

This Mendelian randomization (MR) study provides evidence that longer genetically predicted telomeres reduce the risk of thyrotoxicosis¹⁹. Directionally concordant estimates across IVW, MR-Egger, maximum likelihood, MR-PRESSO, and MR-RAPS indicate a robust protective association, and directionality checks support a TL → thyrotoxicosis pathway rather than the reverse²⁰. The biological plausibility is consistent with the role of telomeres in preserving chromosomal integ.......

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
1000 Genomes Project	Reference data for linkage disequilibrium (LD) clumping.	1000 Genomes Project	-
Cochran’s Q statistic	Statistical method used for heterogeneity testing in MR.	N/A	-
FinnGen dataset	GWAS summary statistics for thyrotoxicosis (cases and controls).	FinnGen Consortium	Release 2021, finn-b-thyROTOXICOSIS
IEU OpenGWAS dataset	GWAS summary statistics for telomere length.	IEU OpenGWAS	Dataset ID: ieu-b-4879
ieugwasr package	R package used for programmatic access to GWAS data.	CRAN	Version 0.1.5
mr.raps package	R package for robust estimation in Mendelian randomization under weak instruments.	CRAN	Version 0.1.2
MR-Egger regression	Sensitivity analysis method to test for directional pleiotropy.	N/A	-
MR-PRESSO outlier test	Statistical test used to identify and correct outliers in MR analyses.	N/A	-
MRPRESSO package	R package used for outlier detection and distortion testing in MR analysis.	CRAN	Version 1.0
R software	Statistical computing and graphics environment used for all analyses.	R Foundation for Statistical Computing	Version 4.3.1
RadialMR package	R package for radial visualization of MR results.	CRAN	Version 1.1.2
TwoSampleMR package	R package used for Mendelian randomization analyses.	CRAN	Version 0.5.7