Mendelian Randomization Study Investigating the Causal Relationship Between Thyroid Dysfunction and Cerebral Infarction

Overview

Journal Brain Behav

Specialty Psychology

Date 2024 Dec 12

PMID 39663756

Authors

Letai Li

Jiajie Leng

Haibing Xiong

Zishan Deng

Meng Ye

Haiyan Wang

Xin Guo

Shi Zeng

Haofeng Xiong

Jianhong Huo

Affiliations

Soon will be listed here.

Abstract

Background: There is an association between thyroid dysfunction and cerebral infarction (CI), but the causality cannot be determined. A two-sample two-way Mendelian randomization (MR) study was conducted to assess the causal relationship between thyroid function and CI.

Methods: We selected single-nucleotide polymorphisms (SNPs) associated with five phenotypes, including CI from the UK Biobank (n = 361,194), hyperthyroidism from the IEU Open GWAS database (n = 484,598), hypothyroidism from the IEU Open GWAS database (n = 473,703), normal thyroid-stimulating hormone (TSH) (n = 271,040), and normal free thyroxine (FT4) (n = 119,120) from the Thyroidomics Consortium database. For the forward MR analysis, the exposures were hyperthyroidism, hypothyroidism, TSH, and FT4. The inverse variance weighted (IVW) method, weighted median (WM), and MR-Egger revealed the causality with CI. For the reverse MR analysis, CI was regarded as the exposure, and four thyroid function phenotypes were the outcomes. The sensitivity and heterogeneity test was assessed using Cochran's Q test, MR-Egger regression, and leave-one-out analysis.

Results: The MR analysis indicated that genetic susceptibility to hyperthyroidism increased the risk of CI (IVW-OR = 1.070; 95% CI: 1.015-1.128; p = 0.003). In reverse MR, genetic susceptibility to RA is not associated with hyperthyroidism (IVW-OR = 1.001; 95% CI: 1.000-1.001; p = 0.144). Any positive or reverse causal relationship between hypothyroidism, FT4, and TSH with CI could not be established. Sensitivity and heterogeneity test consolidated our findings.

Conclusion: The causality between CI and hyperthyroidism demonstrated patients with hyperthyroidism have a risk of genetic variants for CI. In the future, further studies are needed to fully explore their mechanisms of action.

References

Davey Smith G, Ebrahim S . Mendelian randomization: prospects, potentials, and limitations. Int J Epidemiol. 2004; 33(1):30-42. DOI: 10.1093/ije/dyh132. View

Aslan M, Cosar N, Celik H, Aksoy N, Dulger A, Begenik H . Evaluation of oxidative status in patients with hyperthyroidism. Endocrine. 2011; 40(2):285-9. DOI: 10.1007/s12020-011-9472-3. View

Thompson S, Kienast J, Pyke S, Haverkate F, van de Loo J . Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. N Engl J Med. 1995; 332(10):635-41. DOI: 10.1056/NEJM199503093321003. View

Wang W, Jiang B, Sun H, Ru X, Sun D, Wang L . Prevalence, Incidence, and Mortality of Stroke in China: Results from a Nationwide Population-Based Survey of 480 687 Adults. Circulation. 2017; 135(8):759-771. DOI: 10.1161/CIRCULATIONAHA.116.025250. View

Burgess S, Small D, Thompson S . A review of instrumental variable estimators for Mendelian randomization. Stat Methods Med Res. 2015; 26(5):2333-2355. PMC: 5642006. DOI: 10.1177/0962280215597579. View

Davey Smith G, Hemani G . Mendelian randomization: genetic anchors for causal inference in epidemiological studies. Hum Mol Genet. 2014; 23(R1):R89-98. PMC: 4170722. DOI: 10.1093/hmg/ddu328. View

Pierce B, Ahsan H, VanderWeele T . Power and instrument strength requirements for Mendelian randomization studies using multiple genetic variants. Int J Epidemiol. 2010; 40(3):740-52. PMC: 3147064. DOI: 10.1093/ije/dyq151. View

Burgess S, Davey Smith G, Davies N, Dudbridge F, Gill D, Glymour M . Guidelines for performing Mendelian randomization investigations: update for summer 2023. Wellcome Open Res. 2023; 4:186. PMC: 7384151. DOI: 10.12688/wellcomeopenres.15555.3. View

Weihs A, Chaker L, Martin T, Braun K, Campbell P, Cox S . Epigenome-Wide Association Study Reveals CpG Sites Associated with Thyroid Function and Regulatory Effects on . Thyroid. 2023; 33(3):301-311. PMC: 10024591. DOI: 10.1089/thy.2022.0373. View

10.

Venkatesh S, Ferreira T, Benonisdottir S, Rahmioglu N, Becker C, Granne I . Obesity and risk of female reproductive conditions: A Mendelian randomisation study. PLoS Med. 2022; 19(2):e1003679. PMC: 8806071. DOI: 10.1371/journal.pmed.1003679. View

11.

Burgess S, Butterworth A, Thompson S . Mendelian randomization analysis with multiple genetic variants using summarized data. Genet Epidemiol. 2013; 37(7):658-65. PMC: 4377079. DOI: 10.1002/gepi.21758. View

12.

Mokhtari T, Akbari M, Malek F, Kashani I, Rastegar T, Noorbakhsh F . Improvement of memory and learning by intracerebroventricular microinjection of T3 in rat model of ischemic brain stroke mediated by upregulation of BDNF and GDNF in CA1 hippocampal region. Daru. 2017; 25(1):4. PMC: 5312580. DOI: 10.1186/s40199-017-0169-x. View

13.

Chen X, Hong X, Gao W, Luo S, Cai J, Liu G . Causal relationship between physical activity, leisure sedentary behaviors and COVID-19 risk: a Mendelian randomization study. J Transl Med. 2022; 20(1):216. PMC: 9100292. DOI: 10.1186/s12967-022-03407-6. View

14.

Ohba S, Nakagawa T, Murakami H . Concurrent Graves' disease and intracranial arterial stenosis/occlusion: special considerations regarding the state of thyroid function, etiology, and treatment. Neurosurg Rev. 2011; 34(3):297-304. DOI: 10.1007/s10143-011-0311-z. View

15.

Burgess S, Timpson N, Ebrahim S, Davey Smith G . Mendelian randomization: where are we now and where are we going?. Int J Epidemiol. 2015; 44(2):379-88. DOI: 10.1093/ije/dyv108. View

16.

Skrivankova V, Richmond R, Woolf B, Davies N, Swanson S, VanderWeele T . Strengthening the reporting of observational studies in epidemiology using mendelian randomisation (STROBE-MR): explanation and elaboration. BMJ. 2021; 375:n2233. PMC: 8546498. DOI: 10.1136/bmj.n2233. View

17.

Bowden J, Del Greco M F, Minelli C, Zhao Q, Lawlor D, Sheehan N . Improving the accuracy of two-sample summary-data Mendelian randomization: moving beyond the NOME assumption. Int J Epidemiol. 2018; 48(3):728-742. PMC: 6659376. DOI: 10.1093/ije/dyy258. View

18.

Hartwig F, Davey Smith G, Bowden J . Robust inference in summary data Mendelian randomization via the zero modal pleiotropy assumption. Int J Epidemiol. 2017; 46(6):1985-1998. PMC: 5837715. DOI: 10.1093/ije/dyx102. View

19.

Hemani G, Zheng J, Elsworth B, Wade K, Haberland V, Baird D . The MR-Base platform supports systematic causal inference across the human phenome. Elife. 2018; 7. PMC: 5976434. DOI: 10.7554/eLife.34408. View

20.

Rutten-Jacobs L, Larsson S, Malik R, Rannikmae K, Sudlow C, Dichgans M . Genetic risk, incident stroke, and the benefits of adhering to a healthy lifestyle: cohort study of 306 473 UK Biobank participants. BMJ. 2018; 363:k4168. PMC: 6199557. DOI: 10.1136/bmj.k4168. View