Abstract
Introduction: Thyroid hormones play a critical role in brain development. However, the precise causal associations between thyroid function and structural changes in specific brain regions remain uncertain. Methods: We applied the univariate Mendelian randomization (UVMR) method to assess the causal effects of thyroid function on brain structure. Genome-wide association study (GWAS) data on thyroid-related traits from the ThyroidOmics Consortium including free thyroxine (FT4), free tri-iodothyronine (FT3), thyroid-stimulating hormone (TSH), FT3/FT4 ratio, as well as dichotomized high and low TSH levels were used as exposures. GWAS data on cortical thickness, surface area, and volume of subcortical structures served as outcomes. Inverse variance weighted was the main estimate method. Subsequently, multivariable MR (MVMR) was conducted to validate significant causal associations identified in UVMR. Results: UVMR analysis demonstrated a statistically significant inverse association between genetically predicted FT4 and putamen volume (β = −71.91 mm3, 95% confidence interval: −112.11 mm3 to −31.71 mm3, p = 4.54 × 10−4). The findings were robust in sensitivity analysis. MVMR analysis further confirmed a persistent causal relationship between FT4 and putamen volume after adjusting for FT3, TSH, and neuropsychiatric disorders. Functional enrichment analyses indicated the pathways by which FT4 influences putamen volume may be related to the thyroid hormone signaling pathway, sodium-independent organic anion transport, and Rap1 signaling pathway. Conclusion: MR analysis provides evidence for causal relationships between thyroid function and brain structural alterations, particularly highlighting the impact of FT4 on putamen volume. Further research is warranted to elucidate the underlying mechanisms by which thyroid hormones modulate brain structure.
Journal Section:
Research Article
References
1.
Gothié
JD
, Demeneix
B
, Remaud
S
. Comparative approaches to understanding thyroid hormone regulation of neurogenesis
. Mol Cell Endocrinol
. 2017
;459
:104
–15
. 2.
Kapoor
R
, Fanibunda
SE
, Desouza
LA
, Guha
SK
, Vaidya
VA
. Perspectives on thyroid hormone action in adult neurogenesis
. J Neurochem
. 2015
;133
(5
):599
–616
. 3.
Salas-Lucia
F
. Mapping thyroid hormone action in the human brain
. Thyroid
. 2024
;34
(7
):815
–26
. 4.
Thompson
W
, Russell
G
, Baragwanath
G
, Matthews
J
, Vaidya
B
, Thompson-Coon
J
. Maternal thyroid hormone insufficiency during pregnancy and risk of neurodevelopmental disorders in offspring: a systematic review and meta-analysis
. Clin Endocrinol
. 2018
;88
(4
):575
–84
. 5.
Chambers
T
, Anney
R
, Taylor
PN
, Teumer
A
, Peeters
RP
, Medici
M
, et al. Effects of thyroid status on regional brain volumes: a diagnostic and genetic imaging study in UK Biobank
. J Clin Endocrinol Metab
. 2021
;106
(3
):688
–96
. 6.
Alkadhi
KA
. Synaptic plasticity and cognitive ability in experimental adult-onset hypothyroidism
. J Pharmacol Exp Ther
. 2024
;389
(2
):150
–62
. 7.
Kumar
M
, Singh
S
, Modi
S
, Rana
P
, D’souza
M
, Sekhri
T
, et al. Cortical gray matter thickness and volume changes and their association with memory functions in hyperthyroid patients
. Neuroendocrinology
. 2024
;114
(4
):348
–55
. 8.
Jansen
TA
, Korevaar
TIM
, Mulder
TA
, White
T
, Muetzel
RL
, Peeters
RP
, et al. Maternal thyroid function during pregnancy and child brain morphology: a time window-specific analysis of a prospective cohort
. Lancet Diabetes Endocrinol
. 2019
;7
(8
):629
–37
. 9.
Cooke
GE
, Mullally
S
, Correia
N
, O'Mara
SM
, Gibney
J
. Hippocampal volume is decreased in adults with hypothyroidism
. Thyroid
. 2014
;24
(3
):433
–40
. 10.
Zhang
W
, Song
L
, Yin
X
, Zhang
J
, Liu
C
, Wang
J
, et al. Grey matter abnormalities in untreated hyperthyroidism: a voxel-based morphometry study using the DARTEL approach
. Eur J Radiol
. 2014
;83
(1
):e43
–8
. 11.
Singh
S
, Modi
S
, Bagga
D
, Kaur
P
, Shankar
LR
, Khushu
S
. Voxel-based morphometric analysis in hypothyroidism using diffeomorphic anatomic registration via an exponentiated lie algebra algorithm approach
. J Neuroendocrinol
. 2013
;25
(3
):229
–34
. 12.
Göbel
A
, Heldmann
M
, Göttlich
M
, Dirk
AL
, Brabant
G
, Münte
TF
. Effect of experimental thyrotoxicosis on brain gray matter: a voxel-based morphometry study
. Eur Thyroid J
. 2015
;4
(Suppl 1
):113
–8
. 13.
Ittermann
T
, Wittfeld
K
, Nauck
M
, Bülow
R
, Hosten
N
, Völzke
H
, et al. High thyrotropin is associated with reduced hippocampal volume in a population-based study from Germany
. Thyroid
. 2018
;28
(11
):1434
–42
. 14.
Chaker
L
, Cremers
LGM
, Korevaar
TIM
, de Groot
M
, Dehghan
A
, Franco
OH
, et al. Age-dependent association of thyroid function with brain morphology and microstructural organization: evidence from brain imaging
. Neurobiol Aging
. 2018
;61
:44
–51
. 15.
Davies
NM
, Holmes
MV
, Davey Smith
G
. Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians
. BMJ
. 2018
;362
:k601
. 16.
Skrivankova
VW
, Richmond
RC
, Woolf
BAR
, Yarmolinsky
J
, Davies
NM
, Swanson
SA
, et al. Strengthening the reporting of observational studies in epidemiology using Mendelian randomization: the STROBE-MR statement
. JAMA
. 2021
;326
(16
):1614
–21
. 17.
Sterenborg
RBTM
, Steinbrenner
I
, Li
Y
, Bujnis
MN
, Naito
T
, Marouli
E
, et al. Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications
. Nat Commun
. 2024
;15
(1
):888
. 18.
Grasby
KL
, Jahanshad
N
, Painter
JN
, Colodro-Conde
L
, Bralten
J
, Hibar
DP
, et al. The genetic architecture of the human cerebral cortex
. Science
. 2020
;367
(6484
):eaay6690
. 19.
Hibar
DP
, Stein
JL
, Renteria
ME
, Arias-Vasquez
A
, Desrivières
S
, Jahanshad
N
, et al. Common genetic variants influence human subcortical brain structures
. Nature
. 2015
;520
(7546
):224
–9
. 20.
Burgess
S
, Butterworth
A
, Thompson
SG
. Mendelian randomization analysis with multiple genetic variants using summarized data
. Genet Epidemiol
. 2013
;37
(7
):658
–65
. 21.
Burgess
S
, Thompson
SG
; CRP CHD Genetics Collaboration
. Avoiding bias from weak instruments in Mendelian randomization studies
. Int J Epidemiol
. 2011
;40
(3
):755
–64
. 22.
Pierce
BL
, Burgess
S
. Efficient design for Mendelian randomization studies: subsample and 2-sample instrumental variable estimators
. Am J Epidemiol
. 2013
;178
(7
):1177
–84
. 23.
Baranova
A
, Cao
H
, Zhang
F
. Severe COVID-19 increases the risk of schizophrenia
. Psychiatry Res
. 2022
;317
:114809
. 24.
Xu
T
, Li
C
, Liao
Y
, Zhang
X
. Causal relationship between circulating levels of cytokines and bone mineral density: a Mendelian randomization study
. Cytokine
. 2024
;182
:156729
. 25.
Liu
B
, Lyu
L
, Zhou
W
, Song
J
, Ye
D
, Mao
Y
, et al. Associations of the circulating levels of cytokines with risk of amyotrophic lateral sclerosis: a Mendelian randomization study
. BMC Med
. 2023
;21
(1
):39
. 26.
Bowden
J
, Davey Smith
G
, Haycock
PC
, Burgess
S
. Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator
. Genet Epidemiol
. 2016
;40
(4
):304
–14
. 27.
Bowden
J
, Davey Smith
G
, Burgess
S
. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression
. Int J Epidemiol
. 2015
;44
(2
):512
–25
. 28.
Liu
Z
, Zhang
Y
, Graham
S
, Wang
X
, Cai
D
, Huang
M
, et al. Causal relationships between NAFLD, T2D and obesity have implications for disease subphenotyping
. J Hepatol
. 2020
;73
(2
):263
–76
. 29.
Bowden
J
, Del Greco M
F
, Minelli
C
, Zhao
Q
, Lawlor
DA
, Sheehan
NA
, et al. Improving the accuracy of two-sample summary-data Mendelian randomization: moving beyond the NOME assumption
. Int J Epidemiol
. 2019
;48
(3
):728
–42
. 30.
Verbanck
M
, Chen
CY
, Neale
B
, Do
R
. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases
. Nat Genet
. 2018
;50
(5
):693
–8
. 31.
Hemani
G
, Tilling
K
, Davey Smith
G
. Orienting the causal relationship between imprecisely measured traits using GWAS summary data
. PLoS Genet
. 2017
;13
(11
):e1007081
. 32.
Mullins
N
, Forstner
AJ
, O'Connell
KS
, Coombes
B
, Coleman
JRI
, Qiao
Z
, et al. Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology
. Nat Genet
. 2021
;53
(6
):817
–29
. 33.
Trubetskoy
V
, Pardiñas
AF
, Qi
T
, Panagiotaropoulou
G
, Awasthi
S
, Bigdeli
TB
, et al. Mapping genomic loci implicates genes and synaptic biology in schizophrenia
. Nature
. 2022
;604
(7906
):502
–8
. 34.
Wray
NR
, Ripke
S
, Mattheisen
M
, Trzaskowski
M
, Byrne
EM
, Abdellaoui
A
, et al. Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression
. Nat Genet
. 2018
;50
(5
):668
–81
. 35.
Rosoff
DB
, Smith
GD
, Lohoff
FW
. Prescription opioid use and risk for major depressive disorder and anxiety and stress-related disorders: a multivariable Mendelian randomization analysis
. JAMA Psychiatry
. 2021
;78
(2
):151
–60
. 36.
Zha
LF
, Dong
JT
, Wang
JL
, Chen
QW
, Wu
JF
, Zhou
YC
, et al. Effects of insomnia on peptic ulcer disease using Mendelian randomization
. Oxid Med Cell Longev
. 2021
;2021
:2216314
. 37.
de Jong
FJ
, den Heijer
T
, Visser
TJ
, de Rijke
YB
, Drexhage
HA
, Hofman
A
, et al. Thyroid hormones, dementia, and atrophy of the medial temporal lobe
. J Clin Endocrinol Metab
. 2006
;91
(7
):2569
–73
. 38.
Yeap
BB
, Alfonso
H
, Chubb
SA
, Puri
G
, Hankey
GJ
, Flicker
L
, et al. Higher free thyroxine levels predict increased incidence of dementia in older men: the Health in Men Study
. J Clin Endocrinol Metab
. 2012
;97
(12
):E2230
–7
. 39.
Hogervorst
E
, Huppert
F
, Matthews
FE
, Brayne
C
. Thyroid function and cognitive decline in the MRC cognitive function and ageing study
. Psychoneuroendocrinology
. 2008
;33
(7
):1013
–22
. 40.
de Jong
FJ
, Masaki
K
, Chen
H
, Remaley
AT
, Breteler
MM
, Petrovitch
H
, et al. Thyroid function, the risk of dementia and neuropathologic changes: the Honolulu-Asia aging study
. Neurobiol Aging
. 2009
;30
(4
):600
–6
. 41.
Quinlan
P
, Horvath
A
, Eckerström
C
, Wallin
A
, Svensson
J
. Higher thyroid function is associated with accelerated hippocampal volume loss in Alzheimer’s disease
. Psychoneuroendocrinology
. 2022
;139
:105710
. 42.
Wu
Q
, Hu
H
, Chen
W
, Chen
HH
, Chen
L
, Zhou
J
, et al. Disrupted topological organization of the brain structural network in patients with thyroid-associated ophthalmopathy
. Invest Ophthalmol Vis Sci
. 2021
;62
(4
):5
. 43.
Conway
BR
. The organization and operation of inferior temporal cortex
. Annu Rev Vis Sci
. 2018
;4
:381
–402
. 44.
Rogge
B
, Heldmann
M
, Chatterjee
K
, Moran
C
, Göttlich
M
, Uter
J
, et al. Changes in brain structure in subjects with resistance to thyroid hormone due to THRB mutations
. Thyroid Res
. 2023
;16
(1
):34
. 45.
Haas
MJ
, Fishman
M
, Mreyoud
A
, Mooradian
AD
. Thyroid Hormone Responsive Protein (THRP) mediates thyroid hormone-induced cytotoxicity in primary neuronal cultures
. Exp Brain Res
. 2005
;160
(4
):424
–32
. 46.
Nho
K
, Kueider-Paisley
A
, MahmoudianDehkordi
S
, Arnold
M
, Risacher
SL
, Louie
G
, et al. Altered bile acid profile in mild cognitive impairment and Alzheimer’s Disease: relationship to neuroimaging and CSF biomarkers
. Alzheimers Dement
. 2019
;15
(2
):232
–44
. 47.
Sun
X
, Wang
Y
, Zhao
Y
, Xu
X
, Lu
W
, Li
Y
, et al. Activation of the Epac/Rap1 signaling pathway alleviates blood-brain barrier disruption and brain damage following cerebral ischemia/reperfusion injury
. Int Immunopharmacol
. 2023
;117
:110014
. © 2024 S. Karger AG, Basel
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
2024
You do not currently have access to this content.
