Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications

RBTM Sterenborg; I Steinbrenner; Y Li; MN Bujnis; T Naito; E Marouli; TE Galesloot; O Babajide; L Andreasen; A Astrup; BO Åsvold; S Bandinelli; M Beekman; JP Beilby; J Bork-Jensen; T Boutin; JA Brody; SJ Brown; B Brumpton; PJ Campbell; AR Cappola; G Ceresini; L Chaker; DI Chasman; MP Concas; R Coutinho de Almeida; SM Cross; F Cucca; IJ Deary; AD Kjaergaard; JB Echouffo Tcheugui; C Ellervik; JG Eriksson; L Ferrucci; J Freudenberg; Christian Fuchsberger; C Gieger; F Giulianini; Martin Gögele; SE Graham; N Grarup; I Gunjača; T Hansen; BN Harding; SE Harris; S Haunsø; C Hayward; J Hui; T Ittermann; JW Jukema; E Kajantie; JK Kanters; LL Kårhus; LALM Kiemeney; M Kloppenburg; B Kühnel; J Lahti; C Langenberg; B Lapauw; G Leese; S Li; DCM Liewald; A Linneberg; JVT Lominchar; J Luan; NG Martin; A Matana; ME Meima; T Meitinger; I Meulenbelt; BD Mitchell; LT Møllehave; S Mora; S Naitza; M Nauck; RT Netea-Maier; R Noordam; C Nursyifa; Y Okada; S Onano; A Papadopoulou; CNA Palmer; Cristian Pattaro; O Pedersen; A Peters; M Pietzner; O Polašek; Peter P. Pramstaller; BM Psaty; A Punda; D Ray; P Redmond; JB Richards; PM Ridker; TC Russ; KA Ryan; MS Olesen; UT Schultheiss; E Selvin; MK Siddiqui; C Sidore; PE Slagboom; TIA Sørensen; E Soto-Pedre; TD Spector; B Spedicati; S Srinivasan; JM Starr; DJ Stott; T Tanaka; V Torlak; S Trompet; J Tuhkanen; AG Uitterlinden; EB van den Akker; T van den Eynde; MM van der Klauw; D van Heemst; C Verroken; WE Visser; D Vojinovic; H Völzke; M Waldenberger; JP Walsh; NJ Wareham; S Weiss; CJ Willer; SG Wilson; BHR Wolffenbuttel; HJCM Wouters; MJ Wright; Q Yang; T Zemunik; W Zhou; G Zhu; S Zöllner; JWA Smit; RP Peeters; A Köttgen; A Teumer; M Medici

doi:10.1038/s41467-024-44701-9

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Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications

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Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications

RBTM Sterenborg, I Steinbrenner, Y Li, MN Bujnis, T Naito, E Marouli, TE Galesloot, O Babajide, L Andreasen, A Astrup, …

Nature Communications, Vol.15(1), 888

30/01/2024

DOI: https://doi.org/10.1038/s41467-024-44701-9

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https://hdl.handle.net/10863/39962

PMID: 38291025

Abstract

Biostatistics & Epidemiology

Biomedical Informatics

CHRIS study

To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases.

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Title: Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications
Creators: RBTM Sterenborg
I Steinbrenner
Y Li
MN Bujnis
T Naito
E Marouli
TE Galesloot
O Babajide
L Andreasen
A Astrup
BO Åsvold
S Bandinelli
M Beekman
JP Beilby
J Bork-Jensen
T Boutin
JA Brody
SJ Brown
B Brumpton
PJ Campbell
AR Cappola
G Ceresini
L Chaker
DI Chasman
MP Concas
R Coutinho de Almeida
SM Cross
F Cucca
IJ Deary
AD Kjaergaard
JB Echouffo Tcheugui
C Ellervik
JG Eriksson
L Ferrucci
J Freudenberg
Christian Fuchsberger - -, Institute for Biomedicine
C Gieger
F Giulianini
Martin Gögele
SE Graham
N Grarup
I Gunjača
T Hansen
BN Harding
SE Harris
S Haunsø
C Hayward
J Hui
T Ittermann
JW Jukema
E Kajantie
JK Kanters
LL Kårhus
LALM Kiemeney
M Kloppenburg
B Kühnel
J Lahti
C Langenberg
B Lapauw
G Leese
S Li
DCM Liewald
A Linneberg
JVT Lominchar
J Luan
NG Martin
A Matana
ME Meima
T Meitinger
I Meulenbelt
BD Mitchell
LT Møllehave
S Mora
S Naitza
M Nauck
RT Netea-Maier
R Noordam
C Nursyifa
Y Okada
S Onano
A Papadopoulou
CNA Palmer
Cristian Pattaro
O Pedersen
A Peters
M Pietzner
O Polašek
Peter P. Pramstaller
BM Psaty
A Punda
D Ray
P Redmond
JB Richards
PM Ridker
TC Russ
KA Ryan
MS Olesen
UT Schultheiss
E Selvin
MK Siddiqui
C Sidore
PE Slagboom
TIA Sørensen
E Soto-Pedre
TD Spector
B Spedicati
S Srinivasan
JM Starr
DJ Stott
T Tanaka
V Torlak
S Trompet
J Tuhkanen
AG Uitterlinden
EB van den Akker
T van den Eynde
MM van der Klauw
D van Heemst
C Verroken
WE Visser
D Vojinovic
H Völzke
M Waldenberger
JP Walsh
NJ Wareham
S Weiss
CJ Willer
SG Wilson
BHR Wolffenbuttel
HJCM Wouters
MJ Wright
Q Yang
T Zemunik
W Zhou
G Zhu
S Zöllner
JWA Smit
RP Peeters
A Köttgen
A Teumer
M Medici
Contributors: GHS DiscovEHR (Institution)
Regeneron Genetics Center (Institution)
Publication Details: Nature Communications, Vol.15(1), 888
EISSN: 2041-1723
Series / Volume: 15
Publisher: Springer Science and Business Media LLC
Identifiers: (EURAC)28170530
991006748497101241
Web of Science ID: WOS:001188050100001
Copyright: https://creativecommons.org/licenses/by/4.0
Academic Unit: Institute for Biomedicine
Language: English
Resource Type: Journal article
Description coverage: international
Description audience: Scientific
Local Fields: Scientific
Author Names String: Sterenborg RBTM, Steinbrenner I, Li Y, Bujnis MN, Naito T, Marouli E, Galesloot TE, Babajide O, Andreasen L, Astrup A, Åsvold BO, Bandinelli S, Beekman M, Beilby JP, Bork-Jensen J, Boutin T, Brody JA, Brown SJ, Brumpton B, Campbell PJ, Cappola AR, Ceresini G, Chaker L, Chasman DI, Concas MP, Coutinho de Almeida R, Cross SM, Cucca F, Deary IJ, Kjaergaard AD, Echouffo Tcheugui JB, Ellervik C, Eriksson JG, Ferrucci L, Freudenberg J; GHS DiscovEHR; Regeneron Genetics Center; Fuchsberger C, Gieger C, Giulianini F, Gögele M, Graham SE, Grarup N, Gunjača I, Hansen T, Harding BN, Harris SE, Haunsø S, Hayward C, Hui J, Ittermann T, Jukema JW, Kajantie E, Kanters JK, Kårhus LL, Kiemeney LALM, Kloppenburg M, Kühnel B, Lahti J, Langenberg C, Lapauw B, Leese G, Li S, Liewald DCM, Linneberg A, Lominchar JVT, Luan J, Martin NG, Matana A, Meima ME, Meitinger T, Meulenbelt I, Mitchell BD, Møllehave LT, Mora S, Naitza S, Nauck M, Netea-Maier RT, Noordam R, Nursyifa C, Okada Y, Onano S, Papadopoulou A, Palmer CNA, Pattaro C, Pedersen O, Peters A, Pietzner M, Polašek O, Pramstaller PP, Psaty BM, Punda A, Ray D, Redmond P, Richards JB, Ridker PM, Russ TC, Ryan KA, Olesen MS, Schultheiss UT, Selvin E, Siddiqui MK, Sidore C, Slagboom PE, Sørensen TIA, Soto-Pedre E, Spector TD, Spedicati B, Srinivasan S, Starr JM, Stott DJ, Tanaka T, Torlak V, Trompet S, Tuhkanen J, Uitterlinden AG, van den Akker EB, van den Eynde T, van der Klauw MM, van Heemst D, Verroken C, Visser WE, Vojinovic D, Völzke H, Waldenberger M, Walsh JP, Wareham NJ, Weiss S, Willer CJ, Wilson SG, Wolffenbuttel BHR, Wouters HJCM, Wright MJ, Yang Q, Zemunik T, Zhou W, Zhu G, Zöllner S, Smit JWA, Peeters RP, Köttgen A, Teumer A, Medici M

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