Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation

LifeLines Cohort Study

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves’ disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets.

Original languageEnglish
Article number4455
JournalNature Communications
Volume9
Issue number1
DOIs
Publication statusPublished - 1 Dec 2018

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hormones
genome
Thyroid Hormones
Genes
Thyroid Diseases
Genome
Thyroid Gland
Genome-Wide Association Study
Graves Disease
Physiology
Public health
Medical problems
Metabolism
public health
transporter
physiology
Meta-Analysis
mortality
metabolism
Public Health

Cite this

@article{3a2b4df97df545ee9fb74b73bd96f06d,
title = "Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation",
abstract = "Thyroid dysfunction is an important public health problem, which affects 10{\%} of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves’ disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets.",
author = "{LifeLines Cohort Study} and Alexander Teumer and Layal Chaker and Stefan Groeneweg and Yong Li and {Di Munno}, Celia and Caterina Barbieri and Schultheiss, {Ulla T.} and Michela Traglia and Ahluwalia, {Tarunveer S.} and Masato Akiyama and Appel, {Emil Vincent R.} and Arking, {Dan E.} and Alice Arnold and Arne Astrup and Marian Beekman and Beilby, {John P.} and Sofie Bekaert and Eric Boerwinkle and Brown, {Suzanne J.} and {De Buyzere}, Marc and Campbell, {Purdey J.} and Graziano Ceresini and Charlotte Cerqueira and Francesco Cucca and Deary, {Ian J.} and Joris Deelen and Eckardt, {Kai Uwe} and Ekici, {Arif B.} and Eriksson, {Johan G.} and Luigi Ferrrucci and Tom Fiers and Edoardo Fiorillo and Ian Ford and Fox, {Caroline S.} and Christian Fuchsberger and Galesloot, {Tessel E.} and Christian Gieger and Martin G{\"o}gele and {De Grandi}, Alessandro and Niels Grarup and Greiser, {Karin Halina} and Kadri Haljas and Torben Hansen and Harris, {Sarah E.} and {van Heemst}, Diana and {den Heijer}, Martin and Hicks, {Andrew A.} and {den Hollander}, Wouter and Georg Homuth and Jennie Hui and Ikram, {M. Arfan} and Till Ittermann and Jensen, {Richard A.} and Jiaojiao Jing and Jukema, {J. Wouter} and Eero Kajantie and Yoichiro Kamatani and Elisa Kasbohm and Kaufman, {Jean Marc} and Kiemeney, {Lambertus A.} and Margreet Kloppenburg and Florian Kronenberg and Michiaki Kubo and Jari Lahti and Bruno Lapauw and Shuo Li and Liewald, {David C.M.} and Alizadeh, {Behrooz Z.} and Boezen, {H. Marike} and Lude Franke and {van der Harst}, Pim and Gerjan Navis and Marianne Rots and Harold Snieder and Swertz, {Morris A A.} and Cisca Wijmenga and Lim, {Ee Mun} and Allan Linneberg and Michela Marina and Deborah Mascalzoni and Koichi Matsuda and Daniel Medenwald and Christa Meisinger and Ingrid Meulenbelt and {De Meyer}, Tim and {Meyer zu Schwabedissen}, {Henriette E.} and Rafael Mikolajczyk and Matthijs Moed and Netea-Maier, {Romana T.} and Nolte, {Ilja M.} and Yukinori Okada and Mauro Pala and Cristian Pattaro and Oluf Pedersen and Astrid Petersmann and Eleonora Porcu and Iris Postmus and Pramstaller, {Peter P.} and Psaty, {Bruce M.} and Ramos, {Yolande F.M.} and Rajesh Rawal and Paul Redmond and Richards, {J. Brent} and Rietzschel, {Ernst R.} and Fernando Rivadeneira and Greet Roef and Rotter, {Jerome I.} and Sala, {Cinzia F.} and David Schlessinger and Elizabeth Selvin and Slagboom, {P. Eline} and Nicole Soranzo and S{\o}rensen, {Thorkild I.A.} and Spector, {Timothy D.} and Starr, {John M.} and Stott, {David J.} and Youri Taes and Daniel Taliun and Toshiko Tanaka and Betina Thuesen and Daniel Tiller and Daniela Toniolo and Uitterlinden, {Andre G.} and Visser, {W. Edward} and Walsh, {John P.} and Wilson, {Scott G.} and Wolffenbuttel, {Bruce H.R.} and Qiong Yang and Zheng, {Hou Feng} and Anne Cappola and Peeters, {Robin P.} and Silvia Naitza and Henry V{\"o}lzke and Serena Sanna and Anna K{\"o}ttgen and Visser, {Theo J.} and Marco Medici",
year = "2018",
month = "12",
day = "1",
doi = "10.1038/s41467-018-06356-1",
language = "English",
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journal = "Nature Communications",
issn = "2041-1723",
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Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation. / LifeLines Cohort Study.

In: Nature Communications, Vol. 9, No. 1, 4455, 01.12.2018.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation

AU - LifeLines Cohort Study

AU - Teumer, Alexander

AU - Chaker, Layal

AU - Groeneweg, Stefan

AU - Li, Yong

AU - Di Munno, Celia

AU - Barbieri, Caterina

AU - Schultheiss, Ulla T.

AU - Traglia, Michela

AU - Ahluwalia, Tarunveer S.

AU - Akiyama, Masato

AU - Appel, Emil Vincent R.

AU - Arking, Dan E.

AU - Arnold, Alice

AU - Astrup, Arne

AU - Beekman, Marian

AU - Beilby, John P.

AU - Bekaert, Sofie

AU - Boerwinkle, Eric

AU - Brown, Suzanne J.

AU - De Buyzere, Marc

AU - Campbell, Purdey J.

AU - Ceresini, Graziano

AU - Cerqueira, Charlotte

AU - Cucca, Francesco

AU - Deary, Ian J.

AU - Deelen, Joris

AU - Eckardt, Kai Uwe

AU - Ekici, Arif B.

AU - Eriksson, Johan G.

AU - Ferrrucci, Luigi

AU - Fiers, Tom

AU - Fiorillo, Edoardo

AU - Ford, Ian

AU - Fox, Caroline S.

AU - Fuchsberger, Christian

AU - Galesloot, Tessel E.

AU - Gieger, Christian

AU - Gögele, Martin

AU - De Grandi, Alessandro

AU - Grarup, Niels

AU - Greiser, Karin Halina

AU - Haljas, Kadri

AU - Hansen, Torben

AU - Harris, Sarah E.

AU - van Heemst, Diana

AU - den Heijer, Martin

AU - Hicks, Andrew A.

AU - den Hollander, Wouter

AU - Homuth, Georg

AU - Hui, Jennie

AU - Ikram, M. Arfan

AU - Ittermann, Till

AU - Jensen, Richard A.

AU - Jing, Jiaojiao

AU - Jukema, J. Wouter

AU - Kajantie, Eero

AU - Kamatani, Yoichiro

AU - Kasbohm, Elisa

AU - Kaufman, Jean Marc

AU - Kiemeney, Lambertus A.

AU - Kloppenburg, Margreet

AU - Kronenberg, Florian

AU - Kubo, Michiaki

AU - Lahti, Jari

AU - Lapauw, Bruno

AU - Li, Shuo

AU - Liewald, David C.M.

AU - Alizadeh, Behrooz Z.

AU - Boezen, H. Marike

AU - Franke, Lude

AU - van der Harst, Pim

AU - Navis, Gerjan

AU - Rots, Marianne

AU - Snieder, Harold

AU - Swertz, Morris A A.

AU - Wijmenga, Cisca

AU - Lim, Ee Mun

AU - Linneberg, Allan

AU - Marina, Michela

AU - Mascalzoni, Deborah

AU - Matsuda, Koichi

AU - Medenwald, Daniel

AU - Meisinger, Christa

AU - Meulenbelt, Ingrid

AU - De Meyer, Tim

AU - Meyer zu Schwabedissen, Henriette E.

AU - Mikolajczyk, Rafael

AU - Moed, Matthijs

AU - Netea-Maier, Romana T.

AU - Nolte, Ilja M.

AU - Okada, Yukinori

AU - Pala, Mauro

AU - Pattaro, Cristian

AU - Pedersen, Oluf

AU - Petersmann, Astrid

AU - Porcu, Eleonora

AU - Postmus, Iris

AU - Pramstaller, Peter P.

AU - Psaty, Bruce M.

AU - Ramos, Yolande F.M.

AU - Rawal, Rajesh

AU - Redmond, Paul

AU - Richards, J. Brent

AU - Rietzschel, Ernst R.

AU - Rivadeneira, Fernando

AU - Roef, Greet

AU - Rotter, Jerome I.

AU - Sala, Cinzia F.

AU - Schlessinger, David

AU - Selvin, Elizabeth

AU - Slagboom, P. Eline

AU - Soranzo, Nicole

AU - Sørensen, Thorkild I.A.

AU - Spector, Timothy D.

AU - Starr, John M.

AU - Stott, David J.

AU - Taes, Youri

AU - Taliun, Daniel

AU - Tanaka, Toshiko

AU - Thuesen, Betina

AU - Tiller, Daniel

AU - Toniolo, Daniela

AU - Uitterlinden, Andre G.

AU - Visser, W. Edward

AU - Walsh, John P.

AU - Wilson, Scott G.

AU - Wolffenbuttel, Bruce H.R.

AU - Yang, Qiong

AU - Zheng, Hou Feng

AU - Cappola, Anne

AU - Peeters, Robin P.

AU - Naitza, Silvia

AU - Völzke, Henry

AU - Sanna, Serena

AU - Köttgen, Anna

AU - Visser, Theo J.

AU - Medici, Marco

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves’ disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets.

AB - Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves’ disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets.

UR - http://www.scopus.com/inward/record.url?scp=85055612686&partnerID=8YFLogxK

U2 - 10.1038/s41467-018-06356-1

DO - 10.1038/s41467-018-06356-1

M3 - Article

VL - 9

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 4455

ER -