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

A Teumer, L Chaker, S Groeneweg, Y Li, C Di Munno, C Barbieri, UT Schultheiss, M Traglia, TS Ahluwalia, M Akiyama, EVR Appel, DE Arking, A Arnold, A Astrup, M Beekman, JP Beilby, S Bekaert, E Boerwinkle, SJ Brown, M De BuyzerePJ Campbell, G Ceresini, C Cerqueira, F Cucca, IJ Deary, J Deelen, KU Eckardt, AB Ekici, JG Eriksson, L Ferrrucci, T Fiers, E Fiorillo, I Ford, CS Fox, C Fuchsberger, TE Galesloot, C Gieger, M Gögele, A De Grandi, N Grarup, KH Greiser, K Haljas, T Hansen, SE Harris, D van Heemst, M den Heijer, AA Hicks, W den Hollander, G Homuth, J Hui, MA Ikram, T Ittermann, RA Jensen, J Jing, JW Jukema, E Kajantie, Y Kamatani, E Kasbohm, JM Kaufman, LA Kiemeney, M Kloppenburg, F Kronenberg, M Kubo, J Lahti, B Lapauw, S Li, DCM Liewald, Lifelines Cohort Study, EM Lim, A Linneberg, M Marina, D Mascalzoni, K Matsuda, D Medenwald, C Meisinger, I Meulenbelt, T De Meyer, HE Meyer zu Schwabedissen, R Mikolajczyk, M Moed, RT Netea-Maier, IM Nolte, Y Okada, M Pala, C Pattaro, O Pedersen, A Petersmann, E Porcu, I Postmus, PP Pramstaller, BM Psaty, YFM Ramos, R Rawal, P Redmond, JB Richards, ER Rietzschel, F Rivadeneira, G Roef, JI Rotter, CF Sala, D Schlessinger, E Selvin, PE Slagboom, N Soranzo, TIA Sørensen, TD Spector, JM Starr, DJ Stott, Y Taes, D Taliun, T Tanaka, B Thuesen, D Tiller, D Toniolo, AG Uitterlinden, WE Visser, JP Walsh, SG Wilson, BHR Wolffenbuttel, Q Yang, H-F Zheng, A Cappola, RP Peeters, S Naitza, H Völzke, S Sanna, A Köttgen, TJ Visser, M Medici

Research output: Contribution to journalArticle

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. © 2018, The Author(s).
Original languageEnglish
Article number4455
JournalNature Communications
Volume9
DOIs
Publication statusPublished - 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

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Teumer, A., Chaker, L., Groeneweg, S., Li, Y., Di Munno, C., Barbieri, C., ... Medici, M. (2018). Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation. Nature Communications, 9, [4455]. https://doi.org/10.1038/s41467-018-06356-1

Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation. / Teumer, A; Chaker, L; Groeneweg, S; Li, Y; Di Munno, C; Barbieri, C; Schultheiss, UT; Traglia, M; Ahluwalia, TS; Akiyama, M; Appel, EVR; Arking, DE; Arnold, A; Astrup, A; Beekman, M; Beilby, JP; Bekaert, S; Boerwinkle, E; Brown, SJ; De Buyzere, M; Campbell, PJ; Ceresini, G; Cerqueira, C; Cucca, F; Deary, IJ; Deelen, J; Eckardt, KU; Ekici, AB; Eriksson, JG; Ferrrucci, L; Fiers, T; Fiorillo, E; Ford, I; Fox, CS; Fuchsberger, C; Galesloot, TE; Gieger, C; Gögele, M; De Grandi, A; Grarup, N; Greiser, KH; Haljas, K; Hansen, T; Harris, SE; van Heemst, D; den Heijer, M; Hicks, AA; den Hollander, W; Homuth, G; Hui, J; Ikram, MA; Ittermann, T; Jensen, RA; Jing, J; Jukema, JW; Kajantie, E; Kamatani, Y; Kasbohm, E; Kaufman, JM; Kiemeney, LA; Kloppenburg, M; Kronenberg, F; Kubo, M; Lahti, J; Lapauw, B; Li, S; Liewald, DCM; Study, Lifelines Cohort; Lim, EM; Linneberg, A; Marina, M; Mascalzoni, D; Matsuda, K; Medenwald, D; Meisinger, C; Meulenbelt, I; De Meyer, T; Meyer zu Schwabedissen, HE; Mikolajczyk, R; Moed, M; Netea-Maier, RT; Nolte, IM; Okada, Y; Pala, M; Pattaro, C; Pedersen, O; Petersmann, A; Porcu, E; Postmus, I; Pramstaller, PP; Psaty, BM; Ramos, YFM; Rawal, R; Redmond, P; Richards, JB; Rietzschel, ER; Rivadeneira, F; Roef, G; Rotter, JI; Sala, CF; Schlessinger, D; Selvin, E; Slagboom, PE; Soranzo, N; Sørensen, TIA; Spector, TD; Starr, JM; Stott, DJ; Taes, Y; Taliun, D; Tanaka, T; Thuesen, B; Tiller, D; Toniolo, D; Uitterlinden, AG; Visser, WE; Walsh, JP; Wilson, SG; Wolffenbuttel, BHR; Yang, Q; Zheng, H-F; Cappola, A; Peeters, RP; Naitza, S; Völzke, H; Sanna, S; Köttgen, A; Visser, TJ; Medici, M.

In: Nature Communications, Vol. 9, 4455, 2018.

Research output: Contribution to journalArticle

Teumer, A, Chaker, L, Groeneweg, S, Li, Y, Di Munno, C, Barbieri, C, Schultheiss, UT, Traglia, M, Ahluwalia, TS, Akiyama, M, Appel, EVR, Arking, DE, Arnold, A, Astrup, A, Beekman, M, Beilby, JP, Bekaert, S, Boerwinkle, E, Brown, SJ, De Buyzere, M, Campbell, PJ, Ceresini, G, Cerqueira, C, Cucca, F, Deary, IJ, Deelen, J, Eckardt, KU, Ekici, AB, Eriksson, JG, Ferrrucci, L, Fiers, T, Fiorillo, E, Ford, I, Fox, CS, Fuchsberger, C, Galesloot, TE, Gieger, C, Gögele, M, De Grandi, A, Grarup, N, Greiser, KH, Haljas, K, Hansen, T, Harris, SE, van Heemst, D, den Heijer, M, Hicks, AA, den Hollander, W, Homuth, G, Hui, J, Ikram, MA, Ittermann, T, Jensen, RA, Jing, J, Jukema, JW, Kajantie, E, Kamatani, Y, Kasbohm, E, Kaufman, JM, Kiemeney, LA, Kloppenburg, M, Kronenberg, F, Kubo, M, Lahti, J, Lapauw, B, Li, S, Liewald, DCM, Study, LC, Lim, EM, Linneberg, A, Marina, M, Mascalzoni, D, Matsuda, K, Medenwald, D, Meisinger, C, Meulenbelt, I, De Meyer, T, Meyer zu Schwabedissen, HE, Mikolajczyk, R, Moed, M, Netea-Maier, RT, Nolte, IM, Okada, Y, Pala, M, Pattaro, C, Pedersen, O, Petersmann, A, Porcu, E, Postmus, I, Pramstaller, PP, Psaty, BM, Ramos, YFM, Rawal, R, Redmond, P, Richards, JB, Rietzschel, ER, Rivadeneira, F, Roef, G, Rotter, JI, Sala, CF, Schlessinger, D, Selvin, E, Slagboom, PE, Soranzo, N, Sørensen, TIA, Spector, TD, Starr, JM, Stott, DJ, Taes, Y, Taliun, D, Tanaka, T, Thuesen, B, Tiller, D, Toniolo, D, Uitterlinden, AG, Visser, WE, Walsh, JP, Wilson, SG, Wolffenbuttel, BHR, Yang, Q, Zheng, H-F, Cappola, A, Peeters, RP, Naitza, S, Völzke, H, Sanna, S, Köttgen, A, Visser, TJ & Medici, M 2018, 'Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation', Nature Communications, vol. 9, 4455. https://doi.org/10.1038/s41467-018-06356-1
Teumer, A ; Chaker, L ; Groeneweg, S ; Li, Y ; Di Munno, C ; Barbieri, C ; Schultheiss, UT ; Traglia, M ; Ahluwalia, TS ; Akiyama, M ; Appel, EVR ; Arking, DE ; Arnold, A ; Astrup, A ; Beekman, M ; Beilby, JP ; Bekaert, S ; Boerwinkle, E ; Brown, SJ ; De Buyzere, M ; Campbell, PJ ; Ceresini, G ; Cerqueira, C ; Cucca, F ; Deary, IJ ; Deelen, J ; Eckardt, KU ; Ekici, AB ; Eriksson, JG ; Ferrrucci, L ; Fiers, T ; Fiorillo, E ; Ford, I ; Fox, CS ; Fuchsberger, C ; Galesloot, TE ; Gieger, C ; Gögele, M ; De Grandi, A ; Grarup, N ; Greiser, KH ; Haljas, K ; Hansen, T ; Harris, SE ; van Heemst, D ; den Heijer, M ; Hicks, AA ; den Hollander, W ; Homuth, G ; Hui, J ; Ikram, MA ; Ittermann, T ; Jensen, RA ; Jing, J ; Jukema, JW ; Kajantie, E ; Kamatani, Y ; Kasbohm, E ; Kaufman, JM ; Kiemeney, LA ; Kloppenburg, M ; Kronenberg, F ; Kubo, M ; Lahti, J ; Lapauw, B ; Li, S ; Liewald, DCM ; Study, Lifelines Cohort ; Lim, EM ; Linneberg, A ; Marina, M ; Mascalzoni, D ; Matsuda, K ; Medenwald, D ; Meisinger, C ; Meulenbelt, I ; De Meyer, T ; Meyer zu Schwabedissen, HE ; Mikolajczyk, R ; Moed, M ; Netea-Maier, RT ; Nolte, IM ; Okada, Y ; Pala, M ; Pattaro, C ; Pedersen, O ; Petersmann, A ; Porcu, E ; Postmus, I ; Pramstaller, PP ; Psaty, BM ; Ramos, YFM ; Rawal, R ; Redmond, P ; Richards, JB ; Rietzschel, ER ; Rivadeneira, F ; Roef, G ; Rotter, JI ; Sala, CF ; Schlessinger, D ; Selvin, E ; Slagboom, PE ; Soranzo, N ; Sørensen, TIA ; Spector, TD ; Starr, JM ; Stott, DJ ; Taes, Y ; Taliun, D ; Tanaka, T ; Thuesen, B ; Tiller, D ; Toniolo, D ; Uitterlinden, AG ; Visser, WE ; Walsh, JP ; Wilson, SG ; Wolffenbuttel, BHR ; Yang, Q ; Zheng, H-F ; Cappola, A ; Peeters, RP ; Naitza, S ; Völzke, H ; Sanna, S ; Köttgen, A ; Visser, TJ ; Medici, M. / Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation. In: Nature Communications. 2018 ; Vol. 9.
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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. {\circledC} 2018, The Author(s).",
author = "A Teumer and L Chaker and S Groeneweg and Y Li and {Di Munno}, C and C Barbieri and UT Schultheiss and M Traglia and TS Ahluwalia and M Akiyama and EVR Appel and DE Arking and A Arnold and A Astrup and M Beekman and JP Beilby and S Bekaert and E Boerwinkle and SJ Brown and {De Buyzere}, M and PJ Campbell and G Ceresini and C Cerqueira and F Cucca and IJ Deary and J Deelen and KU Eckardt and AB Ekici and JG Eriksson and L Ferrrucci and T Fiers and E Fiorillo and I Ford and CS Fox and C Fuchsberger and TE Galesloot and C Gieger and M G{\"o}gele and {De Grandi}, A and N Grarup and KH Greiser and K Haljas and T Hansen and SE Harris and {van Heemst}, D and {den Heijer}, M and AA Hicks and {den Hollander}, W and G Homuth and J Hui and MA Ikram and T Ittermann and RA Jensen and J Jing and JW Jukema and E Kajantie and Y Kamatani and E Kasbohm and JM Kaufman and LA Kiemeney and M Kloppenburg and F Kronenberg and M Kubo and J Lahti and B Lapauw and S Li and DCM Liewald and Study, {Lifelines Cohort} and EM Lim and A Linneberg and M Marina and D Mascalzoni and K Matsuda and D Medenwald and C Meisinger and I Meulenbelt and {De Meyer}, T and {Meyer zu Schwabedissen}, HE and R Mikolajczyk and M Moed and RT Netea-Maier and IM Nolte and Y Okada and M Pala and C Pattaro and O Pedersen and A Petersmann and E Porcu and I Postmus and PP Pramstaller and BM Psaty and YFM Ramos and R Rawal and P Redmond and JB Richards and ER Rietzschel and F Rivadeneira and G Roef and JI Rotter and CF Sala and D Schlessinger and E Selvin and PE Slagboom and N Soranzo and TIA S{\o}rensen and TD Spector and JM Starr and DJ Stott and Y Taes and D Taliun and T Tanaka and B Thuesen and D Tiller and D Toniolo and AG Uitterlinden and WE Visser and JP Walsh and SG Wilson and BHR Wolffenbuttel and Q Yang and H-F Zheng and A Cappola and RP Peeters and S Naitza and H V{\"o}lzke and S Sanna and A K{\"o}ttgen and TJ Visser and M Medici",
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journal = "Nature Communications",
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TY - JOUR

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

AU - Teumer, A

AU - Chaker, L

AU - Groeneweg, S

AU - Li, Y

AU - Di Munno, C

AU - Barbieri, C

AU - Schultheiss, UT

AU - Traglia, M

AU - Ahluwalia, TS

AU - Akiyama, M

AU - Appel, EVR

AU - Arking, DE

AU - Arnold, A

AU - Astrup, A

AU - Beekman, M

AU - Beilby, JP

AU - Bekaert, S

AU - Boerwinkle, E

AU - Brown, SJ

AU - De Buyzere, M

AU - Campbell, PJ

AU - Ceresini, G

AU - Cerqueira, C

AU - Cucca, F

AU - Deary, IJ

AU - Deelen, J

AU - Eckardt, KU

AU - Ekici, AB

AU - Eriksson, JG

AU - Ferrrucci, L

AU - Fiers, T

AU - Fiorillo, E

AU - Ford, I

AU - Fox, CS

AU - Fuchsberger, C

AU - Galesloot, TE

AU - Gieger, C

AU - Gögele, M

AU - De Grandi, A

AU - Grarup, N

AU - Greiser, KH

AU - Haljas, K

AU - Hansen, T

AU - Harris, SE

AU - van Heemst, D

AU - den Heijer, M

AU - Hicks, AA

AU - den Hollander, W

AU - Homuth, G

AU - Hui, J

AU - Ikram, MA

AU - Ittermann, T

AU - Jensen, RA

AU - Jing, J

AU - Jukema, JW

AU - Kajantie, E

AU - Kamatani, Y

AU - Kasbohm, E

AU - Kaufman, JM

AU - Kiemeney, LA

AU - Kloppenburg, M

AU - Kronenberg, F

AU - Kubo, M

AU - Lahti, J

AU - Lapauw, B

AU - Li, S

AU - Liewald, DCM

AU - Study, Lifelines Cohort

AU - Lim, EM

AU - Linneberg, A

AU - Marina, M

AU - Mascalzoni, D

AU - Matsuda, K

AU - Medenwald, D

AU - Meisinger, C

AU - Meulenbelt, I

AU - De Meyer, T

AU - Meyer zu Schwabedissen, HE

AU - Mikolajczyk, R

AU - Moed, M

AU - Netea-Maier, RT

AU - Nolte, IM

AU - Okada, Y

AU - Pala, M

AU - Pattaro, C

AU - Pedersen, O

AU - Petersmann, A

AU - Porcu, E

AU - Postmus, I

AU - Pramstaller, PP

AU - Psaty, BM

AU - Ramos, YFM

AU - Rawal, R

AU - Redmond, P

AU - Richards, JB

AU - Rietzschel, ER

AU - Rivadeneira, F

AU - Roef, G

AU - Rotter, JI

AU - Sala, CF

AU - Schlessinger, D

AU - Selvin, E

AU - Slagboom, PE

AU - Soranzo, N

AU - Sørensen, TIA

AU - Spector, TD

AU - Starr, JM

AU - Stott, DJ

AU - Taes, Y

AU - Taliun, D

AU - Tanaka, T

AU - Thuesen, B

AU - Tiller, D

AU - Toniolo, D

AU - Uitterlinden, AG

AU - Visser, WE

AU - Walsh, JP

AU - Wilson, SG

AU - Wolffenbuttel, BHR

AU - Yang, Q

AU - Zheng, H-F

AU - Cappola, A

AU - Peeters, RP

AU - Naitza, S

AU - Völzke, H

AU - Sanna, S

AU - Köttgen, A

AU - Visser, TJ

AU - Medici, M

PY - 2018

Y1 - 2018

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. © 2018, The Author(s).

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. © 2018, The Author(s).

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

M1 - 4455

ER -