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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.

SUBMITTER: Teumer A

PROVIDER: S-EPMC6203810 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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

Teumer Alexander A Chaker Layal L Groeneweg Stefan S Li Yong Y Di Munno Celia C Barbieri Caterina C Schultheiss Ulla T UT Traglia Michela M Ahluwalia Tarunveer S TS Akiyama Masato M Appel Emil Vincent R EVR Arking Dan E DE Arnold Alice A Astrup Arne A Beekman Marian M Beilby John P JP Bekaert Sofie S Boerwinkle Eric E Brown Suzanne J SJ De Buyzere Marc M Campbell Purdey J PJ Ceresini Graziano G Cerqueira Charlotte C Cucca Francesco F Deary Ian J IJ Deelen Joris J Eckardt Kai-Uwe KU Ekici Arif B AB Eriksson Johan G JG Ferrrucci Luigi L Fiers Tom T Fiorillo Edoardo E Ford Ian I Fox Caroline S CS Fuchsberger Christian C Galesloot Tessel E TE Gieger Christian C Gögele Martin M De Grandi Alessandro A Grarup Niels N Greiser Karin Halina KH Haljas Kadri K Hansen Torben T Harris Sarah E SE van Heemst Diana D den Heijer Martin M Hicks Andrew A AA den Hollander Wouter W Homuth Georg G Hui Jennie J Ikram M Arfan MA Ittermann Till T Jensen Richard A RA Jing Jiaojiao J Jukema J Wouter JW Kajantie Eero E Kamatani Yoichiro Y Kasbohm Elisa E Kaufman Jean-Marc JM Kiemeney Lambertus A LA Kloppenburg Margreet M Kronenberg Florian F Kubo Michiaki M Lahti Jari J Lapauw Bruno B Li Shuo S Liewald David C M DCM Lim Ee Mun EM Linneberg Allan A Marina Michela M Mascalzoni Deborah D Matsuda Koichi K Medenwald Daniel D Meisinger Christa C Meulenbelt Ingrid I De Meyer Tim T Meyer Zu Schwabedissen Henriette E HE Mikolajczyk Rafael R Moed Matthijs M Netea-Maier Romana T RT Nolte Ilja M IM Okada Yukinori Y Pala Mauro M Pattaro Cristian C Pedersen Oluf O Petersmann Astrid A Porcu Eleonora E Postmus Iris I Pramstaller Peter P PP Psaty Bruce M BM Ramos Yolande F M YFM Rawal Rajesh R Redmond Paul P Richards J Brent JB Rietzschel Ernst R ER Rivadeneira Fernando F Roef Greet G Rotter Jerome I JI Sala Cinzia F CF Schlessinger David D Selvin Elizabeth E Slagboom P Eline PE Soranzo Nicole N Sørensen Thorkild I A TIA Spector Timothy D TD Starr John M JM Stott David J DJ Taes Youri Y Taliun Daniel D Tanaka Toshiko T Thuesen Betina B Tiller Daniel D Toniolo Daniela D Uitterlinden Andre G AG Visser W Edward WE Walsh John P JP Wilson Scott G SG Wolffenbuttel Bruce H R BHR Yang Qiong Q Zheng Hou-Feng HF Cappola Anne A Peeters Robin P RP Naitza Silvia S Völzke Henry H Sanna Serena S Köttgen Anna A Visser Theo J TJ Medici Marco M

Nature communications 20181026 1

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-n ...[more]

PMID: 30367059

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Project description:BackgroundL-ascorbic acid (AsA; vitamin C) is essential for all living plants where it functions as the main hydrosoluble antioxidant. It has diverse roles in the regulation of plant cell growth and expansion, photosynthesis, and hormone-regulated processes. AsA is also an essential component of the human diet, being tomato fruit one of the main sources of this vitamin. To identify genes responsible for AsA content in tomato fruit, transcriptomic studies followed by clustering analysis were applied to two groups of fruits with contrasting AsA content. These fruits were identified after AsA profiling of an F8 Recombinant Inbred Line (RIL) population generated from a cross between the domesticated species Solanum lycopersicum and the wild relative Solanum pimpinellifollium.ResultsWe found large variability in AsA content within the RIL population with individual RILs with up to 4-fold difference in AsA content. Transcriptomic analysis identified genes whose expression correlated either positively (PVC genes) or negatively (NVC genes) with the AsA content of the fruits. Cluster analysis using SOTA allowed the identification of subsets of co-regulated genes mainly involved in hormones signaling, such as ethylene, ABA, gibberellin and auxin, rather than any of the known AsA biosynthetic genes. Data mining of the corresponding PVC and NVC orthologs in Arabidopis databases identified flagellin and other ROS-producing processes as cues resulting in differential regulation of a high percentage of the genes from both groups of co-regulated genes; more specifically, 26.6% of the orthologous PVC genes, and 15.5% of the orthologous NVC genes were induced and repressed, respectively, under flagellin22 treatment in Arabidopsis thaliana.ConclusionResults here reported indicate that the content of AsA in red tomato fruit from our selected RILs are not correlated with the expression of genes involved in its biosynthesis. On the contrary, the data presented here supports that AsA content in tomato fruit co-regulates with genes involved in hormone signaling and they are dependent on the oxidative status of the fruit.

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

Publications

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

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