ESPE Yearbook of Paediatric Endocrinology

Brief summary: The so far largest GWAS study on thyroid function in 72’167 individuals testing 8 million genetic variants identified 92 common genetic variants associated with variation of TSH and FT4 in the reference range. These variants explained 21% of the variance in normal thyroid function, however many identified variants were localized in genes without obvious link to thyroid function (1). This GWAS paper was commented in the 2019 Yearbook. The same research team aimed now at defining the role of variants in genes involved in the hypothalamo-pituitary thyroid axis.

For this, the authors analyzed variants in 96 genes known to be involved in thyroid development (transcription factors such as FOXE1, PAX8, NKX2-1), regulation of thyroid function (e.g. TRH, TRHR, TSHR), thyroid hormone synthesis (e.g. TPO, TG, SLC27A7), and thyroid hormone metabolism and action (e.g. DIO2, ABCB1, SLC16A2) in a large cohort from the ThyroidOmics Consortium with 54’288 and 49’269 participants with TSH and FT4 data. With this extensive study, the authors identified 23 and 25 new genetic variants, associated with TSH levels, and FT4 levels in the normal range, respectively. Variants of genes of the hypothalamo-pituitary-thyroid axis were predominantly associated with TSH levels, while variants of genes responsible for thyroid hormone metabolism and action were mainly associated with FT4 levels. However, unexpectedly, these large number of genetic variants in thyroid hormone axis genes explained only 1.9% and 2.6% of variance of TSH, and FT4 levels respectively in contrast to GWAS results of the whole genome.

In conclusion, these important results did not confirm the hypothesis of the authors that genetic variants in genes involved in thyroid axis had an important contribution to variance of TSH and FT4 in the normal population. First, based on the previous GWAS data, these results suggest the presence of yet unknown pathways being involved in thyroid hormone level regulation. Second, the authors recommend analyzing not only frequent but also rare genetic variants in future large genetic studies.

Reference: 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; Lifelines Cohort Study, 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 HF, 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. Nat Commun. 2018;9:4455. doi: 10.1038/s41467-018-06356-1. PMID: 30367059.