ESPEYB19 3. Thyroid New genes (2 abstracts)
3.10. GWAS of thyroid dysgenesis identifies a risk locus at 2q33.3 linked to regulation of Wnt signaling
Narumi S , Opitz R , Nagasaki K , Muroya K , Asakura Y , Adachi M , Abe K , Sugisawa C , Kühnen P , Ishii T , Nöthen MM , Krude H & Hasegawa T
Hum Mol Genet. 2022 May 10:ddac093. doi: 10.1093/hmg/ddac093. Online ahead of print. PMID: 35535691
Brief Summary: This genome-wide association study (GWAS) of patients with thyroid dysgenesis identified a genetic risk locus for thyroid athyreosis and ectopy. In depth genetic analyses of the disease associated region suggested a new disease mechanism of thyroid dysgenesis mediated by impaired Wnt pathway signalling.
To elucidate the pathogenesis of thyroid dysgenesis, the authors performed GWAS in well-phenotyped Japanese patients with thyroid dysgenesis (n=142). They identified a risk locus at 2q33.3 for thyroid athyreosis and ectopy and confirmed its relevance in an independent German patient cohort (n=80 patients with thyroid dysgenesis) conferring an overall risk (OR) of 2.23 for thyroid dysgenesis, and of 3.17, and 3.12 for athyreosis and ectopy, respectively. Combined in silico epigenome, transcriptome, genotype-tissue expression, and chromatin interaction studies revealed that the risk locus contained cis-regulatory sequences of two genes of the Wnt pathway (FZD5, and CCNYL1). Higher expression of these two genes was associated with the risk genotype, suggesting enhanced Wnt signalling as a possible disease mechanism for thyroid athyreosis and ectopy, consistent with recent data in a zebrafish model [1].
This first GWAS on two homogenous cohorts of patients with thyroid dysgenesis suggests a new genetic pathological mechanism for thyroid dysgenesis, extending current knowledge on the molecular basis of congenital hypothyroidism.
Reference: 1. Enhanced Canonical Wnt Signaling During Early Zebrafish Development Perturbs the Interaction of Cardiac Mesoderm and Pharyngeal Endoderm and Causes Thyroid Specification Defects. Vandernoot I, Haerlingen B, Gillotay P, Trubiroha A, Janssens V, Opitz R, Costagliola S. Thyroid. 2021 Mar;31(3):420–438. doi: 10.1089/thy.2019.0828. Epub 2020 Sep 16. PMID: 32777984.
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ESPE Yearbook of Paediatric Endocrinology
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