PUBLICATION
GWAS of thyroid dysgenesis identifies a risk locus at 2q33.3 linked to regulation of Wnt signaling
- Authors
- Narumi, S., Opitz, R., Nagasaki, K., Muroya, K., Asakura, Y., Adachi, M., Abe, K., Sugisawa, C., Kühnen, P., Ishii, T., Nöthen, M.M., Krude, H., Hasegawa, T.
- ID
- ZDB-PUB-220511-6
- Date
- 2022
- Source
- Human molecular genetics 31(23): 3967-3974 (Journal)
- Registered Authors
- Ishii, Tomohiro, Opitz, Robert
- Keywords
- Congenital Hypothyroidism Thyroid Dysgenesis Genome-Wide Association Study Wnt Signaling Pathway
- MeSH Terms
-
- Animals
- Genetic Predisposition to Disease
- Genome-Wide Association Study*
- Humans
- Rare Diseases
- Thyroid Dysgenesis*/genetics
- Wnt Signaling Pathway/genetics
- Zebrafish/genetics
- PubMed
- 35535691 Full text @ Hum. Mol. Genet.
Citation
Narumi, S., Opitz, R., Nagasaki, K., Muroya, K., Asakura, Y., Adachi, M., Abe, K., Sugisawa, C., Kühnen, P., Ishii, T., Nöthen, M.M., Krude, H., Hasegawa, T. (2022) GWAS of thyroid dysgenesis identifies a risk locus at 2q33.3 linked to regulation of Wnt signaling. Human molecular genetics. 31(23):3967-3974.
Abstract
Congenital hypothyroidism due to thyroid dysgenesis (TD), presented as thyroid aplasia, hypoplasia or ectopia, is one of the most prevalent rare diseases with an isolated organ malformation. The pathogenesis of TD is largely unknown, although a genetic predisposition has been suggested. We performed a genome-wide association study (GWAS) with 142 Japanese TD cases and 8380 controls, and found a significant locus at 2q33.3 (top SNP, rs9789446: P = 4.4 × 10-12), which was replicated in a German patient cohort (P = 0.0056). A subgroup analysis showed that rs9789446 confers a risk for thyroid aplasia (per allele odds ratio = 3.17) and ectopia (3.12) but not for hypoplasia. Comprehensive epigenomic characterization of the 72-kb disease-associated region revealed that it was enriched for active enhancer signatures in human thyroid. Analysis of chromosome conformation capture data showed long-range chromatin interactions of this region with promoters of two genes, FZD5 and CCNYL, mediating Wnt signaling. Moreover, the finding that rs9789446 is a thyroid-specific expression quantitative trait loci, adding further evidence for a cis-regulatory function of this region in thyroid tissue. Specifically, because the risk rs9789446 allele is associated with increased thyroidal expression of FDZ5 and CCNYL1 and given the recent demonstration of perturbed early thyroid development following over-activation of Wnt signaling in zebrafish embryos, an enhanced Wnt signaling in risk allele carriers provide a biologically plausible TD mechanism. In conclusion, our work found the first risk locus for TD, exemplifying that in rare diseases with relatively low biological complexity, GWAS may provide mechanistic insights even with a small sample size.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping