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Genome-wide analysis of thyroid function in Australian adolescents highlights SERPINA7 and NCOA3

Citation

Nolan, J and Campbell, PJ and Brown, SJ and Zhu, G and Gordon, S and Lim, EM and Joseph, J and Cross, S and Panicker, V and Medland, SE and Melton, P and Beilin, LJ and Mori, TA and Mullin, B and Pennell, C and Wang, C and Dudbridge, F and Walsh, JP and Martin, NG and Wilson, SG, Genome-wide analysis of thyroid function in Australian adolescents highlights SERPINA7 and NCOA3, European Journal of Endocrinology, 185, (5) pp. 743-753. ISSN 0804-4643 (2021) [Refereed Article]


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Copyright Statement

Copyright: European Society of Endocrinology 2021The definitive version is now available at https://doi.org/10.1530/EJE-21-0614

DOI: doi:10.1530/EJE-21-0614

Abstract

Objective

Genetic factors underpin the narrow intraindividual variability of thyroid function, although precise contributions of environmental vs genetic factors remain uncertain. We sought to clarify the heritability of thyroid function traits and thyroid peroxidase antibody (TPOAb) positivity and identify single nucleotide polymorphisms (SNPs) contributing to the trait variance.

Methods

Heritability of thyroid-stimulating hormone (TSH), free T4 (fT4), free T3 (fT3) and TPOAb in a cohort of 2854 euthyroid, dizygous and monozygous twins (age range 11.916.9 years) from the Brisbane Longitudinal Twin Study (BLTS) was assessed using structural equation modelling. A genome-wide analysis was conducted on 2832 of these individuals across 7 522 526 SNPs as well as gene-based association analyses. Replication analysis of the association results was performed in the Raine Study (n = 1115) followed by meta-analysis to maximise power for discovery.

Results

Heritability of thyroid function parameters in the BLTS was 70.8% (95% CI: 66.774.9%) for TSH, 67.5% (59.875.3%) for fT4, 59.7% (54.465.0%) for fT3 and 48.8% (40.656.9%) for TPOAb. The genome-wide association study (GWAS) in the discovery cohort identified a novel association between rs2026401 upstream of NCOA3 and TPOAb. GWAS meta-analysis found associations between TPOAb and rs445219, also near NCOA3, and fT3 and rs12687280 near SERPINA7. Gene-based association analysis highlighted SERPINA7 for fT3 and NPAS3 for fT4.

Conclusion

Our findings resolve former contention regarding heritability estimates of thyroid function traits and TPOAb positivity. GWAS and gene-based association analysis identified variants accounting for a component of this heritability.

Item Details

Item Type:Refereed Article
Keywords:thyroid, adolescence, SERINA7, NCOA3, GWAS
Research Division:Biomedical and Clinical Sciences
Research Group:Clinical sciences
Research Field:Endocrinology
Objective Division:Health
Objective Group:Public health (excl. specific population health)
Objective Field:Public health (excl. specific population health) not elsewhere classified
UTAS Author:Melton, P (Dr Phillip Melton)
ID Code:148679
Year Published:2021
Web of Science® Times Cited:1
Deposited By:Menzies Institute for Medical Research
Deposited On:2022-02-02
Last Modified:2022-03-01
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