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

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journal contribution
posted on 2023-05-21, 05:28 authored by Nolan, J, Campbell, PJ, Brown, SJ, Zhu, G, Gordon, S, Lim, EM, Joseph, J, Cross, S, Panicker, V, Medland, SE, Phillip MeltonPhillip Melton, Beilin, LJ, Mori, TA, Mullin, B, Pennell, C, Wang, C, Dudbridge, F, Walsh, JP, Martin, NG, Wilson, SG

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 11.9–16.9 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: 66.7–74.9%) for TSH, 67.5% (59.8–75.3%) for fT4, 59.7% (54.4–65.0%) for fT3 and 48.8% (40.6–56.9%) 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.

History

Publication title

European Journal of Endocrinology

Volume

185

Issue

5

Pagination

743-753

ISSN

0804-4643

Department/School

Menzies Institute for Medical Research

Publisher

Bio Scientifica Ltd

Place of publication

Euro House, 22 Apex Court Woodlands, Bradley Stoke, Bristol, England, Bs324Jt

Rights statement

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

Repository Status

  • Open

Socio-economic Objectives

Public health (excl. specific population health) not elsewhere classified

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    University Of Tasmania

    Categories

    Keywords

    thyroidadolescenceSERINA7NCOA3GWAS

    Licence

    In Copyright

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