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

James Nolan, Purdey J Campbell, Suzanne J Brown, Gu Zhu, Scott Gordon, Ee Mun Lim, John Joseph, Simone Cross, Vijay Panicker, Sarah E Medland, Phillip Melton, Lawrence J Beilin, Trevor A Mori, Benjamin Mullin, Craig Pennell, Carol Wang, Frank Dudbridge, John P Walsh, Nicholas G Martin, Scott G Wilson

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)
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Abstract

Objective Genetic factors underpin the narrow intraindividual variability of thyroid function, although precise contributions of environmental versus 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 single nucleotide polymorphisms 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.

Original languageEnglish
Pages (from-to)743-753
Number of pages11
JournalEuropean Journal of Endocrinology
Volume185
Issue number5
DOIs
Publication statusPublished - Nov 2021

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