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.

中文翻译：

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澳大利亚青少年甲状腺功能的全基因组分析强调 SERPINA7 和 NCOA3

客观的

尽管环境因素与遗传因素的确切贡献仍不确定，但遗传因素支撑了甲状腺功能狭窄的个体差异。我们试图阐明甲状腺功能性状和甲状腺过氧化物酶抗体 (TPOAb) 阳性的遗传力，并确定导致性状变异的单核苷酸多态性 (SNP)。

方法

来自布里斯班纵向双胞胎研究 (BLTS) 的 2854 名甲状腺功能正常、双卵和单卵双胞胎（年龄范围 11.9-16.9 岁）的促甲状腺激素 (TSH)、游离 T4 (fT4)、游离 T3 (fT3) 和 TPOAb 的遗传力) 使用结构方程模型进行评估。对这些个体中的 2832 人进行了全基因组分析，涉及 7 522 526 个 SNP 以及基于基因的关联分析。在 Raine 研究 ( n = 1115)中对关联结果进行了重复分析， 然后进行了荟萃分析，以最大限度地提高发现能力。

结果

BLTS 中甲状腺功能参数的遗传力为：TSH 为 70.8%（95% CI：66.7-74.9%），fT4 为 67.5%（59.8-75.3%），fT3 为 59.7%（54.4-65.0%）和 48.8%（40.6 –56.9%) 用于 TPOAb。发现队列中的全基因组关联研究 (GWAS) 确定了NCOA3上游 rs2026401和 TPOAb 之间的新关联。GWAS 荟萃分析发现 TPOAb 和 rs445219 之间的关联，也在NCOA3附近，以及 fT3 和 rs12687280 在SERPINA7附近。基于基因的关联分析突出了 fT3 的 SERPINA7 和fT4的NPAS3。

结论

我们的研究结果解决了以前关于甲状腺功能特征和 TPOAb 阳性的遗传力估计的争论。GWAS 和基于基因的关联分析确定了占这种遗传力组成部分的变体。