Department of Endocrinology & Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.
QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Eur J Endocrinol. 2021 Oct 11;185(5):743-753. doi: 10.1530/EJE-21-0614.
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.
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.
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.
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.
遗传因素是甲状腺功能个体内变异性小的基础，但环境因素和遗传因素的确切贡献仍不确定。我们试图阐明甲状腺功能特征和甲状腺过氧化物酶抗体（TPOAb）阳性的遗传性，并确定导致特征变异的单核苷酸多态性（SNP）。
采用结构方程模型评估来自布里斯班纵向双胞胎研究（BLTS）的 2854 名甲状腺功能正常、二卵双胞胎和单卵双胞胎（年龄 11.9-16.9 岁）队列中促甲状腺激素（TSH）、游离 T4（fT4）、游离 T3（fT3）和 TPOAb 的遗传率。对其中 2832 名个体的 7522526 个 SNP 进行全基因组分析，并进行基于基因的关联分析。对 Raine 研究（n=1115）中的关联结果进行复制分析，然后进行荟萃分析以最大限度地提高发现的功效。
BLTS 中甲状腺功能参数的遗传率为 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%），TPOAb 为 48.8%（40.6-56.9%）。在发现队列中的全基因组关联研究（GWAS）中，发现 NCOA3 上游的 rs2026401 与 TPOAb 之间存在新的关联。GWAS 荟萃分析发现 TPOAb 与 NCOA3 附近的 rs445219 以及 fT3 与 SERPINA7 附近的 rs12687280 之间存在关联。基于基因的关联分析突出了 SERPINA7 与 fT3 和 NPAS3 与 fT4 之间的关系。
我们的研究结果解决了关于甲状腺功能特征和 TPOAb 阳性遗传率的争议。GWAS 和基于基因的关联分析确定了导致这一遗传率的一部分的变体。
