Wade Alisha N, Guare Lindsay, Hayat Mahtaab, Straub Peter, Gao Ziyue, Medici Marco, Teumer Alexander, Davis Lea K, Ramsay Michèle, Ritchie Marylyn D, BioBank Penn Medicine, Cappola Anne R
Research in Metabolism and Endocrinology, Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
MRC/Wits Rural Public Health and Health Transitions Research Unit, School of Public Health, University of the Witwatersrand, Johannesburg, South Africa.
Thyroid. 2025 Feb;35(2):131-142. doi: 10.1089/thy.2024.0525. Epub 2025 Jan 27.
Epidemiological data suggest the population distribution of thyrotropin (TSH) values is shifted toward lower values in self-identified Black non-Hispanic individuals compared with self-identified White non-Hispanic individuals. It is unknown whether genetic differences between individuals with genetic similarities to African reference populations (GSA) and those with similarities to European reference populations (GSE) contribute to these observed differences. We aimed to compare genome-wide associations with TSH and putative causal TSH-associated variants between GSA and GSE groups. We performed genome-wide association studies (GWAS) in 9827 GSA individuals and 9827 GSE individuals with TSH values between 0.45 and 4.5 mU/L. We compared effect sizes and allele frequencies of previously reported putative causal TSH-associated variants and our power to detect associations with these variants between the two groups. We additionally focused on variants in and , loci that have been most strongly associated with TSH in previous GWAS in GSE populations. Four loci attained genome-wide significance in the GSA group compared with seven in the GSE group. was not significantly associated with TSH in the GSA group, despite its strong association in the GSE group. Eight putative causal variants had significantly different effect sizes between groups. There was ≥80% power in the GSA group to detect significant associations with variants in , , , and , with higher expected power than in the GSE group for variants in , , and and similar power for other variants in and No additional putative causal variants in and had effect sizes that differed significantly between the groups; power to identify associations with additional putative causal variants in and was similar between the groups. Patterns of genetic associations with TSH differed between identically sized GSA and GSE groups. Failure to replicate the strongest associations previously reported in GSE individuals in our GSA population was not fully explained by differences in allele frequencies or power, assuming similar effect sizes. Larger GSA population GWAS are necessary to confirm our findings and further investigate the contribution of genetic factors to population differences in the distribution of TSH values.
流行病学数据表明，与自我认定的非西班牙裔白人个体相比，自我认定的非西班牙裔黑人个体中促甲状腺激素（TSH）值的人群分布向更低值偏移。与非洲参考人群（GSA）基因相似的个体和与欧洲参考人群（GSE）基因相似的个体之间的基因差异是否导致了这些观察到的差异尚不清楚。我们旨在比较GSA组和GSE组之间全基因组与TSH的关联以及假定的因果TSH相关变体。我们对9827名TSH值在0.45至4.5 mU/L之间的GSA个体和9827名GSE个体进行了全基因组关联研究（GWAS）。我们比较了先前报道的假定因果TSH相关变体的效应大小和等位基因频率，以及我们检测两组之间与这些变体关联的能力。我们还重点关注了在GSE人群先前的GWAS中与TSH关联最强烈的和位点的变体。与GSE组的7个位点相比，GSA组有4个位点达到全基因组显著性。尽管在GSE组中与TSH有很强的关联，但在GSA组中与TSH没有显著关联。8个假定的因果变体在两组之间有显著不同的效应大小。GSA组有≥80%的能力检测与、、和位点变体的显著关联，对于、和位点的变体，其预期能力高于GSE组，对于和位点的其他变体，能力相似。和位点没有其他假定的因果变体在两组之间有显著不同的效应大小；识别与和位点其他假定因果变体关联的能力在两组之间相似。在大小相同的GSA组和GSE组中，与TSH的基因关联模式不同。假设效应大小相似，在我们的GSA人群中未能重复先前在GSE个体中报道的最强关联，不能完全用等位基因频率或能力的差异来解释。需要更大规模的GSA人群GWAS来证实我们的发现，并进一步研究遗传因素对TSH值分布人群差异的贡献。
