PDF(Pubmed)
Abstract：
UNASSIGNED: Thyroid hormones have systemic effects on the human body and play a key role in the development and function of virtually all tissues. They are regulated via the hypothalamic-pituitary-thyroid (HPT) axis and have a heritable component. Using genetic information, we applied tissue-specific transcriptome-wide association studies (TWAS) and plasma proteome-wide association studies (PWAS) to elucidate gene products related to thyrotropin (TSH) and free thyroxine (FT4) levels.
UNASSIGNED: TWAS identified 297 and 113 transcripts associated with TSH and FT4 levels, respectively (25 shared), including transcripts not identified by genome-wide association studies (GWAS) of these traits, demonstrating the increased power of this approach. Testing for genetic colocalization revealed a shared genetic basis of 158 transcripts with TSH and 45 transcripts with FT4, including independent, FT4-associated genetic signals within the CAPZB locus that were differentially associated with CAPZB expression in different tissues. PWAS identified 18 and ten proteins associated with TSH and FT4, respectively (HEXIM1 and QSOX2 with both). Among these, the cognate genes of five TSH- and 7 FT4-associated proteins mapped outside significant GWAS loci. Colocalization was observed for five plasma proteins each with TSH and FT4. There were ten TSH and one FT4-related gene(s) significant in both TWAS and PWAS. Of these, ANXA5 expression and plasma annexin A5 levels were inversely associated with TSH (PWAS: P = 1.18 × 10-13, TWAS: P = 7.61 × 10-12 (whole blood), P = 6.40 × 10-13 (hypothalamus), P = 1.57 × 10-15 (pituitary), P = 4.27 × 10-15 (thyroid)), supported by colocalizations.
UNASSIGNED: Our analyses revealed new thyroid function-associated genes and prioritized candidates in known GWAS loci, contributing to a better understanding of transcriptional regulation and protein levels relevant to thyroid function.
UNASSIGNED: TWAS identified 297 and 113 transcripts associated with TSH and FT4 levels, respectively (25 shared), including transcripts not identified by genome-wide association studies (GWAS) of these traits, demonstrating the increased power of this approach. Testing for genetic colocalization revealed a shared genetic basis of 158 transcripts with TSH and 45 transcripts with FT4, including independent, FT4-associated genetic signals within the CAPZB locus that were differentially associated with CAPZB expression in different tissues. PWAS identified 18 and ten proteins associated with TSH and FT4, respectively (HEXIM1 and QSOX2 with both). Among these, the cognate genes of five TSH- and 7 FT4-associated proteins mapped outside significant GWAS loci. Colocalization was observed for five plasma proteins each with TSH and FT4. There were ten TSH and one FT4-related gene(s) significant in both TWAS and PWAS. Of these, ANXA5 expression and plasma annexin A5 levels were inversely associated with TSH (PWAS: P = 1.18 × 10-13, TWAS: P = 7.61 × 10-12 (whole blood), P = 6.40 × 10-13 (hypothalamus), P = 1.57 × 10-15 (pituitary), P = 4.27 × 10-15 (thyroid)), supported by colocalizations.
UNASSIGNED: Our analyses revealed new thyroid function-associated genes and prioritized candidates in known GWAS loci, contributing to a better understanding of transcriptional regulation and protein levels relevant to thyroid function.
摘要：
简介甲状腺激素对人体具有系统性作用，并在几乎所有组织的发育和功能中起关键作用。它们通过下丘脑-垂体-甲状腺（HPT）轴调节，并具有可遗传成分。利用遗传信息，我们应用了组织特异性全转录组关联研究(TWAS)和血浆全蛋白质组关联研究(PWAS)来阐明与促甲状腺激素(TSH)和游离甲状腺素(FT4)水平相关的基因产物.结果TWAS鉴定出297和113个与TSH和FT4水平相关的转录本，分别（25个共享），包括这些性状的全基因组关联研究（GWAS）未鉴定的转录本，展示了这种方法的强大力量。遗传共定位检测揭示了158个TSH转录本和45个FT4转录本的共同遗传基础，包括独立的，CAPZB基因座内的FT4相关遗传信号与不同组织中的CAPZB表达差异相关。PWAS鉴定出18种和10种分别与TSH和FT4相关的蛋白质(HEXIM1和QSOX2两者)。其中,5个TSH-和7个FT4相关蛋白的同源基因定位在重要的GWAS基因座之外。观察到5种血浆蛋白各自与TSH和FT4的共定位。在TWAS和PWAS中均存在10个TSH和1个FT4相关基因。其中,ANXA5表达和血浆膜联蛋白A5水平与TSH呈负相关(PWAS:p=1.18×10-13,TWAS:p=7.61×10-12[全血],p=6.40×10-13[下丘脑]，p=1.57×10-15[垂体]，p=4.27×10-15[甲状腺])，由共同定位支持。结论我们的分析揭示了新的甲状腺功能相关基因和已知GWAS位点的优先候选基因。有助于更好地理解与甲状腺功能相关的转录调控和蛋白质水平。
