Genome-wide Association Analysis in Humans Links Nucleotide Metabolism to Leukocyte Telomere Length
Genome-wide Association Analysis in Humans Links Nucleotide Metabolism to Leukocyte Telomere Length
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DOI：
10.1016/j.ajhg.2020.02.006
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发表时间：
2020-03-05
影响因子：
9.8
通讯作者：
Codd, Veryan
中科院分区：
文献类型：
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作者：
Li, Chen;Stoma, Svetlana;Codd, Veryan
白细胞端粒长度（LTL）是基因组衰老的可遗传生物标志物。在这项研究中，我们通过汇集大规模欧洲后裔研究（包括78,592个个体）的密集基因分型和估算关联结果，对LTL进行了全基因组荟萃分析。我们确定了49个错误发现率(FDR) < 0.05阈值的基因组区域，并对31个基因进行了优先排序，其中5个突出核苷酸代谢是LTL的重要调节因子。我们报告了SENP7、MOB1B、CARMIL1、PRRC2A、TERF2和RFWD3中或附近的6个全基因组重要位点，我们的结果支持最近发现的PARP1、POT1、ATM和MPHOSPH6位点。对英国生物银行（UK Biobank） 35万名参与者的全表型分析表明，基因端粒长度较短会增加甲状腺功能减退的风险，并降低甲状腺癌、淋巴瘤和一系列增生性疾病的风险。我们的研究结果重复了先前报道的与冠状动脉疾病风险增加和多种癌症类型风险降低的关联。我们的研究结果大大扩展了目前关于调节LTL的基因及其对人类健康和疾病影响的知识。
Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) < 0.05 threshold and prioritize genes at 31, with five highlighting nucleotide metabolism as an important regulator of LTL. We report six genome-wide significant loci in or near SENP7, MOB1B, CARMIL1 , PRRC2A, TERF2, and RFWD3, and our results support recently identified PARP1, POT1, ATM, and MPHOSPH6 loci. Phenome-wide analyses in >350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease.