Polygenic Risk Score of Adolescent Idiopathic Scoliosis for Potential Clinical Use
Polygenic Risk Score of Adolescent Idiopathic Scoliosis for Potential Clinical Use
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DOI：
10.1002/jbmr.4324
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发表时间：
2021-06-22
影响因子：
6.2
通讯作者：
Terao, Chikashi
中科院分区：
文献类型：
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作者：
Otomo, Nao;Lu, Hsing-Fang;Terao, Chikashi
青少年特发性脊柱侧凸（AIS）是一种常见的疾病，导致多达3%的青少年脊柱三维畸形。开发一种能够准确预测AIS发作和进展的方法是临床实践的迫切需要。由于在双胞胎研究中AIS的遗传率估计高达87.5%，因此基于遗传数据预测其发病和进展是一个有希望的选择。我们显示了多基因风险评分（PRS）预测AIS发病和进展的有用性。我们使用了AIS全基因组关联研究（GWAS）数据，包括三个队列中的79，211名受试者，并基于包括31，999名女性受试者的发现集中的关联统计量构建了PRS。在使用验证数据集进行校准后，我们将PRS应用于测试数据集。通过整合显示变异选择中遗传性富集的功能注释，PRS证明了与AIS易感性的相关性（p = 3.5 x 10（-40），受试者操作特征下面积[AUROC] = 0.674，灵敏度= 0.644，特异性= 0.622）。PRS最高的十分位数与十分位数中的第五位数相比，发展AIS的优势比高达3.36（p = 1.4 x 10（-10））。增加仅具有单一临床参数（体重指数）的预测模型改善了AIS发展的预测能力（AUROC = 0.722，净重新分类改善[NRI] 0.505 +/- 0.054，p = 1.6 x 10（-8）），增强了预测模型的临床应用。此外，我们发现Cobb角（CA），AIS的严重程度测量，是一个多基因性状，显示出与AIS易感性的显着遗传相关性（rg = 0.6，p = 3.0 x 10（-4））。AIS PRS与CA有显著相关性。这些结果表明AIS的发病和进展之间存在共享的多基因结构，PRS在临床环境中作为促进AIS早期干预和避免侵入性手术的预测因子的潜在有用性。(c)2021年美国骨与矿物质研究学会（ASBMR）。
Adolescent idiopathic scoliosis (AIS) is a common disease causing three-dimensional spinal deformity in as many as 3% of adolescents. Development of a method that can accurately predict the onset and progression of AIS is an immediate need for clinical practice. Because the heritability of AIS is estimated as high as 87.5% in twin studies, prediction of its onset and progression based on genetic data is a promising option. We show the usefulness of polygenic risk score (PRS) for the prediction of onset and progression of AIS. We used AIS genomewide association study (GWAS) data comprising 79,211 subjects in three cohorts and constructed a PRS based on association statistics in a discovery set including 31,999 female subjects. After calibration using a validation data set, we applied the PRS to a test data set. By integrating functional annotations showing heritability enrichment in the selection of variants, the PRS demonstrated an association with AIS susceptibility (p = 3.5 x 10(-40) with area under the receiver-operating characteristic [AUROC] = 0.674, sensitivity = 0.644, and specificity = 0.622). The decile with the highest PRS showed an odds ratio of as high as 3.36 (p = 1.4 x 10(-10)) to develop AIS compared with the fifth in decile. The addition of a predictive model with only a single clinical parameter (body mass index) improved predictive ability for development of AIS (AUROC = 0.722, net reclassification improvement [NRI] 0.505 +/- 0.054, p = 1.6 x 10(-8)), potentiating clinical use of the prediction model. Furthermore, we found the Cobb angle (CA), the severity measurement of AIS, to be a polygenic trait that showed a significant genetic correlation with AIS susceptibility (rg = 0.6, p = 3.0 x 10(-4)). The AIS PRS demonstrated a significant association with CA. These results indicate a shared polygenic architecture between onset and progression of AIS and the potential usefulness of PRS in clinical settings as a predictor to promote early intervention of AIS and avoid invasive surgery. (c) 2021 American Society for Bone and Mineral Research (ASBMR).