@article{ff395ba99ca94f79a57f36588a403096,
title = "Polygenic Risk Score of Adolescent Idiopathic Scoliosis for Potential Clinical Use",
abstract = "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 × 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 × 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 × 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 × 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.",
keywords = "HUMAN ASSOCIATION STUDIES, ORTHOPEDICS, SKELETAL MUSCLE, STATISTICAL METHODS",
author = "Nao Otomo and Lu, \{Hsing Fang\} and Masaru Koido and Ikuyo Kou and Kazuki Takeda and Yukihide Momozawa and Michiaki Kubo and Yoichiro Kamatani and Yoji Ogura and Yohei Takahashi and Masahiro Nakajima and Shohei Minami and Koki Uno and Noriaki Kawakami and Manabu Ito and Tatsuya Sato and Kei Watanabe and Takashi Kaito and Haruhisa Yanagida and Hiroshi Taneichi and Katsumi Harimaya and Yuki Taniguchi and Hideki Shigematsu and Takahiro Iida and Satoru Demura and Ryo Sugawara and Nobuyuki Fujita and Mitsuru Yagi and Eijiro Okada and Naobumi Hosogane and Katsuki Kono and Masaya Nakamura and Kazuhiro Chiba and Toshiaki Kotani and Tsuyoshi Sakuma and Tsutomu Akazawa and Teppei Suzuki and Kotaro Nishida and Kenichiro Kakutani and Taichi Tsuji and Hideki Sudo and Akira Iwata and Kazuo Kaneko and Satoshi Inami and Yuta Kochi and Chang, \{Wei Chiao\} and Morio Matsumoto and Kota Watanabe and Shiro Ikegawa and Chikashi Terao",
note = "Funding Information: We thank all participating subjects and clinical staff at collaborating institutes. We also thank Yoshie Takahashi, Tomomi Oguma, Tomoko Kusadokoro, Hirodhi Takuwa, and Hiroyuki Suetsugu for technical assistance; Kenichi Sasada and Yoshiyuki Yukawa for statistical analysis assistance; and Rebecca Carlson for English editing. All genomic DNA from patients were examined after obtaining informed consent. The Medical Ethics Committee of the Keio University Hospital, Tokyo, approved the study protocol (20080129). We have obtained written informed consent for publication of clinical details of the patients. This work was supported by JSPS KAKENHI (grant no. 16H05453 to MM and no. 18H02931 to IK) and by RIKEN-MOST (to W-CC and SI). H-FL is supported by RIKEN IPA. Authors? roles: CT, SIk, W-CC, and KoW supervised the project. NO and CT designed the project and provided overall project management. NO, H-FL, and CT drafted the manuscript. YM and MKu performed the genotyping for the GWAS. CT, NO, H-FL, YKa, YKo, and MKo analyzed the GWAS data and performed integrative analyses. MNakajima and IK contributed to preparing the manuscript. NO, KT, YO, YoT, SM, NK, KU, MI, KeW, TKa, HY, HT, KH, YuT, TKo, TT, TSato, KKaneko, HSu, AI, SIn, TSakuma, NF, MY, MNakamura, KC, KKo, TSu, TA, KN, KKakutani, HShi, TI, SD, RS, NH, EO, MM, and KoW collected and managed clinical data. Funding Information: All genomic DNA from patients were examined after obtaining informed consent. The Medical Ethics Committee of the Keio University Hospital, Tokyo, approved the study protocol (20080129). We have obtained written informed consent for publication of clinical details of the patients. This work was supported by JSPS KAKENHI (grant no. 16H05453 to MM and no. 18H02931 to IK) and by RIKEN‐MOST (to W‐CC and SI). H‐FL is supported by RIKEN IPA. Publisher Copyright: {\textcopyright} 2021 American Society for Bone and Mineral Research (ASBMR).",
year = "2021",
month = aug,
doi = "10.1002/jbmr.4324",
language = "English",
volume = "36",
pages = "1481--1491",
journal = "Journal of Bone and Mineral Research",
issn = "0884-0431",
publisher = "Oxford University Press",
number = "8",
}
