TY - JOUR
T1 - Polygenic Risk Score of Adolescent Idiopathic Scoliosis for Potential Clinical Use
AU - Otomo, Nao
AU - Lu, Hsing Fang
AU - Koido, Masaru
AU - Kou, Ikuyo
AU - Takeda, Kazuki
AU - Momozawa, Yukihide
AU - Kubo, Michiaki
AU - Kamatani, Yoichiro
AU - Ogura, Yoji
AU - Takahashi, Yohei
AU - Nakajima, Masahiro
AU - Minami, Shohei
AU - Uno, Koki
AU - Kawakami, Noriaki
AU - Ito, Manabu
AU - Sato, Tatsuya
AU - Watanabe, Kei
AU - Kaito, Takashi
AU - Yanagida, Haruhisa
AU - Taneichi, Hiroshi
AU - Harimaya, Katsumi
AU - Taniguchi, Yuki
AU - Shigematsu, Hideki
AU - Iida, Takahiro
AU - Demura, Satoru
AU - Sugawara, Ryo
AU - Fujita, Nobuyuki
AU - Yagi, Mitsuru
AU - Okada, Eijiro
AU - Hosogane, Naobumi
AU - Kono, Katsuki
AU - Nakamura, Masaya
AU - Chiba, Kazuhiro
AU - Kotani, Toshiaki
AU - Sakuma, Tsuyoshi
AU - Akazawa, Tsutomu
AU - Suzuki, Teppei
AU - Nishida, Kotaro
AU - Kakutani, Kenichiro
AU - Tsuji, Taichi
AU - Sudo, Hideki
AU - Iwata, Akira
AU - Kaneko, Kazuo
AU - Inami, Satoshi
AU - Kochi, Yuta
AU - Chang, Wei Chiao
AU - Matsumoto, Morio
AU - Watanabe, Kota
AU - Ikegawa, Shiro
AU - Terao, Chikashi
N1 - 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:
© 2021 American Society for Bone and Mineral Research (ASBMR).
PY - 2021/8
Y1 - 2021/8
N2 - 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.
AB - 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.
KW - HUMAN ASSOCIATION STUDIES
KW - ORTHOPEDICS
KW - SKELETAL MUSCLE
KW - STATISTICAL METHODS
UR - http://www.scopus.com/inward/record.url?scp=85108251842&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85108251842&partnerID=8YFLogxK
U2 - 10.1002/jbmr.4324
DO - 10.1002/jbmr.4324
M3 - Article
C2 - 34159637
AN - SCOPUS:85108251842
SN - 0884-0431
VL - 36
SP - 1481
EP - 1491
JO - Journal of Bone and Mineral Research
JF - Journal of Bone and Mineral Research
IS - 8
ER -
