Research Publications on Idiopathic Scoliosis


The Canadian Scoliosis Screening Coalition


Contact us at: CSSC@scoliosiscanada.ca          Added May 5, 2025. Revised July 7, 30 Aug 1, 3, 25, 27 2025

Research Publications on Adolescent Idiopathic Scoliosis:

The following is a curated list of links to international research publications on AIS in chronological order. The list below represents just a small fraction of published studies with a bias towards biomedical genetic studies. School screening also contributes towards epidemeological research studies and it is reflected in the quantity of publications. Click here for links to recent research publications on technological advances in "Developing and Recent Digital Screening & Monitoring AIS Tools" .

  1. Dupuis F, Ng PTT, Duncombe P, van den Hoorn W, Izatt MT, Labrom RD, Tucker K. Asymmetry in the Onset of Paraspinal Muscles Activity Differs in Adolescents With Idiopathic Scoliosis Compared With Those With a Symmetrical Spine. Clin Orthop Relat Res. 2025 Jun 1;483(6):1112-1121. doi: 10.1097/CORR.0000000000003364. Epub 2025 Jan 7. PMID: 39774429; PMCID: PMC12106240."...Conclusion: Erector spinae muscle activation is asymmetrical at the T9/apex vertebral level during a rapid bilateral arm raise task. This asymmetry was opposite between the AIS and control cohorts, with left-side activation delayed in AIS. Clinical relevance: It is well established in conditions such as cerebral palsy that muscles forces can influence bone development in children. In children with AIS, there is growing evidence of asymmetrical paraspinal muscle size, composition, and activation amplitude. Each of these factors contribute to paraspinal muscle force generation. Our findings add to what we know by identifying an asymmetry in the timing of erector spinae activation during a well-controlled, bilateral movement task. Combined with previous research, these results support further investigation into whether asymmetrical paraspinal muscle forces might contribute to the curve progression and asymmetrical bony development in AIS. This is important as muscle forces are modifiable through targeted rehabilitation..."
  2. Welborn, Michelle C. MD*; Samdani, Amer F. MD†; Szczodry, Michal MD‡; Gupta, Purnendu MD‡; Stone, Joseph MD§; Coghlan, Ryan MS*; Bouton, Daniel MD*; Cho, Robert H. MD∥; Poon, Selina MD∥; Talwalkar, Vishwas R. MD¶; Sanders, James O. MD§; Sienko, Susan PhD*. Biomarker Longitudinal Idiopathic Scoliosis Study: Predicting Growth in Idiopathic Scoliosis. Journal of Pediatric Orthopaedics ():10.1097/BPO.0000000000003022, June 19, 2025. | DOI: 10.1097/BPO.0000000000003022 "...Growth has been theorized as one of the main risk factors for idiopathic scoliosis (IS) progression. Determining the amount and timing of growth is surprisingly challenging. Radiographic measures of skeletal maturity do not provide insight into the amount that individuals will grow. In addition, anthropometrics do not differentiate between early versus late growers. Biological measures have historically been nonspecific for growth, however, Collagen X Biomarker (CXM) is a direct measure of endochondral ossification and longitudinal bone growth. ...this study found that absolute height was the best measure of growth in adolescents with IS who are braced and CXM is the best measure of growth potential. Further study using advanced analytics will determine whether CXM in combination with other radiographic measures provides enhanced information from which to make clinical decisions regarding bracing and surgical intervention."
  3. ***Khatami N, Caraus I, Rahaman M, Nepotchatykh E, Elbakry M, Elremaly W, Franco A, Beauséjour M, Laberge AM, Parent S, Labelle H, Aubin CÉ, Lachaine J, Moreau A. Genome-wide profiling of circulating microRNAs in adolescent idiopathic scoliosis and their relation to spinal deformity severity, and disease pathophysiology. Sci Rep. 2025 Feb 12;15(1):5305. doi: 10.1038/s41598-025-88985-3. PMID: 39939711; PMCID: PMC11822005. "Abstract: Adolescent Idiopathic Scoliosis (AIS) is the most common orthopedic condition requiring surgery, affecting 4% of adolescents. There is currently no proven method or prognostic test to identify symptomatic patients at risk of developing severe scoliosis who could benefit from growth-guided devices or minimally invasive non-fusion instrumentation surgeries. These innovative treatments must be performed at an early disease stage in younger patients to benefit from their growth potential. In this prospective cross-sectional study, we investigated the clinical utility of circulating microRNAs (miRNAs), an important class of small non-coding RNA, as biomarkers to predict the risk of developing severe scoliosis in AIS. Blood samples and clinical data were collected from 116 AIS patients who were followed until skeletal maturity and stratified according to their clinical outcome. Genome-wide expression profiling of miRNAs was performed with plasma obtained at the time of diagnosis of AIS (mean age of 13.3 ± 1.7 years with a mean Cobb angle of 24.4° ± 12.4°). This approach led to the identification of 15 circulating miRNAs that are upregulated in AIS patients who developed a severe scoliosis (Cobb angle ≥ 45°) at skeletal maturity compared to moderate and mild scoliosis groups (Cobb angle between 25°-44° and < 25° respectively). After optimization and the application of Random Forest Models a panel of six miRNAs (miR-1-3p, miR-19a-3p, miR-19b-3p, miR-133b, miR-143-3p, and miR-148b-3p) out of 15 led us to develop an algorithm predicting the risk of developing a severe scoliosis with great accuracy (100%), sensitivity (100%) and specificity (100%). Having a scoliosis predictive bioassay and decision-making tools to predict curve progression in order to find the best treatment plan will undoubtedly transform the orthopedic care system in the field of pediatric scoliosis by integrating innovative precision medicine approaches. In addition, investigation of genes targeted by these miRNAs could fill our gaps in our understanding of AIS pathogenesis and reveal new actionable targets."
  4. Sheng K, Bisson DG, Saran N, Bourdages J, Coluni C, Upshaw K, Tiedemann K, Komarova SV, Ouellet JA, Haglund L. The TLR-M-CSF axis is implicated in increased bone turnover and curve progression in adolescent idiopathic scoliosis. Arthritis Res Ther. 2025 Mar 31;27(1):68. doi: 10.1186/s13075-025-03535-6. PMID: 40165259; PMCID: PMC11956469. “...Facet joint osteoarthritis (OA) is prevalent in patients with adolescent idiopathic scoliosis (AIS). The most pronounced OA presents above and below the curve's apex where the intervertebral rotation is the greatest. This indicates that facet joint OA is implicated and potentially contributes to AIS progression. OA impacts both cartilage and bone and we have previously demonstrated an association between lower bone quality and more severe OA in AIS facet joints...our findings suggest that the TLR-M-CSF axis is implicated in osteoclastogenesis, resulting in increased bone turnover and may contribute to curve progression in AIS patients. ...”
  5. Dai, Zhicheng PhDa,b; Min, Kaixing MSb; Wu, Zhichong PhDb; Xu, Leilei MDb; Feng, Zhenhua MSb; Qiu, Yong MDa,b; Zhu, Zezhang MDa,b. Genetic Variants Can Predict the Outcome of Brace Treatment in Patients With Adolescent Idiopathic Scoliosis. Spine 50(4):p 238-242, February 15, 2025. | DOI: 10.1097/BRS.0000000000005137 "....Results. A total of 259 female AIS patients were included in this study, 30.5% of the well-braced patients had curve progression exceeding 5° and 69.5% of the patients undergo an improvement or progression of <5°. Allele C of rs10738445 (BNC2) could significantly add to the risk of bracing failure, with odds ratio of 1.59. No significant association with bracing outcomes was found for rs12946942 (SOX9/KCNJ2), rs1978060 (TBX1), rs1017861 (CHD7), and rs35333564 (MIR4300HG)...SNP rs10738445 were significantly associated with brace treatment effectiveness..."
  6. Elbakry M, Khatami N, Akoume MY, Julien C, Bouhanik S, Franco A, Caraus I, Elremaly W, Moreau A. Loss of Tyrosine Phosphatase Mu Promotes Scoliosis Progression Through Osteopontin-α5β1 Integrin Signaling and PIPK1γ90 Activity. Int J Mol Sci. 2025 Jan 26;26(3):1042. doi: 10.3390/ijms26031042. PMID: 39940812; PMCID: PMC11816665. "...Whole-exome sequencing of a French-Canadian AIS cohort with severe scoliosis identified rare variants in the PTPRM gene, which encodes Protein Tyrosine Phosphatase μ (PTPµ). However, these rare variants alone did not account for the pronounced reduction in PTPµ at both mRNA and protein levels in severe AIS cases. This led us to investigate epigenetic regulators and the identification of five microRNAs (miR-103a-3p, miR-107, miR-148a-3p, miR-148b-3p, and miR-152-3p) that target PTPRM mRNA. These microRNAs were significantly elevated in plasma from severe AIS patients, and miR-148b-3p was also upregulated in AIS osteoblasts. Phenotypic analysis of bipedal Ptrprm knockout (PTPµ -/-) mice showed increased prevalence and severity of scoliosis, while quadrupedal PTPµ -/- mice did not develop scoliosis, underscoring PTPµ's role as a disease-modifying factor. Mechanistically, PTPµ deficiency was found to disrupt Gi-coupled receptor signaling in osteoblasts by enhancing the interaction between osteopontin (OPN) and α5β1 integrin, along with increased tyrosine phosphorylation of phosphatidylinositol-4-phosphate 5-kinase type I (PIPKIγ90). These findings provide novel insights into the molecular mechanisms underlying spinal deformity progression in AIS, linking PTPµ depletion to aberrant OPN-α5β1 integrin signaling and highlighting potential therapeutic targets to stop, mitigate, or prevent scoliosis...."
  7. Xie W, Wan WT, Liu SY, Wang JQ, Chen C, Sun X, Liu XY, Yang Q. Causal effects of the RANK-RANKL-OPG system and scoliosis: A bidirectional 2-sample Mendelian randomization study. Medicine (Baltimore). 2024 Dec 13;103(50):e40934. doi: 10.1097/MD.0000000000040934. PMID: 39686424; PMCID: PMC11651458."Abstract Epidemiological studies and a recent Mendelian randomization (MR) study have identified an association between low bone mass and an increased risk of scoliosis. Previous research suggests that bone loss in patients with scoliosis may be related to the RANK-RANKL-OPG system. This study is to investigate whether a causal relationship exists between the RANK-RANKL-OPG system and the development of scoliosis ... Our study employing MR methodology provides robust evidence supporting a causal relationship between decreased osteoprotegerin (OPG) levels and increased susceptibility to scoliosis. However, no significant relationship was found between scoliosis with the RANK-RANKL-OPG system. This research establishes a basis for further exploration of the pathophysiological mechanisms and potential targeted treatments for scoliosis. Future studies are necessary to understand how OPG influences the development of scoliosis.
  8. Wu, Zhichong et al. Genome-wide methylation association study in monozygotic twins discordant for curve severity of adolescent idiopathic scoliosis, The Spine Journal Volume 25, Issue 4, 785 – 796 November 6, 2024 "...Adolescent idiopathic scoliosis (AIS) is a complex trait with multiple tissues involved, such as muscles, bones, nervous system, and endocrine system [4]. In our study, we analyzed DNA methylation in whole blood as a proxy for systemic epigenetic changes that were associated with curve severity of AIS....While genetic factors predominantly determine the predispositions of the scoliosis initiation, environmental factors highly influenced the curve progression [5]. This is evidenced by discordant profiles of spine curvature among a notable proportion of genetically identical monozygotic twins with AIS [6]. Consequently, identification of specific molecular epigenetic signatures that reflect these environmental influences has become a prominent focus in current research..."
  9. Zhang S, Dai LN, Yin Q, Kang XP, Zeng DD, Jiang T, Zhao GY, Li XH, Li J. Dinucleotide composition representation -based deep learning to predict scoliosis-associated Fibrillin-1 genotypes. Front Genet. 2024 Oct 22;15:1492226. doi: 10.3389/fgene.2024.1492226. PMID: 39502335; PMCID: PMC11534654. "...The present study was designed to intelligently parse, decompose and predict AIS-related variants in ClinVar database. Possible AIS-related variant records downloaded from ClinVar were parsed for various labels, decomposed for Dinucleotide Compositional Representation (DCR) and other traits, screened for high-risk genes with statistical analysis, and then learned intelligently with deep learning to predict high-risk AIS genotypes....58,000 scoliosis-related records were automatically parsed and statistically analyzed for high-risk genes and genotypes, such as FBN1, LAMA2 and SPG11. All variant genes were decomposed for DCR and other traits...In summary, scoliosis risk is predictable by deep learning based on genomic decomposed features of DCR. DCR-based classifier has predicted more scoliosis risk FBN1 variants in ClinVar database..."
  10. Rao J, Qian S, Li X, Xu Y. Single nucleotide polymorphisms of estrogen receptors are risk factors for the progression of adolescent idiopathic scoliosis: a systematic review and meta-analyses. J Orthop Surg Res. 2024 Sep 28;19(1):605. doi: 10.1186/s13018-024-05102-2. Erratum in: J Orthop Surg Res. 2024 Oct 16;19(1):664. doi: 10.1186/s13018-024-05141-9. PMID: 39342385; PMCID: PMC11438150.
  11. Petrosyan E, Fares J, Ahuja CS, Lesniak MS, Koski TR, Dahdaleh NS, El Tecle NE. Genetics and pathogenesis of scoliosis. N Am Spine Soc J. 2024 Sep 6;20:100556. doi: 10.1016/j.xnsj.2024.100556. PMID: 39399722; PMCID: PMC11470263 "...This comprehensive review analyzes the literature on the etiopathogenetic evidence for both idiopathic and adult degenerative scoliosis. ..Results For idiopathic scoliosis, genetic factors are categorized into three groups: genes associated with susceptibility, disease progression, and both. We identify gene groups related to different biological processes and explore multifaceted pathogenesis of idiopathic scoliosis, including evolutionary adaptations to bipedalism and developmental and homeostatic spinal aberrations. For adult degenerative scoliosis, we segregate genetic and pathogenic evidence into categories of angiogenesis and inflammation, extracellular matrix degradation, neural associations, and hormonal influences. Finally, we compare findings in idiopathic scoliosis and adult degenerative scoliosis, discuss current limitations in scoliosis research, propose a new model for scoliosis etiopathogenesis, and highlight promising areas for future studies....Conclusions Scoliosis is a complex, multifaceted disease with largely enigmatic origins and mechanisms of progression, keeping it under continuous scientific scrutiny."
  12. Yang KG, Lee WY, Hung AL, Kumar A, Chui EC, Hung VW, Cheng JC, Lam TP, Lau AY. Distinguishing risk of curve progression in adolescent idiopathic scoliosis with bone microarchitecture phenotyping: a 6-year longitudinal study. J Bone Miner Res. 2024 Aug 5;39(7):956-966. doi: 10.1093/jbmr/zjae083. PMID: 38832703."Abstract:Low bone mineral density and impaired bone quality have been shown to be important prognostic factors for curve progression in adolescent idiopathic scoliosis (AIS). .. In conclusion, 3 distinct bone microarchitecture phenotypes could be clustered by unsupervised machine learning on HR-pQCT–generated bone parameters at peripubertal PHV in AIS. The bone quality reflected by these phenotypes was found to have significant differentiating risk of curve progression and progression to surgical threshold at skeletal maturity in AIS."
  13. Smit TH. On growth and scoliosis. Eur Spine J. 2024 Jun;33(6):2439-2450. doi: 10.1007/s00586-024-08276-9. Epub 2024 May 5. PMID: 38705903."... It has long been shown that the typical curvature and rotation of the scoliotic spine could result from vertebrae and intervertebral discs growing faster than the ligaments attached to them. ...The spine of an AIS patient deviates from healthy spines in various ways. Growth is later but faster, resulting in higher vertebrae and intervertebral discs. Vertebral bone density is lower, which suggests less spinal compression. ... AIS spines grow faster because there is less spinal compression that counteracts the force of growth (Hueter-Volkmann Law). Ligaments consist of collagen fibres that grow by tension, fibrillar sliding and the remodelling of cross-links. Growth and remodelling are enhanced by dynamic loading and by hormones like estrogen. However, they are opposed by static loading...Conclusion: Increased spinal elongation and reduced ligamental growth result in differential strain and a vicious circle of scoliotic deformation. Recognising the physical and biological cues that contribute to differential growth allows earlier diagnosis of AIS and prevention in children at risk."
  14. Soh RCC, Chen BZ, Hartono S, Lee MS, Lee W, Lim SL, Gan J, Maréchal B, Chan LL, Lo YL. The hindbrain and cortico-reticular pathway in adolescent idiopathic scoliosis. Clin Radiol. 2024 May;79(5):e759-e766. doi: 10.1016/j.crad.2024.01.027. Epub 2024 Feb 10. PMID: 38388254."...AIM To characterise the corticoreticular pathway (CRP) in a case–control cohort of adolescent idiopathic scoliosis (AIS) patients using high-resolution slice-accelerated readout-segmented echo-planar diffusion tensor imaging (DTI) ...RESULTS AIS patients demonstrated a significantly larger pons volume compared to controls (p=0.006)....CONCLUSION Relative pontine hypertrophy and asymmetry in CRP DTI metrics suggest central supranuclear inter-hemispheric imbalance in AIS, and support the role of the CRP in axial muscle tone. Longitudinal evaluation of CRP DTI metrics in the prediction of AIS progression may be clinically relevant."
  15. Yuan P, Wang ZH, Jiang H, Wang YH, Yang JY, Li LM, Wang WT, Chen J, Li DH, Long SY, Zhang W, He F, Wang WZ. Prevalence and plasma exosome-derive microRNA diagnostic biomarker screening of adolescent idiopathic scoliosis in Yunnan Province, China. Front Pediatr. 2024 Apr 24;12:1308931. doi: 10.3389/fped.2024.1308931. PMID: 38720947; PMCID: PMC11076730. ”...AIS develops faster during adolescence. Without early detection and intervention, as the degree of deformity worsens, low back pain, impaired cardiorespiratory function, and nerve damage or even paraplegia eventually occur, severely affecting the physical and mental health of children and adolescents...Therefore, early detection and intervention is the current consensus in the treatment of AIS. The diagnosis and screening of AIS primarily rely on the patient's clinical appearance and x-ray images. However, the United States Preventive Services Task Force and the American Academy of Family Physicians recommend against routine scoliosis screening for asymptomatic adolescents due to its low specificity, potentially subjecting many low-risk adolescents to unnecessary x-rays and referrals ...So, there is an urgent need to find new diagnostic markers for AIS to facilitate early screening for AIS. ...These exosome-derived miRNAs hold the potential to serve as molecular markers for diagnosing AIS and may be associated with the progression of the condition.”
  16. Normand É, Franco A, Parent S, Lombardi G, Brayda-Bruno M, Colombini A, Moreau A, Marcil V. Association between the GLP1R A316T Mutation and Adolescent Idiopathic Scoliosis in French Canadian and Italian Cohorts. Genes (Basel). 2024 Apr 11;15(4):481. doi: 10.3390/genes15040481. PMID: 38674415; PMCID: PMC11050147. “...To date, several genetic variants have been associated with AIS. The identified associated genes are involved in conjunctive tissue structures, growth and puberty, bone formation, metabolism, melatonin pathway, and ciliary functions...Our results support that the GLP1R A316T polymorphism is associated with a higher risk of developing AIS, but without being associated with disease severity and progression....”
  17. *Ushiki A, Sheng RR, Zhang Y, Zhao J, Nobuhara M, Murray E, Ruan X, Rios JJ, Wise CA, Ahituv N. Deletion of Pax1 scoliosis-associated regulatory elements leads to a female-biased tail abnormality. Cell Rep. 2024 Mar 26;43(3):113907. doi: 10.1016/j.celrep.2024.113907. Epub 2024 Mar 8. PMID: 38461417; PMCID: PMC11005513. "...A genome-wide association study identified a female-specific AIS susceptibility locus near the PAX1 gene. Here, we use mouse enhancer assays, three mouse enhancer knockouts, and subsequent phenotypic analyses to characterize this region. Using mouse enhancer assays, we characterize a sequence, PEC7, which overlaps the AIS-associated variant, and find it to be active in the tail tip and intervertebral disc. Removal of PEC7 or Xe1, a known sclerotome enhancer nearby, or deletion of both sequences lead to a kinky tail phenotype only in the Xe1 and combined (Xe1+PEC7) knockouts, with only the latter showing a female sex dimorphic phenotype. Extensive phenotypic characterization of these mouse lines implicates several differentially expressed genes and estrogen signaling in the sex dimorphic bias. In summary, our work functionally characterizes an AIS-associated locus and dissects the mechanism for its sexual dimorphism...."
  18. *Yu H, Khanshour AM, Ushiki A, Otomo N, Koike Y, Einarsdottir E, Fan Y, Antunes L, Kidane YH, Cornelia R, Sheng RR, Zhang Y, Pei J, Grishin NV, Evers BM, Cheung JPY, Herring JA, Terao C, Song YQ, Gurnett CA, Gerdhem P, Ikegawa S, Rios JJ, Ahituv N, Wise CA. Association of genetic variation in COL11A1 with adolescent idiopathic scoliosis. Elife. 2024 Jan 26;12:RP89762. doi: 10.7554/eLife.89762. PMID: 38277211; PMCID: PMC10945706."...We previously defined a female-specific AIS genetic risk locus in an enhancer near the PAX1 gene. Here, we sought to define the roles of PAX1 and newly identified AIS-associated genes in the developmental mechanism of AIS. ...AIS is known to be more prevalent in females, a bias that has not been explained. Advances in techniques to study the genetics underlying diseases have revealed that certain variations that increase the risk of AIS affect cartilage and connective tissue. In humans, one such variation is near a gene called Pax1, and it is female-specific. The extracellular matrix is a network of proteins and other molecules in the space between cells that help connect tissues together, and it is particularly important in cartilage and other connective tissues. ..The findings of Yu, Kanshour, Ushiki et al. highlight that cartilage cells in the spine are particularly relevant in AIS. The results also point to specific molecules within the extracellular matrix as important for maintaining proper alignment in the spine when children are growing rapidly. This information may guide future therapies aimed at maintaining healthy spinal cells in adolescent children, particularly girls..."
    eLife assessment "This valuable study analyzes a large cohort of Adolescent Idiopathic Scoliosis (AIS) patients, identifying an association with a variant in COL11A1 (Pro1335Leu). Experimental testing of this potentially pathogenic variant in vitro suggests a connection between Pax1, Col11a1, Mmp3, and estrogen signaling, thus providing solid support for the proposed link between hormonal and matrix components in the development of AIS." https://doi.org/10.7554/eLife.89762.4.sa0
  19. Wang X, Yue M, Cheung JPY, Cheung PWH, Fan Y, Wu M, Wang X, Zhao S, Khanshour AM, Rios JJ, Chen Z, Wang X, Tu W, Chan D, Yuan Q, Qin D, Qiu G, Wu Z, Zhang TJ, Ikegawa S, Wu N, Wise CA, Hu Y, Luk KDK, Song YQ, Gao B. Impaired glycine neurotransmission causes adolescent idiopathic scoliosis. J Clin Invest. 2024 Jan 16;134(2):e168783. doi: 10.1172/JCI168783. PMID: 37962965; PMCID: PMC10786698. “...The AIS patients exhibited increased plasma glycine levels and aberrant paraspinal muscle activities....Our results indicate a neuropathic origin for "idiopathic" scoliosis, involving the dysfunction of synaptic neurotransmission and central pattern generators (CPGs), potentially a common cause of AIS.”
  20. Jiang X, Liu F, Zhang M, Hu W, Zhao Y, Xia B, Xu K. Advances in genetic factors of adolescent idiopathic scoliosis: a bibliometric analysis. Front Pediatr. 2024 Jan 3;11:1301137. doi: 10.3389/fped.2023.1301137. PMID: 38322243; PMCID: PMC10845672. "...A cumulative number of 308 articles have been ascertained. Since 2006, publications relating to genetic factors of AIS have significantly increased. China leads in both productivity and influence in this area, with the Chinese Academy of Medical Sciences being the most productive institution. The most prolific scholars in this field are Y. Qiu and Z. Z. Zhu. The publications that contributed the most were from Spine and European Spine Journal. The most prominent keywords in the genetic factors of AIS were “fibrillin gene”, “menarche”, “calmodulin”, “estrogen receptor gene”, “linkage analysis”, “disc degeneration”, “bone mineral density”, “melatonin signaling dysfunction”, “collagen gene”, “mesenchymal stem cell”, “LBX1”, “promoter polymorphism”, “Bone formation”, “cerebrospinal fluid flow” and “extracellular matrix”. 40 countries have published articles on AIS genetic factors. China was involved in the publication of most articles (50.3%), followed by the United States (25%), Canada (9.4%), Japan (8.8%) and the United Kingdom (4.2%)..."
  21. Roggio F, Trovato B, Sortino M, Onesta MP, Petrigna L, Musumeci G. The Role of Muscle Biomarkers in Adolescent Idiopathic Scoliosis. Journal of Clinical Medicine. 2023; 12(24):7616. https://doi.org/10.3390/jcm12247616 “...Research in this field has tried to delineate the genetic factors behind scoliosis and its association with heredity since AIS is considered a polygenic disease and has different genetic and epigenetic factors. The current study conducted a narrative review of the literature, focusing on biomarkers in the pathophysiology of muscle in AIS patients..”
  22. Tang H, Li J, Li JK, He SH, Xiang G, Rong R, Liang ZT, Zhang HQ. BMP6 participates in the pathogenesis of adolescent idiopathic scoliosis by regulating osteopenia. J Cell Physiol. 2023 Nov;238(11):2586-2599. doi: 10.1002/jcp.31111. Epub 2023 Oct 5. PMID: 37795636. "Adolescent idiopathic scoliosis (AIS) is a complex disease characterized by three-dimensional structural deformities of the spine. Its pathogenesis is associated with osteopenia. Bone-marrow-derived mesenchymal stem cells (BMSCs) play an important role in bone metabolism. We detected 1919 differentially expressed mRNAs and 744 differentially expressed lncRNAs in BMSCs from seven patients with AIS and five patients without AIS via high-throughput sequencing. Multiple analyses identified bone morphogenetic protein-6 (BMP6) as a hub gene that regulates the abnormal osteogenic differentiation of BMSCs in AIS...."
  23. Li MJ, Liang ZT, Sun Y, Li J, Zhang HQ, Deng A. Research progress on the regulation of bone marrow stem cells by noncoding RNAs in adolescent idiopathic scoliosis. J Cell Physiol. 2023 Oct;238(10):2228-2242. doi: 10.1002/jcp.31119. Epub 2023 Sep 8. PMID: 37682901."...Adolescent idiopathic scoliosis (AIS) is a common spinal deformity in young women, but its pathogenesis remains unclear. The primary pathogenic factors contributing to its development include genetics, abnormal bone metabolism, and endocrine factors. Bone marrow stem cells (BMSCs) play a crucial role in the pathogenesis of AIS by regulating its occurrence and progression. Noncoding RNAs (ncRNAs) are also involved in the pathogenesis of AIS, and their role in regulating BMSCs in patients with AIS requires further evaluation. ..."
  24. Zhang H, Yang G, Li J, Xiao L, Guo C, Wang Y. Impaired autophagy activity-induced abnormal differentiation of bone marrow stem cells is related to adolescent idiopathic scoliosis osteopenia. Chin Med J (Engl). 2023 Sep 5;136(17):2077-2085. doi: 10.1097/CM9.0000000000002165. PMID: 36728938; PMCID: PMC10476821. "Osteopenia has been well documented in adolescent idiopathic scoliosis (AIS)...Background..Bone marrow stem cells (BMSCs) are a crucial regulator of bone homeostasis. Our previous study revealed a decreased osteogenic ability of BMSCs in AIS-related osteopenia, but the underlying mechanism of this phenomenon remains unclear..."
  25. Danielewicz A, Wójciak M, Sowa I, Kusz M, Wessely-Szponder J, Dresler S, Latalski M. Metabolic Imbalances and Bone Remodeling Agents in Adolescent Idiopathic Scoliosis: A Study in Postmenarcheal Girls. Int J Mol Sci. 2023 Aug 27;24(17):13286. doi: 10.3390/ijms241713286. PMID: 37686090; PMCID: PMC10487495. "... Conclusions Our study demonstrated that the phosphate–calcium balance and the PTH level appear to be normal in AIS patients. However, we observed decreased serum levels of 25-OH-D and increased levels of FGF23 and PINP in the girls with AIS compared to the healthy girls. A deficiency of vitamin D can lead to a decrease in the absorption of calcium. In turn, an increased level of FGF23 can result in greater urinary excretion of phosphate and reduced phosphate reabsorption. Disruptions in these factors can contribute to decreased bone mineralization. Higher levels of P1NP indicates increased bone formation and turnover. Our study may suggest the involvement of these factors in AIS progression, although further studies are required to elucidate the underlying mechanisms of idiopathic scoliosis."
  26. Otomo N, Khanshour AM, Koido M, Takeda K, Momozawa Y, Kubo M, Kamatani Y, Herring JA, Ogura Y, Takahashi Y, Minami S, Uno K, Kawakami N, Ito M, Sato T, Watanabe K, Kaito T, Yanagida H, Taneichi H, Harimaya K, Taniguchi Y, Shigematsu H, Iida T, Demura S, Sugawara R, Fujita N, Yagi M, Okada E, Hosogane N, Kono K, Nakamura M, Chiba K, Kotani T, Sakuma T, Akazawa T, Suzuki T, Nishida K, Kakutani K, Tsuji T, Sudo H, Iwata A, Inami S, Wise CA, Kochi Y, Matsumoto M, Ikegawa S, Watanabe K, Terao C. Evidence of causality of low body mass index on risk of adolescent idiopathic scoliosis: a Mendelian randomization study. Front Endocrinol (Lausanne). 2023 Jun 20;14:1089414. doi: 10.3389/fendo.2023.1089414. PMID: 37415668; PMCID: PMC10319580. "...Since AIS is a disease caused by multiple factors, it is important to recognize that low BMI is one of the factors affecting the onset of AIS....Conclusions This is a first study conducting MR analysis between AIS and BMI. We showed the possibility that genetically low BMI has a causal effect on onset of AIS. This result was consistent with those of epidemiological study and would contribute the early detection of AIS...."
  27. Shao X, Fu X, Yang J, Sui W, Li S, Yang W, Lin X, Zhang Y, Jia M, Liu H, Liu W, Han L, Yu Y, Deng Y, Zhang T, Yang J, Hu P. The asymmetrical ESR1 signaling in muscle progenitor cells determines the progression of adolescent idiopathic scoliosis. Cell Discov. 2023 Apr 25;9(1):44. doi: 10.1038/s41421-023-00531-5. PMID: 37185898; PMCID: PMC10130095."... Adolescent Idiopathic Scoliosis (AIS) is a common pediatric skeletal disease highly occurred in females. The pathogenesis of AIS has not been fully elucidated. Here, we reveal that ESR1 (Estrogen Receptor 1) expression declines in muscle stem/progenitor cells at the concave side of AIS patients. Furthermore, ESR1 is required for muscle stem/progenitor cell differentiation and disrupted ESR1 signaling leads to differentiation defects. The imbalance of ESR1 signaling in the para-spinal muscles induces scoliosis in mice, while reactivation of ESR1 signaling at the concave side by an FDA approved drug Raloxifene alleviates the curve progression. This work reveals that the asymmetric inactivation of ESR1 signaling is one of the causes of AIS. Reactivation of ESR1 signaling in para-spinal muscle by Raloxifene at the concave side could be a new strategy to treat AIS...."
  28. Wu Z, Zhu X, Xu L, Liu Z, Feng Z, Hung VWY, Cheng JCY, Qiu Y, Lee WYW, Lam TP, et al. More Prevalent and Severe Low Bone-Mineral Density in Boys with Severe Adolescent Idiopathic Scoliosis Than Girls: A Retrospective Study of 798 Surgical Patients. Journal of Clinical Medicine. 2023; 12(8):2991. https://doi.org/10.3390/jcm12082991 "...The present large cohort of surgical AIS patients revealed that low BMD is more prevalent and severe in boys than in girls with severe curves. Low BMD may serve as a more valuable predictive factor for curve progression to the surgical threshold in boys than girls with AIS...."
  29. Lin M-R, Chou P-H, Huang K-J, Ting J, Liu C-Y, Chou W-H, Lin G-H, Chang J-G, Ikegawa S, Wang S-T, et al. Whole-Exome Sequencing Identifies Genetic Variants for Severe Adolescent Idiopathic Scoliosis in a Taiwanese Population. Journal of Personalized Medicine. 2023; 13(1):32. https://doi.org/10.3390/jpm13010032 "...In this study, we performed whole-exome sequencing on 11 unrelated Taiwanese patients with a Cobb’s angle greater than 40 degrees. Our results identified more than 200 potential pathogenic rare variants, however, most of which were carried only by one individual. By in silico pathogenicity annotation studies, we found that TTN, CLCN1, and SOX8 were the most important genes, as multiple pathogenic variants were within these genes. Furthermore, biological functional annotation indicated critical roles of these AIS candidate genes in the skeletal muscle. Importantly, a pathogenic variant on SOX8 was shared by over 35% of the patients. These results highlighted TTN, CLCN1, and SOX8 as the most likely susceptibility genes for severe AIS...."
  30. Normand E, Franco A, Alos N, Parent S, Moreau A, Marcil V. Circulatory Adipokines and Incretins in Adolescent Idiopathic Scoliosis: A Pilot Study. Children (Basel). 2022 Oct 25;9(11):1619. doi: 10.3390/children9111619. PMID: 36360347; PMCID: PMC9688531."Abstract...Energy metabolism discrepancies, including alterations in adipokine and incretin circulatory levels, could influence these parameters and contribute to disease pathophysiology. This pilot study aims to compare the anthropometry, BMD, and metabolic profile of 19 AIS girls to 19 age-matched healthy controls..."
  31. Xie H, Li M, Kang Y, Zhang J, Zhao C. Zebrafish: an important model for understanding scoliosis. Cell Mol Life Sci. 2022 Sep 4;79(9):506. doi: 10.1007/s00018-022-04534-5. PMID: 36059018; PMCID: PMC9441191.
  32. ***Zloof Y, Ankory R, Braun AE, Braun M, Abuhasira S, Schwartz N, Yaari D, Glassberg E, Shlaifer A. The Hereditary Nature of Adolescent Spinal Deformities: A Study of Over 600,000 Adolescents. Spine (Phila Pa 1976). 2022 Jun 15;47(12):841-846. doi: 10.1097/BRS.0000000000004355. Epub 2022 Apr 21. PMID: 35472202. “...Results... the odds ratios (OR) for ASD among adolescents whose father, mother, or both parents had spinal deformity were 1.46, 1.74, and 2.58, respectively... Conclusion: We have found a considerable increased risk for adolescent spinal deformities among adolescents whose parents suffered from spinal deformities. We believe that our findings should serve the leading medical organizations when considering the screening of targeted populations....”(Note: this study may also aide in genetic counselling for AIS for prospective parents with scoliosis.)
  33. Marya S, Tambe AD, Millner PA, Tsirikos AI. Adolescent idiopathic scoliosis : a review of aetiological theories of a multifactorial disease. Bone Joint J. 2022 Aug;104-B(8):915-921. doi: 10.1302/0301-620X.104B8.BJJ-2021-1638.R1. PMID: 35909373. "...It has been hypothesized that genetic variants act as the initial trigger that allow epigenetic factors to propagate AIS, which could also explain the wide phenotypic variation in the presentation of the disorder. A better understanding of the underlying aetiological mechanisms could help to establish the diagnosis earlier and allow a more accurate prediction of deformity progression..."
  34. Faldini, C.; Manzetti, M.; Neri, S.; Barile, F.; Viroli, G.; Geraci, G.; Ursini, F.; Ruffilli, A.(2022). Epigenetic and Genetic Factors Related to Curve Progression in Adolescent Idiopathic Scoliosis: A Systematic Scoping Review of the Current Literature. International Journal of Molecular Sciences, 23(11), 5914. https://doi.org/10.3390/ijms23115914 "...The aim of this study is to review the available literature regarding the epigenetic and genetic factors associated with the risk of AIS curve progression....Forty studies were included; fifteen genes were reported as having SNPs with significant association with progressive AIS, but none showed sufficient power to sustain clinical applications. In contrast, nine studies reporting epigenetic modifications showed promising results in terms of reliable markers. Prognostic testing for AIS has the potential to significantly modify disease management. Most recent evidence suggests epigenetics as a more promising field for the identification of factors associated with AIS progression, offering a rationale for further investigation in this field."
  35. Kotwicki T, Tomaszewski M, Andrusiewicz M, Śliwa A, Rusin B, Kotwicka M. Estrogen Receptor Type 1 and Type 2 Presence in Paravertebral Skeletal Muscles: Expression Level and Relation to Phenotype in Children with Idiopathic Scoliosis. Genes (Basel). 2022 Apr 22;13(5):739. doi: 10.3390/genes13050739. PMID: 35627124; PMCID: PMC9141030."....The study aimed to detect the presence and assess the expression levels of the estrogen receptors type 1 (ESR1) and type 2 (ESR2) within paravertebral skeletal muscles of female patients with idiopathic scoliosis (IS) ...Conclusions: Two types of estrogen receptors are present in the deep paravertebral muscles of patients with idiopathic scoliosis. Their expression was found to be asymmetrical around the apex of the principal scoliosis curvature. The expression asymmetry was revealed to be related to the magnitude of the scoliotic deformity as well as to scoliotic deformity progression. These findings may contribute to understanding the etiopathogenesis of IS in children..."
  36. Oliazadeh N, Gorman KF, Elbakry M, Moreau A. Altered mechanotransduction in adolescent idiopathic scoliosis osteoblasts: an exploratory in vitro study. Sci Rep. 2022 Feb 3;12(1):1846. doi: 10.1038/s41598-022-05918-0. PMID: 35115632; PMCID: PMC8813918.
  37. Liang ZT, Guo CF, Li J, Zhang HQ. The role of endocrine hormones in the pathogenesis of adolescent idiopathic scoliosis. FASEB J. 2021 Sep;35(9):e21839. doi: 10.1096/fj.202100759R. PMID: 34387890. ”Abstract: Adolescent idiopathic scoliosis (AIS) is a common spinal deformity characterized by changes in the three-dimensional structure of the spine. It usually initiates during puberty, the peak period of human growth when the secretion of numerous hormones is changing, and it is more common in females than in males. ...Accumulating evidence shows that the abnormal levels of many hormones including estrogen, melatonin, growth hormone, leptin, adiponectin and ghrelin, may be related to the occurrence and development of AIS. The purpose of this review is to provide a summary and critique of the research published on each hormone over the past 20 years, and to highlight areas for future study...”
  38. Gargano G, Oliva F, Migliorini F, Maffulli N. Melatonin and adolescent idiopathic scoliosis: The present evidence. Surgeon. 2022 Dec;20(6):e315-e321. doi: 10.1016/j.surge.2021.07.008. Epub 2021 Sep 3. PMID: 34489192.
  39. Montemurro N, Ricciardi L, Scerrati A, Ippolito G, Lofrese G, Trungu S, Stoccoro A. The Potential Role of Dysregulated miRNAs in Adolescent Idiopathic Scoliosis and 22q11.2 Deletion Syndrome. J Pers Med. 2022 Nov 18;12(11):1925. doi: 10.3390/jpm12111925. PMID: 36422101; PMCID: PMC9695868."...Background: Adolescent idiopathic scoliosis (AIS), affecting 2–4% of adolescents, is a multifactorial spinal disease. Interactions between genetic and environmental factors can influence disease onset through epigenetic mechanisms, including DNA methylation, histone modifications and miRNA expression...."
  40. Herdea A, Dragomirescu MC, Ulici A, Lungu CN, Charkaoui A. Controlling the Progression of Curvature in Children and Adolescent Idiopathic Scoliosis Following the Administration of Melatonin, Calcium, and Vitamin D. Children (Basel). 2022 May 21;9(5):758. doi: 10.3390/children9050758. PMID: 35626935; PMCID: PMC9140159."Abstract...In this perspective, randomized, case-control, interventional study, the impact of using melatonin, calcium, and vitamin D, respectively, on idiopathic scoliosis patients was analyzed. Our preliminary results showed that these drugs positively affected the illness progression quantified by the spine curvature. Patients with idiopathic scoliosis may benefit from a novel treatment by supplementation with vitamin D, calcium, and melatonin....The treatment of childhood and adolescent idiopathic scoliosis follows the guidelines based on Cobb angle and other factors such as age, gender, or menarche status for girls. The staging of treatment includes physiotherapy, wearing a brace, and surgery for advanced cases. None of these steps takes into account the possible existence of a metabolic factor that aggravates the evolution of the disease...."
  41. Tang, N. L., Dobbs, M. B., Gurnett, C. A., Qiu, Y., Lam, T. P., Cheng, J. C., & Hadley-Miller, N. (2021) A Decade in Review after Idiopathic Scoliosis Was First Called a Complex Trait—A Tribute to the Late Dr. Yves Cotrel for His Support in Studies of Etiology of Scoliosis Genes, 12(7), 1033."...In 1999, Dr. Yves Cotrel founded the Cotrel Foundation in the Institut de France, which supported collaboration of international researchers to work together to better understand the etiology of AIS. This new concept of AIS as a complex trait evolved in this setting among researchers who joined the annual Cotrel meetings.... In 2007, Dr. Cotrel and team listed 10 potential categories of underlying causes of scoliosis. It was a key mission of the Cotrel Foundation to find out the primary etiology of adolescent idiopathic scoliosis (AIS). They include genetics, biomechanics, neurology, Oto-Rhino-laryngology, molecular biology, endocrinology, neurophysiology, biochemistry, sensory physiology, and anatomical pathology ...For an early intervention to become available and effective, patients need to be identified early...early diagnosis is also required to evaluate the effectiveness of any early intervention. Hong Kong is among the few regions in the World that practice universal scoliosis screening of school children. Screening enables detection of early patients with milder curves, whereas hospital cases are usually biased toward severe cases so that a comprehensive, full-spectrum understanding of the epidemiology of AIS is possible. In addition, patients with mild curves could be studied so that risk factors for curve progression can be analyzed. The recent advance in low-dose radiation imaging instruments allows accurate and close monitoring of curve progression which was not possible before..."
  42. Carry PM, Terhune EA, Trahan GD, Vanderlinden LA, Wethey CI, Ebrahimi P, McGuigan F, Åkesson K, Hadley-Miller N. Severity of Idiopathic Scoliosis Is Associated with Differential Methylation: An Epigenome-Wide Association Study of Monozygotic Twins with Idiopathic Scoliosis. Genes (Basel). 2021 Jul 30;12(8):1191. doi: 10.3390/genes12081191. PMID: 34440365; PMCID: PMC8391702. "...Epigenetic mechanisms may contribute to idiopathic scoliosis (IS). We identified 8 monozygotic twin pairs with IS, 6 discordant (Cobb angle difference > 10°) and 2 concordant (Cobb angle difference ≤ 2°).Genome-wide methylation in blood was measured with the Infinium HumanMethylation EPIC Beadchip. We tested for differences in methylation and methylation variability between discordant twins and tested the association between methylation and curve severity in all twins. Differentially methylated region (DMR) analyses identified gene promoter regions. ...Among DMRs, 21 were correlated with bone methylation. Prioritization of regions based on methylation concordance in bone identified promoter regions for WNT10A (WNT signaling), NPY (regulator of bone and energy homeostasis), and others predicted to be relevant for bone formation/remodeling. These regions may aid in understanding the complex interplay between genetics, environment, and IS. ....
  43. Mathieu H, Spataru A, Aragon-Martin JA, Child A, Barchi S, Fortin C, Parent S, Moldovan F. Prevalence of POC5 Coding Variants in French-Canadian and British AIS Cohort. Genes (Basel). 2021 Jul 1;12(7):1032. doi: 10.3390/genes12071032. PMID: 34356048; PMCID: PMC8306370. " ...1. Introduction... it is now widely accepted that this disorder has a genetic component, as supported by family history, and higher concordance rates for monozygotic twins compared to dizygotic twins [5,6,7]. Approximatively 40% of AIS patients have a family history. The genetic model for AIS remains unclear; indeed, several studies have suggested that it is a polygenic and multifactorial disease [9]. However, other analyses suggest mendelian inheritance, such as autosomal dominant or sex-related, could show with incomplete penetrance [10,11,12]. Since the advent of next-generation sequencing, candidate-gene analysis using pedigrees and population-based genome-wide association studies (GWAS) have been widely used to assess the genetic etiology of AIS. Despite all these efforts, only a few of the candidate genes have been functionally linked to the development of AIS..."
  44. Beauséjour M, Vaillancourt F, Akoume MY, Franco A, Parent S, Labelle H, Joncas J, Desbiens-Blais F, Mac-Thiong JM, Roy-Beaudry M, Aubin CÉ, Moreau A. Patient outcomes in idiopathic scoliosis are associated with biological endophenotypes: 2020 SOSORT award winner. Eur Spine J. 2021 May;30(5):1125-1131. doi: 10.1007/s00586-020-06579-1. Epub 2020 Aug 29. PMID: 32860536."...Conclusion: Associations between biological endophenotypes and outcomes suggest differences in progression and/or bracing response among IS patients. Outcomes were most favorable in FG3 patients. The results pave the way for establishing personalized treatments, distinguishing who may benefit or not from treatment."
  45. Makki N, Zhao J, Liu Z, Eckalbar WL, Ushiki A, Khanshour AM, Wu J, Rios J, Gray RS, Wise CA, Ahituv N. Genomic characterization of the adolescent idiopathic scoliosis-associated transcriptome and regulome. Hum Mol Genet. 2021 Jan 21;29(22):3606-3615. doi: 10.1093/hmg/ddaa242. PMID: 33179741; PMCID: PMC7823110."...we set out to define the expression of AIS-associated genes and active regulatory elements by performing RNA-seq and chromatin immunoprecipitation-sequencing against H3 lysine 27 acetylation in these tissues in mouse and human. Our study highlights genetic pathways involving AIS-associated loci that regulate chondrogenesis, IVD development and connective tissue maintenance and homeostasis. In addition, we identify thousands of putative AIS-associated regulatory elements which may orchestrate tissue-specific expression in musculoskeletal tissues of the spine. Quantification of enhancer activity of several candidate regulatory elements from our study identifies three functional enhancers carrying AIS-associated GWAS SNPs at the ADGRG6 and BNC2 loci. Our findings provide a novel genome-wide catalog of AIS-relevant genes and regulatory elements and aid in the identification of novel targets for AIS causality and treatment..."
  46. Wang Y, Zhang H, Yang G, Xiao L, Li J, Guo C. Dysregulated Bone Metabolism Is Related to High Expression of miR-151a-3p in Severe Adolescent Idiopathic Scoliosis. Biomed Res Int. 2020 Sep 26;2020:4243015. doi: 10.1155/2020/4243015. PMID: 33029507; PMCID: PMC7537684.
  47. Rose CD, Pompili D, Henke K, Van Gennip JLM, Meyer-Miner A, Rana R, Gobron S, Harris MP, Nitz M, Ciruna B. SCO-Spondin Defects and Neuroinflammation Are Conserved Mechanisms Driving Spinal Deformity across Genetic Models of Idiopathic Scoliosis. Curr Biol. 2020 Jun 22;30(12):2363-2373.e6. doi: 10.1016/j.cub.2020.04.020. Epub 2020 May 7. PMID: 32386528.
  48. Janusz P, Chmielewska M, Andrusiewicz M, Kotwicka M, Kotwicki T. Methylation of Estrogen Receptor 1 Gene in the Paraspinal Muscles of Girls with Idiopathic Scoliosis and Its Association with Disease Severity. Genes (Basel). 2021 May 21;12(6):790. doi: 10.3390/genes12060790. PMID: 34064195; PMCID: PMC8224318. "Idiopathic scoliosis (IS) is a multifactorial disease with epigenetic modifications.
  49. Bisson DG, Sheng K, Kocabas S, Krock E, Teles A, Saran N, Ouellet JA, Haglund L. Toll-like receptor involvement in adolescent scoliotic facet joint degeneration. J Cell Mol Med. 2020 Oct;24(19):11355-11365. doi: 10.1111/jcmm.15733. Epub 2020 Aug 27. PMID: 32853438; PMCID: PMC7576299.
  50. Wise CA, Sepich D, Ushiki A, Khanshour AM, Kidane YH, Makki N, Gurnett CA, Gray RS, Rios JJ, Ahituv N, Solnica-Krezel L. The cartilage matrisome in adolescent idiopathic scoliosis. Bone Res. 2020 Mar 9;8:13. doi: 10.1038/s41413-020-0089-0. PMID: 32195011; PMCID: PMC7062733. "...Identifying patients with a high likelihood of curve progression is a top priority of AIS clinical management....
  51. Li J, Li N, Chen Y, Hui S, Fan J, Ye B, Fan Z, Zhang J, Zhao RC, Zhuang Q. SPRY4 is responsible for pathogenesis of adolescent idiopathic scoliosis by contributing to osteogenic differentiation and melatonin response of bone marrow-derived mesenchymal stem cells. Cell Death Dis. 2019 Oct 23;10(11):805. doi: 10.1038/s41419-019-1949-7. PMID: 31645544; PMCID: PMC6811559.
  52. Zaydman AM, Strokova EL, O Stepanova A, Laktionov PP, Shevchenko AI, Subbotin VM. A New Look at Causal Factors of Idiopathic Scoliosis: Altered Expression of Genes Controlling Chondroitin Sulfate Sulfation and Corresponding Changes in Protein Synthesis in Vertebral Body Growth Plates. Int J Med Sci. 2019 Jan 1;16(2):221-230. doi: 10.7150/ijms.29312. PMID: 30745802; PMCID: PMC6367535.
  53. Khanshour AM, Kou I, Fan Y, Einarsdottir E, Makki N, Kidane YH, Kere J, Grauers A, Johnson TA, Paria N, Patel C, Singhania R, Kamiya N, Takeda K, Otomo N, Watanabe K, Luk KDK, Cheung KMC, Herring JA, Rios JJ, Ahituv N, Gerdhem P, Gurnett CA, Song YQ, Ikegawa S, Wise CA. Genome-wide meta-analysis and replication studies in multiple ethnicities identify novel adolescent idiopathic scoliosis susceptibility loci. Hum Mol Genet. 2018 Nov 15;27(22):3986-3998. doi: 10.1093/hmg/ddy306. PMID: 30395268; PMCID: PMC6488972.
  54. Baschal EE, Terhune EA, Wethey CI, Baschal RM, Robinson KD, Cuevas MT, Pradhan S, Sutphin BS, Taylor MRG, Gowan K, Pearson CG, Niswander LA, Jones KL, Miller NH. Idiopathic Scoliosis Families Highlight Actin-Based and Microtubule-Based Cellular Projections and Extracellular Matrix in Disease Etiology. G3 (Bethesda). 2018 Jul 31;8(8):2663-2672. doi: 10.1534/g3.118.200290. PMID: 29930198; PMCID: PMC6071588. “...Idiopathic scoliosis (IS) is a structural lateral spinal curvature of ≥10° that affects up to 3% of otherwise healthy children and can lead to life-long problems in severe cases. It is well-established that IS is a genetic disorder. Previous studies have identified genes that may contribute to the IS phenotype, but the overall genetic etiology of IS is not well understood. We used exome sequencing to study five multigenerational families with IS....Across the five families, we identified a total of 270 variants with predicted functional consequences in 246 genes, and found that eight genes were shared by two families...Our results suggest that there are multiple paths to IS and provide a foundation for future studies of IS pathogenesis...” (Note, IS is another reference used for AIS)
  55. G Bisson D, Lama P, Abduljabbar F, Rosenzweig DH, Saran N, Ouellet JA, Haglund L. Facet joint degeneration in adolescent idiopathic scoliosis. JOR Spine. 2018 May 24;1(2):e1016. doi: 10.1002/jsp2.1016. PMID: 31463443; PMCID: PMC6686828. “... Facet joint degeneration in adolescent idiopathic scoliosis. JOR Spine. 2018 May 24;1(2):e1016. doi: 10.1002/jsp2.1016. PMID: 31463443; PMCID: PMC6686828. “...AIS facet joint cartilage shows hallmarks of OA including proteoglycan loss, overexpression of pro-inflammatory mediators, increased synthesis of matrix-degrading proteases and fragmentation of SLRPs. As with patients with age-related OA, the premature joint degeneration seen in scoliotic patients is likely to contribute to the pain perceived in some individuals....”
  56. Ogura Y, Takeda K, Kou I, Khanshour A, Grauers A, Zhou H, Liu G, Fan YH, Zhou T, Wu Z, Takahashi Y, Matsumoto M; Japan Scoliosis Clinical Research Group (JSCRG); Texas Scottish Rite Hospital for Children Clinical Group (TSRHCCG); Einarsdottir E, Kere J, Huang D, Qiu G, Xu L, Qiu Y, Wise CA, Song YQ, Wu N, Su P, Gerdhem P, Watanabe K, Ikegawa S. An international meta-analysis confirms the association of BNC2 with adolescent idiopathic scoliosis. Sci Rep. 2018 Mar 16;8(1):4730. doi: 10.1038/s41598-018-22552-x. PMID: 29549362; PMCID: PMC5856832."...Discussion In the present study, we have performed a meta-analysis for the genetic association of rs3904778 with AIS using more than 36,000 subjects from eight independent multi-ethnic cohorts....The present study not only gave solid evidence of association of the locus in additional Chinese cohorts, but also revealed that it had significant association in Caucasian, suggesting the global significance of this AIS locus. Previous lack of association in Caucasian may be due to lack of power because the OR of this locus is about 1.2, suggesting relatively large sample size is optimal for identification...."
  57. Nada D, Julien C, Samuels ME, Moreau A. A Replication Study for Association of LBX1 Locus With Adolescent Idiopathic Scoliosis in French-Canadian Population. Spine (Phila Pa 1976). 2018 Feb 1;43(3):172-178. doi: 10.1097/BRS.0000000000002280. PMID: 28604496.
  58. Rudrapatna S, Peterson D, Missiuna P, Aditya I, Drew B, Sahar N, Thabane L, Samaan MC. Understanding muscle-immune interactions in adolescent idiopathic scoliosis: a feasibility study. Pilot Feasibility Stud. 2017 Dec 5;3:50. doi: 10.1186/s40814-017-0193-0. PMID: 29225911; PMCID: PMC5715623.
  59. Giampietro PF, Pourquie O, Raggio C, Ikegawa S, Turnpenny PD, Gray R, Dunwoodie SL, Gurnett CA, Alman B, Cheung K, Kusumi K, Hadley-Miller N, Wise CA. Summary of the first inaugural joint meeting of the International Consortium for scoliosis genetics and the International Consortium for vertebral anomalies and scoliosis, March 16-18, 2017, Dallas, Texas. Am J Med Genet A. 2018 Jan;176(1):253-256. doi: 10.1002/ajmg.a.38550. Epub 2017 Nov 21. PMID: 29159998; PMCID: PMC6525596. (now both combined and renamed the International Consortium for Spinal Genetics, Development and Disease ICSGDD
  60. Oliazadeh N, Gorman KF, Eveleigh R, Bourque G, Moreau A. Identification of Elongated Primary Cilia with Impaired Mechanotransduction in Idiopathic Scoliosis Patients. Sci Rep. 2017 Mar 14;7:44260. doi: 10.1038/srep44260. PMID: 28290481; PMCID: PMC5349607.
  61. Tsz Ping Lam 1, , Benjamin Hon Kei Yip 2, , Gene Chi Wai Man 1, , Wayne YW Lee 1, , Elisa Man Shan Tam 1, , Kwong Man Lee 1, , Fiona Wai Ping Yu 1, , Bobby Kin Wah Ng 1, & Jack Chun Yiu Cheng 1,Effective therapeutic control of curve progression using calcium and vitamin D supplementation for adolescent idiopathic scoliosis – a randomized double-blinded placebo-controlled trial Bone Abstracts (2017) 6 OC8 | DOI: 10.1530/boneabs.6.OC8 "...Conclusion: The results of this study provide strong evidences that calcium+Vit-D supplementation can improve bone strength in AIS. Its therapeutic effect on preventing curve progression is correlated with increase in FEA parameters, low baseline 25(OH)Vit-D level and low baseline dietary calcium intake.
  62. Balioglu MB, Aydin C, Kargin D, Albayrak A, Atici Y, Tas SK, Kaygusuz MA. Vitamin-D measurement in patients with adolescent idiopathic scoliosis. J Pediatr Orthop B. 2017 Jan;26(1):48-52. doi: 10.1097/BPB.0000000000000320. PMID: 27089048."...Vitamin-D levels were lower in the AIS group, with no sex-specific effects, indicative of a possible vitamin-D resistance in AIS. Vitamin-D levels correlated positively with Ca levels and negatively with Cobb’s angle, indicative of a possible role of vitamin D in the etiopathogenesis of AIS. Patients with AIS should be monitored for vitamin-D deficiency/insufficiency..."
  63. Silva RTE, Fernandes RJR, Ono AHA, Marcon RM, Cristante AF, Barros TEP Filho. ROLE OF DIFFERENT HORMONES IN THE PATHOGENESIS AND SEVERITY OF ADOLESCENT IDIOPATHIC SCOLIOSIS. Acta Ortop Bras. 2017 Jan-Feb;25(1):15-17. doi: 10.1590/1413-785220172501168600. PMID: 28642644; PMCID: PMC5474396.
  64. Simony A, Carreon LY, H Jmark K, Kyvik KO, Andersen MØ. Concordance Rates of Adolescent Idiopathic Scoliosis in a Danish Twin Population. Spine (Phila Pa 1976). 2016 Oct 1;41(19):1503-1507. doi: 10.1097/BRS.0000000000001681. PMID: 27163371.
  65. Haller G, Alvarado D, Mccall K, Yang P, Cruchaga C, Harms M, Goate A, Willing M, Morcuende JA, Baschal E, Miller NH, Wise C, Dobbs MB, Gurnett CA. A polygenic burden of rare variants across extracellular matrix genes among individuals with adolescent idiopathic scoliosis. Hum Mol Genet. 2016 Jan 1;25(1):202-9. doi: 10.1093/hmg/ddv463. Epub 2015 Nov 12. PMID: 26566670; PMCID: PMC4690498."Adolescent idiopathic scoliosis (AIS) is a complex inherited spinal deformity whose etiology has been elusive. ..In conclusion, genome-wide pathway burden analysis of exome sequence data identifies ECM genes as a major class of genes contributing to the polygenic inheritance of AIS. More specifically, novel coding variants in musculoskeletal collagen genes increase AIS risk by >2-fold with those in COL11A2 being most strongly associated. Importantly, while damaging mutations in collagen genes have been long known to cause Mendelian disorders, our study demonstrates a role for less damaging mutations in isolated AIS consistent with complex and polygenic inheritance..."
  66. Liu, Zhen PhD; Wang, Fei PhD; Xu, Lei-lei PhD; Sha, Shi-fu PhD; Zhang, Wen PhD; Qiao, Jun PhD; Bao, Hong-da PhD; Qiu, Yong MD; Jiang, Qing MD; Zhu, Ze-zhang PhD, MD. Polymorphism of rs2767485 in Leptin Receptor Gene is Associated With the Occurrence of Adolescent Idiopathic Scoliosis. Spine 40(20):p 1593-1598, October 15, 2015. | DOI: 10.1097/BRS.0000000000001095
  67. Yang M, Wei X, Yang W, Li Y, Ni H, Zhao Y, Chen Z, Bai Y, Li M. The polymorphisms of melatonin receptor 1B gene (MTNR1B) (rs4753426 and rs10830963) and susceptibility to adolescent idiopathic scoliosis: a meta-analysis. J Orthop Sci. 2015 Jul;20(4):593-600. doi: 10.1007/s00776-015-0725-5. Epub 2015 Apr 22. PMID: 25898821. "...Conclusion: MTNR1B rs4753426 and MTNR1B rs10830963 polymorphisms are not obviously associated with risk of AIS in either Asian populations or Caucasian populations.
  68. Zhu Z, Xu L, Qiu Y. Current progress in genetic research of adolescent idiopathic scoliosis. Ann Transl Med. 2015 May;3(Suppl 1):S19. doi: 10.3978/j.issn.2305-5839.2015.02.04. PMID: 26046064; PMCID: PMC4437942. “...Recently, two genome-wide association studies of AIS performed in Japan revealed that ladybird homeobox 1 (LBX1) gene and G protein–coupled receptor 126 (GPR126) gene could play a role in the etiopathogenesis of the disease. Since the association between these two genes and AIS were successfully validated in the Caucasian and the Chinese population, LBX1 gene and GPR126 gene were the most reliable genetic variants underling the development of AIS...”
  69. Deng M, Hui SC, Yu FW, Lam TP, Qiu Y, Ng BK, Cheng JC, Chu WC. MRI-based morphological evidence of spinal cord tethering predicts curve progression in adolescent idiopathic scoliosis. Spine J. 2015 Jun 1;15(6):1391-401. doi: 10.1016/j.spinee.2015.02.033. Epub 2015 Feb 25. PMID: 25725365.
  70. Sharma, S., Londono, D., Eckalbar, W. et al. A PAX1 enhancer locus is associated with susceptibility to idiopathic scoliosis in females. Nat Commun 6, 6452 (2015). https://doi.org/10.1038/ncomms7452"...Idiopathic scoliosis (IS) is a common paediatric musculoskeletal disease that displays a strong female bias. By performing a genome-wide association study (GWAS) of 3,102 individuals, we identify significant associations with 20p11.22 SNPs for females (P=6.89 × 10−9) but not males (P=0.71). This association with IS is also found in independent female cohorts from the United States of America and Japan (overall P=2.15 × 10−10, OR=1.30 (rs6137473)). Unexpectedly, the 20p11.22 IS risk alleles were previously associated with protection from early-onset alopecia, another sexually dimorphic condition. The 174-kb associated locus is distal to PAX1, which encodes paired box 1, a transcription factor involved in spine development. We identify a sequence in the associated locus with enhancer activity in zebrafish somitic muscle and spinal cord, an activity that is abolished by IS-associated SNPs. We thus identify a sexually dimorphic IS susceptibility locus, and propose the first functionally defined candidate mutations in an enhancer that may regulate expression in specific spinal cells...."
  71. Londono D, Kou I, Johnson TA, Sharma S, Ogura Y, Tsunoda T, Takahashi A, Matsumoto M, Herring JA, Lam TP, Wang X, Tam EM, Song YQ, Fan YH, Chan D, Cheah KS, Qiu X, Jiang H, Huang D; Japanese Scoliosis Clinical Research Group; TSRHC IS Clinical Group, International Consortium for Scoliosis Genetics, Su P, Sham P, Cheung KM, Luk KD, Gordon D, Qiu Y, Cheng J, Tang N, Ikegawa S, Wise CA. A meta-analysis identifies adolescent idiopathic scoliosis association with LBX1 locus in multiple ethnic groups. J Med Genet. 2014 Jun;51(6):401-6. doi: 10.1136/jmedgenet-2013-102067. Epub 2014 Apr 10. PMID: 24721834.
  72. Tam EM, Yu FW, Hung VW, Liu Z, Liu KL, Ng BK, Lee SK, Qiu Y, Cheng JC, Lam TP. Are volumetric bone mineral density and bone micro-architecture associated with leptin and soluble leptin receptor levels in adolescent idiopathic scoliosis?--A case-control study. PLoS One. 2014 Feb 6;9(2):e87939. doi: 10.1371/journal.pone.0087939. PMID: 24516571; PMCID: PMC3916359.
  73. Nowak R, Szota J, Mazurek U. Vitamin D receptor gene (VDR) transcripts in bone, cartilage, muscles and blood and microarray analysis of vitamin D responsive genes expression in paravertebral muscles of juvenile and adolescent idiopathic scoliosis patients. BMC Musculoskelet Disord. 2012 Dec 23;13:259. doi: 10.1186/1471-2474-13-259. PMID: 23259508; PMCID: PMC3532837.
  74. Gorman KF, Julien C, Moreau A. The genetic epidemiology of idiopathic scoliosis. Eur Spine J. 2012 Oct;21(10):1905-19. doi: 10.1007/s00586-012-2389-6. Epub 2012 Jun 14. PMID: 22695700; PMCID: PMC3463687."...Idiopathic scoliosis is a complex developmental syndrome defined by an abnormal structural curvature of the spine. High treatment costs, chronic pain/discomfort, and the need for monitoring at-risk individuals contribute to the global healthcare burden of this musculoskeletal disease...The objective of this comprehensive review was to summarize genetic associations/linkages with idiopathic scoliosis, as well as explore the strengths and weaknesses of each study, such that it may serve as a guide for the design and interpretation of future genetic studies in scoliosis..."
  75. Girardo M, Bettini N, Dema E, Cervellati S. The role of melatonin in the pathogenesis of adolescent idiopathic scoliosis (AIS). Eur Spine J. 2011 May;20 Suppl 1(Suppl 1):S68-74. doi: 10.1007/s00586-011-1750-5. Epub 2011 Mar 18. PMID: 21416282; PMCID: PMC3087042.
  76. Takahashi Y, Kou I, Takahashi A, Johnson TA, Kono K, Kawakami N, Uno K, Ito M, Minami S, Yanagida H, Taneichi H, Tsuji T, Suzuki T, Sudo H, Kotani T, Watanabe K, Chiba K, Hosono N, Kamatani N, Tsunoda T, Toyama Y, Kubo M, Matsumoto M, Ikegawa S. A genome-wide association study identifies common variants near LBX1 associated with adolescent idiopathic scoliosis. Nat Genet. 2011 Oct 23;43(12):1237-40. doi: 10.1038/ng.974. PMID: 22019779.
  77. Sharma S, Gao X, Londono D, Devroy SE, Mauldin KN, Frankel JT, Brandon JM, Zhang D, Li QZ, Dobbs MB, Gurnett CA, Grant SF, Hakonarson H, Dormans JP, Herring JA, Gordon D, Wise CA. Genome-wide association studies of adolescent idiopathic scoliosis suggest candidate susceptibility genes. Hum Mol Genet. 2011 Apr 1;20(7):1456-66. doi: 10.1093/hmg/ddq571. Epub 2011 Jan 7. PMID: 21216876; PMCID: PMC3049353.
  78. Edery P, Margaritte-Jeannin P, Biot B, Labalme A, Bernard JC, Chastang J, Kassai B, Plais MH, Moldovan F, Clerget-Darpoux F. New disease gene location and high genetic heterogeneity in idiopathic scoliosis. Eur J Hum Genet. 2011 Aug;19(8):865-9. doi: 10.1038/ejhg.2011.31. Epub 2011 Mar 16. PMID: 21407261; PMCID: PMC3172921. “..To date, no dominant IS gene has been identified, and we hope that the present study will prove to be an important step towards this goal...”
  79. Burwell RG, Aujla RK, Grevitt MP, Dangerfield PH, Moulton A, Randell TL, Anderson SI. Pathogenesis of adolescent idiopathic scoliosis in girls - a double neuro-osseous theory involving disharmony between two nervous systems, somatic and autonomic expressed in the spine and trunk: possible dependency on sympathetic nervous system and hormones with implications for medical therapy. Scoliosis. 2009 Oct 31;4:24. doi: 10.1186/1748-7161-4-24. PMID: 19878575; PMCID: PMC2781798.
  80. Qiu XS, Tang NL, Yeung HY, Lee KM, Hung VW, Ng BK, Ma SL, Kwok RH, Qin L, Qiu Y, Cheng JC. Melatonin receptor 1B (MTNR1B) gene polymorphism is associated with the occurrence of adolescent idiopathic scoliosis. Spine (Phila Pa 1976). 2007 Jul 15;32(16):1748-53. doi: 10.1097/BRS.0b013e3180b9f0ff. PMID: 17632395.
  81. Andersen MO, Thomsen K, Kyvik KO. Adolescent idiopathic scoliosis in twins: a population-based survey. Spine (Phila Pa 1976). 2007 Apr 15;32(8):927-30. doi: 10.1097/01.brs.0000259865.08984.00. PMID: 17426641.
  82. Grivas TB, Vasiliadis E, Mouzakis V, Mihas C, Koufopoulos G. Association between adolescent idiopathic scoliosis prevalence and age at menarche in different geographic latitudes. Scoliosis. 2006 May 23;1:9. doi: 10.1186/1748-7161-1-9. PMID: 16759371; PMCID: PMC1501058. "...Conclusion In this survey it appears that late age at menarche is parallel with higher prevalence of AIS, especially in latitudes northern than 30 degrees. Pubarche appears later in girls that live in northern latitudes and thus prolongs the period of spine vulnerability while other pre-existing or aetiological factors are contributing to the development of AIS."

Refer also to Links to Publications on AIS references which includes links to research on curve progression and more.




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