Unraveling the Genetic and Epigenetic Threads of Idiopathic Scoliosis: Analyzing Mechanisms, Interactions, and Future Directions in Research and Therapy
Main Article Content
Abstract
Idiopathic scoliosis (IS) is a complex, multifactorial spinal deformity with a largely elusive etiology. This review synthesizes current research on the genetic and epigenetic factors contributing to IS development and progression. Genome-wide association studies have identified key susceptibility loci—such as LBX1, GPR126, and BNC2—while family and twin studies underscore a significant heritable component. Chromosomal anomalies and polygenic interactions further complicate the genetic landscape. Concurrently, epigenetic mechanisms—including DNA methylation, histone modifications, and non-coding RNAs—have emerged as critical mediators of gene-environment interactions, influenced by factors such as mechanical load, nutrition, and endocrine disruptors. Multi-omic approaches integrating genomics, transcriptomics, and epigenomics offer new insights into pathophysiology and therapeutic targeting. Ethical considerations surrounding genetic testing and the need for population-specific models are also discussed. Ultimately, this review supports a shift toward precision medicine, highlighting the potential of early molecular biomarkers and epigenetic modulation as tools for individualized scoliosis management and intervention.
Article Details
How to Cite
MORNINGSTAR, Mark W..
Unraveling the Genetic and Epigenetic Threads of Idiopathic Scoliosis: Analyzing Mechanisms, Interactions, and Future Directions in Research and Therapy.
Medical Research Archives, [S.l.], v. 13, n. 8, aug. 2025.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/6863>. Date accessed: 13 dec. 2025.
doi: https://doi.org/10.18103/mra.v13i8.6863.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Weinstein SL, Dolan LA, Cheng JCY, Danielsson A, Morcuende, JA. Adolescent idiopathic scoliosis. Lancet 2008; 371(9623): 1527–1537.
2. Konieczny MR, Senyurt H, Krauspe R. Epidemiology of adolescent idiopathic scoliosis. J Child Orthop 2013; 7(1): 3–9.
3. Negrini S, Donzelli S, Aulisa AG, et al. 2016 SOSORT guidelines: Orthopaedic and rehabilitation treatment of idiopathic scoliosis during growth. Scoliosis and Spinal Disorders 2018; 13: 3.
4. Lonstein JE. Adolescent idiopathic scoliosis. Lancet 1994; 344(8934): 1407–1412.
5. Reichel D, Schanz J. Developmental psychological aspects of scoliosis treatment. Pediatr Rehabil 2003; 6(3-4): 221–225.
6. Tsiligiannis T, Grivas TB. Pulmonary function in children with idiopathic scoliosis. Scoliosis 2012; 7: 7.
7. Faldini C, Manzetti M, Neri S, Barile F, Viroli G, Geraci G, Ursini F, Ruffilli A. Epigenetic and genetic factors related to curve progression in adolescent idiopathic scoliosis: a systematic scoping review of the current literature. Int J Mol Sci. 2022;23(11):5914.
8. Kesling KL, Reinker KA. Scoliosis in twins: A meta-analysis. Spine 1978; 3(2): 136–138.
9. Miller NH. Genetics of familial idiopathic scoliosis. Clin Orthop Related Res 2007; 462, 6–10.
10. Kou I, Takahashi Y, Johnson TA, et al. Genetic variants in GPR126 are associated with adolescent idiopathic scoliosis. Nat Genet 2013; 45(6): 676–679.
11. Ogura Y, Kou I, Takahashi Y, et al. A Functional SNP in BNC2 Is Associated with Adolescent Idiopathic Scoliosis. Am J Hum Genet. 2015;97(2):337-42.
12. Karner CM, Long F, Monk KR. Gpr126/Adgrg6 deletion in cartilage models idiopathic scoliosis and pectus excavatum in mice. Hum Mol Genet. 2015;24(15):4365-73.
13. Takahashi Y, Kou I, Takahashi A, et al. A genome-wide association study identifies common variants near LBX1 associated with adolescent idiopathic scoliosis. Nat Genet 2011; 43(12): 1237–1240.
14. Miller NH, Justice CM, Marosy B, et al. Identification of candidate regions for familial idiopathic scoliosis. Spine 2005;30(10):1181-7.
15. Xu JF, Yang GH, Pan XH, et al. Altered microRNA expression profile in plasma of patients with adolescent idiopathic scoliosis. PLoS ONE 2015; 10(10): e0138946.
16. Gao X, Gordon D, Zhang D, et al. CHD7 gene polymorphisms are associated with susceptibility to idiopathic scoliosis. Am J Hum Genet 2007; 80(5): 957–965.
17. Liu G, Wang L, Wang J, et al. Whole-Genome Methylation Analysis of Phenotype Discordant Monozygotic Twins Reveals Novel Epigenetic Perturbation Contributing to the Pathogenesis of Adolescent Idiopathic Scoliosis. Front Bioeng Biotechnol 2019;7:364.
18. Cheng JCY, Castelein RM, Chu WCW, et al. Adolescent idiopathic scoliosis. Nat Rev Dis Primers 2015; 7(1): 9.
19. Carry PM, Terhune EA, Trahan GD, et al. Severity of Idiopathic Scoliosis Is Associated with Differential Methylation: An Epigenome-Wide Association Study of Monozygotic Twins with Idiopathic Scoliosis. Genes 2021; 12(8):1191.
20. Guo L, Huang W, Chen B, et al. gga-mir-133a-3p Regulates Myoblasts Proliferation and Differentiation by Targeting PRRX1. Front Genet 2018;9:577.
21. Xu JF, Yang GH, Pan XH, et al. Association of GPR126 gene polymorphism with adolescent idiopathic scoliosis in Chinese populations. Genomics 2015;105(2):101-7.
22. Nowak R, Kwiecien M, Tkacz M, Mazurek U. Transforming growth factor-beta (TGF- β) signaling in paravertebral muscles in juvenile and adolescent idiopathic scoliosis. Biomed Res Int. 2014;2014:594287.
23. Grauers A, Wang J, Einarsdottir E, et al. Candidate gene analysis and exome sequencing confirm LBX1 as a susceptibility gene for idiopathic scoliosis. Spine J 2015; 15(10), 2239–2246.
24. Wang YP, Qin SL, Yang S, et al. Association of IL‑6 and MMP‑3 gene polymorphisms with adolescent idiopathic scoliosis: A systematic review and meta‑analysis. Exp Ther Med. 2024;27(6):267..
25. Bilgin E, Tezcan Unlu H, Cecener G, et al. Investigation of LBX1, TIMP2, GPR126 and CHD7 Gene Polymorphisms in Adolescent Idiopathic Scoliosis Patients. Global Spine J; 2025:21925682251356933.
26. Wise CA, Gao X, Shoemaker S, Gordon D, Herring JA. Understanding genetic factors in idiopathic scoliosis, a complex disease of childhood. Curr Genomics 2008; 9(1): 51–59.
27. Burwell, R.G., Aujla, R.K., Grevitt, M.P. et al. 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;4: 24.
28. Yang Y, Chen Z, Huang Z, et al. Risk factors associated with low bone mineral density in children with idiopathic scoliosis: a scoping review. BMC Musculoskelet Disord 2023;24(1):48.
29. Egger G, Liang G, Aparicio A, Jones PA. Epigenetics in human disease and prospects for epigenetic therapy. Nature 2004;429: 457–63.
30. Sun D, Ding Z, Hai Y, Cheng Y. Advances in epigenetic research of adolescent idiopathic scoliosis and congenital scoliosis. Front Genet. 2023;14:1211376.
31. Haller G, Alvarado D, McCall K, et al. A polygenic burden of rare variants across extracellular matrix genes among individuals with adolescent idiopathic scoliosis. Hum Mol Genet 2016; 25(9): 202–209.
32. Liu XY, Wang L, Yu B, Zhuang QY, Wang YP. Expression Signatures of Long Noncoding RNAs in Adolescent Idiopathic Scoliosis. Biomed Res Int 2015;2015:276049.
33. Tiller J, Otlowski M, Lacaze P. Should Australia Ban the Use of Genetic Test Results in Life Insurance? Front Public Health 2017;5:330.
34. Hudson KL, Holohan MK, Collins FS. Keeping pace with the times--the Genetic Information Nondiscrimination Act of 2008. N Engl J Med. 2008;358(25):2661-3.
35. Guttmacher AE, Collins FS. Welcome to the genomic era. N Engl J Med. 2003;349(10):996-8.
36. Morningstar MW, Stitzel CJ, Strauchman M. Functional genomic variant patterns in Caucasian patients diagnosed with idiopathic scoliosis: a controlled, observational study. Medical Research Archives 2019; 7(9):1-9.
37. You JS, Jones PA. Cancer genetics and epigenetics: two sides of the same coin? Cancer Cell 2012;22(1):9-20.
38. Voisin S, Eynon N, Yan X, Bishop DJ. Exercise training and DNA methylation in humans. Acta Physiol (Oxf) 2015;213(1):39-59.
39. Schmid S, Studer D, Hasler CC, Romkes J, Taylor WR, Lorenzetti S, Brunner R. Quantifying spinal gait kinematics using an enhanced optical motion capture approach in adolescent idiopathic scoliosis. Gait Posture 2016;44:231-7.
2. Konieczny MR, Senyurt H, Krauspe R. Epidemiology of adolescent idiopathic scoliosis. J Child Orthop 2013; 7(1): 3–9.
3. Negrini S, Donzelli S, Aulisa AG, et al. 2016 SOSORT guidelines: Orthopaedic and rehabilitation treatment of idiopathic scoliosis during growth. Scoliosis and Spinal Disorders 2018; 13: 3.
4. Lonstein JE. Adolescent idiopathic scoliosis. Lancet 1994; 344(8934): 1407–1412.
5. Reichel D, Schanz J. Developmental psychological aspects of scoliosis treatment. Pediatr Rehabil 2003; 6(3-4): 221–225.
6. Tsiligiannis T, Grivas TB. Pulmonary function in children with idiopathic scoliosis. Scoliosis 2012; 7: 7.
7. Faldini C, Manzetti M, Neri S, Barile F, Viroli G, Geraci G, Ursini F, Ruffilli A. Epigenetic and genetic factors related to curve progression in adolescent idiopathic scoliosis: a systematic scoping review of the current literature. Int J Mol Sci. 2022;23(11):5914.
8. Kesling KL, Reinker KA. Scoliosis in twins: A meta-analysis. Spine 1978; 3(2): 136–138.
9. Miller NH. Genetics of familial idiopathic scoliosis. Clin Orthop Related Res 2007; 462, 6–10.
10. Kou I, Takahashi Y, Johnson TA, et al. Genetic variants in GPR126 are associated with adolescent idiopathic scoliosis. Nat Genet 2013; 45(6): 676–679.
11. Ogura Y, Kou I, Takahashi Y, et al. A Functional SNP in BNC2 Is Associated with Adolescent Idiopathic Scoliosis. Am J Hum Genet. 2015;97(2):337-42.
12. Karner CM, Long F, Monk KR. Gpr126/Adgrg6 deletion in cartilage models idiopathic scoliosis and pectus excavatum in mice. Hum Mol Genet. 2015;24(15):4365-73.
13. Takahashi Y, Kou I, Takahashi A, et al. A genome-wide association study identifies common variants near LBX1 associated with adolescent idiopathic scoliosis. Nat Genet 2011; 43(12): 1237–1240.
14. Miller NH, Justice CM, Marosy B, et al. Identification of candidate regions for familial idiopathic scoliosis. Spine 2005;30(10):1181-7.
15. Xu JF, Yang GH, Pan XH, et al. Altered microRNA expression profile in plasma of patients with adolescent idiopathic scoliosis. PLoS ONE 2015; 10(10): e0138946.
16. Gao X, Gordon D, Zhang D, et al. CHD7 gene polymorphisms are associated with susceptibility to idiopathic scoliosis. Am J Hum Genet 2007; 80(5): 957–965.
17. Liu G, Wang L, Wang J, et al. Whole-Genome Methylation Analysis of Phenotype Discordant Monozygotic Twins Reveals Novel Epigenetic Perturbation Contributing to the Pathogenesis of Adolescent Idiopathic Scoliosis. Front Bioeng Biotechnol 2019;7:364.
18. Cheng JCY, Castelein RM, Chu WCW, et al. Adolescent idiopathic scoliosis. Nat Rev Dis Primers 2015; 7(1): 9.
19. Carry PM, Terhune EA, Trahan GD, et al. Severity of Idiopathic Scoliosis Is Associated with Differential Methylation: An Epigenome-Wide Association Study of Monozygotic Twins with Idiopathic Scoliosis. Genes 2021; 12(8):1191.
20. Guo L, Huang W, Chen B, et al. gga-mir-133a-3p Regulates Myoblasts Proliferation and Differentiation by Targeting PRRX1. Front Genet 2018;9:577.
21. Xu JF, Yang GH, Pan XH, et al. Association of GPR126 gene polymorphism with adolescent idiopathic scoliosis in Chinese populations. Genomics 2015;105(2):101-7.
22. Nowak R, Kwiecien M, Tkacz M, Mazurek U. Transforming growth factor-beta (TGF- β) signaling in paravertebral muscles in juvenile and adolescent idiopathic scoliosis. Biomed Res Int. 2014;2014:594287.
23. Grauers A, Wang J, Einarsdottir E, et al. Candidate gene analysis and exome sequencing confirm LBX1 as a susceptibility gene for idiopathic scoliosis. Spine J 2015; 15(10), 2239–2246.
24. Wang YP, Qin SL, Yang S, et al. Association of IL‑6 and MMP‑3 gene polymorphisms with adolescent idiopathic scoliosis: A systematic review and meta‑analysis. Exp Ther Med. 2024;27(6):267..
25. Bilgin E, Tezcan Unlu H, Cecener G, et al. Investigation of LBX1, TIMP2, GPR126 and CHD7 Gene Polymorphisms in Adolescent Idiopathic Scoliosis Patients. Global Spine J; 2025:21925682251356933.
26. Wise CA, Gao X, Shoemaker S, Gordon D, Herring JA. Understanding genetic factors in idiopathic scoliosis, a complex disease of childhood. Curr Genomics 2008; 9(1): 51–59.
27. Burwell, R.G., Aujla, R.K., Grevitt, M.P. et al. 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;4: 24.
28. Yang Y, Chen Z, Huang Z, et al. Risk factors associated with low bone mineral density in children with idiopathic scoliosis: a scoping review. BMC Musculoskelet Disord 2023;24(1):48.
29. Egger G, Liang G, Aparicio A, Jones PA. Epigenetics in human disease and prospects for epigenetic therapy. Nature 2004;429: 457–63.
30. Sun D, Ding Z, Hai Y, Cheng Y. Advances in epigenetic research of adolescent idiopathic scoliosis and congenital scoliosis. Front Genet. 2023;14:1211376.
31. Haller G, Alvarado D, McCall K, et al. A polygenic burden of rare variants across extracellular matrix genes among individuals with adolescent idiopathic scoliosis. Hum Mol Genet 2016; 25(9): 202–209.
32. Liu XY, Wang L, Yu B, Zhuang QY, Wang YP. Expression Signatures of Long Noncoding RNAs in Adolescent Idiopathic Scoliosis. Biomed Res Int 2015;2015:276049.
33. Tiller J, Otlowski M, Lacaze P. Should Australia Ban the Use of Genetic Test Results in Life Insurance? Front Public Health 2017;5:330.
34. Hudson KL, Holohan MK, Collins FS. Keeping pace with the times--the Genetic Information Nondiscrimination Act of 2008. N Engl J Med. 2008;358(25):2661-3.
35. Guttmacher AE, Collins FS. Welcome to the genomic era. N Engl J Med. 2003;349(10):996-8.
36. Morningstar MW, Stitzel CJ, Strauchman M. Functional genomic variant patterns in Caucasian patients diagnosed with idiopathic scoliosis: a controlled, observational study. Medical Research Archives 2019; 7(9):1-9.
37. You JS, Jones PA. Cancer genetics and epigenetics: two sides of the same coin? Cancer Cell 2012;22(1):9-20.
38. Voisin S, Eynon N, Yan X, Bishop DJ. Exercise training and DNA methylation in humans. Acta Physiol (Oxf) 2015;213(1):39-59.
39. Schmid S, Studer D, Hasler CC, Romkes J, Taylor WR, Lorenzetti S, Brunner R. Quantifying spinal gait kinematics using an enhanced optical motion capture approach in adolescent idiopathic scoliosis. Gait Posture 2016;44:231-7.