{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T17:26:54Z","timestamp":1789579614079,"version":"build-2803163510"},"reference-count":117,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,7,30]],"date-time":"2021-07-30T00:00:00Z","timestamp":1627603200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 AR068292"],"award-info":[{"award-number":["R01 AR068292"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Epigenetic mechanisms may contribute to idiopathic scoliosis (IS). We identified 8 monozygotic twin pairs with IS, 6 discordant (Cobb angle difference &gt; 10\u00b0) and 2 concordant (Cobb angle difference \u2264 2\u00b0). 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. Methylation at cg12959265 (chr. 7 DPY19L1) was less variable in cases (false discovery rate (FDR) = 0.0791). We identified four probes (false discovery rate, FDR &lt; 0.10); cg02477677 (chr. 17, RARA gene), cg12922161 (chr. 2 LOC150622 gene), cg08826461 (chr. 2), and cg16382077 (chr. 7) associated with curve severity. We identified 57 DMRs where hyper- or hypo-methylation was consistent across the region and 28 DMRs with a consistent association with curve severity. 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.<\/jats:p>","DOI":"10.3390\/genes12081191","type":"journal-article","created":{"date-parts":[[2021,7,30]],"date-time":"2021-07-30T12:59:24Z","timestamp":1627649964000},"page":"1191","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Severity of Idiopathic Scoliosis Is Associated with Differential Methylation: An Epigenome-Wide Association Study of Monozygotic Twins with Idiopathic Scoliosis"],"prefix":"10.3390","volume":"12","author":[{"given":"Patrick","family":"Carry","sequence":"first","affiliation":[{"name":"Musculoskeletal Research Center, Children\u2019s Hospital Colorado, Aurora, CO 80045, USA"},{"name":"Department of Orthopedics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Terhune","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"Trahan","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren","family":"Vanderlinden","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Informatics, Colorado School of Public Health, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cambria","family":"Wethey","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Parvaneh","family":"Ebrahimi","sequence":"additional","affiliation":[{"name":"Clinical Sciences Malmo, Clinical and Molecular Osteoporosis Research Unit, Lund University, S-205 02 Malm\u00f6, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fiona","family":"McGuigan","sequence":"additional","affiliation":[{"name":"Clinical Sciences Malmo, Clinical and Molecular Osteoporosis Research Unit, Lund University, S-205 02 Malm\u00f6, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3024-2804","authenticated-orcid":false,"given":"Kristina","family":"\u00c5kesson","sequence":"additional","affiliation":[{"name":"Clinical Sciences Malmo, Clinical and Molecular Osteoporosis Research Unit, Lund University, S-205 02 Malm\u00f6, Sweden"},{"name":"Department of Orthopedics, Skane University Hospital, S-205 02 Malm\u00f6, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy","family":"Hadley-Miller","sequence":"additional","affiliation":[{"name":"Musculoskeletal Research Center, Children\u2019s Hospital Colorado, Aurora, CO 80045, USA"},{"name":"Department of Orthopedics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/j.jspd.2017.03.009","article-title":"Systematic Review of School Scoliosis Screening","volume":"5","author":"Altaf","year":"2017","journal-title":"Spine Deform."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1527","DOI":"10.1016\/S0140-6736(08)60658-3","article-title":"Adolescent idiopathic scoliosis","volume":"371","author":"Weinstein","year":"2008","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1097\/BLO.0b013e318126c062","article-title":"Genetics of familial idiopathic scoliosis","volume":"462","author":"Miller","year":"2007","journal-title":"Clin. Orthop. Relat. Res."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Khanshour, A.M., and Wise, C.A. (2018). The Genetic Architecture of Adolescent Idiopathic Scoliosis. Pathogenesis of Idiopathic Scoliosis, Springer.","DOI":"10.1007\/978-4-431-56541-3_3"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1464","DOI":"10.1002\/jor.22090","article-title":"Genetic epidemiology and heritability of AIS: A study of 415 Chinese female patients","volume":"30","author":"Tang","year":"2012","journal-title":"J. Orthop Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1178","DOI":"10.1002\/ajmg.a.33145","article-title":"Polygenic inheritance of adolescent idiopathic scoliosis: A study of extended families in Utah","volume":"152","author":"Ward","year":"2010","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"994","DOI":"10.1002\/jor.1100140621","article-title":"Genetic analysis of structural elastic fiber and collagen genes in familial adolescent idiopathic scoliosis","volume":"14","author":"Miller","year":"1996","journal-title":"J. Orthop. Res."},{"key":"ref_8","unstructured":"Stokes, I.A. (1998). Genomic Search for X-Linkage in Familial Adolescent Idiopathic Scoliosis. Research into Spinal Deformities 2, IOS Press."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2372","DOI":"10.1097\/00007632-200009150-00017","article-title":"Localization of susceptibility to familial idiopathic scoliosis","volume":"25","author":"Wise","year":"2000","journal-title":"Spine (Phila Pa 1976)"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1086\/341607","article-title":"A genetic locus for adolescent idiopathic scoliosis linked to chromosome 19p13.3","volume":"71","author":"Chan","year":"2002","journal-title":"Am. J. Hum. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1097\/01.BRS.0000049940.39801.E6","article-title":"Familial idiopathic scoliosis: Evidence of an X-linked susceptibility locus","volume":"28","author":"Justice","year":"2003","journal-title":"Spine (Phila Pa 1976)"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1097\/01.brs.0000162282.46160.0a","article-title":"Identification of candidate regions for familial idiopathic scoliosis","volume":"30","author":"Miller","year":"2005","journal-title":"Spine (Phila Pa 1976)"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1815","DOI":"10.1097\/01.brs.0000227264.23603.dc","article-title":"Idiopathic scoliosis: Identification of candidate regions on chromosome 19p13","volume":"31","author":"Alden","year":"2006","journal-title":"Spine (Phila Pa 1976)"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1002\/ajmg.a.31211","article-title":"Linkage analysis of genetic loci for kyphoscoliosis on chromosomes 5p13, 13q13.3, and 13q32","volume":"140","author":"Miller","year":"2006","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1186\/1748-7161-1-21","article-title":"Evidence of a linkage between matrilin-1 gene (MATN1) and idiopathic scoliosis","volume":"1","author":"Montanaro","year":"2006","journal-title":"Scoliosis"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"E94","DOI":"10.1097\/BRS.0b013e31818b88a5","article-title":"Genetic linkage localizes an adolescent idiopathic scoliosis and pectus excavatum gene to chromosome 18 q","volume":"34","author":"Gurnett","year":"2009","journal-title":"Spine (Phila Pa 1976)"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1002\/ajmg.a.33222","article-title":"Identification of susceptibility loci for scoliosis in FIS families with triple curves","volume":"152","author":"Marosy","year":"2010","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"5271","DOI":"10.1093\/hmg\/ddu224","article-title":"Rare variants in FBN1 and FBN2 are associated with severe adolescent idiopathic scoliosis","volume":"23","author":"Buchan","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1534\/g3.114.015669","article-title":"Exome sequencing identifies a rare HSPG2 variant associated with familial idiopathic scoliosis","volume":"5","author":"Baschal","year":"2014","journal-title":"G3"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1124","DOI":"10.1172\/JCI77262","article-title":"Functional variants of POC5 identified in patients with idiopathic scoliosis","volume":"125","author":"Patten","year":"2015","journal-title":"J. Clin. Investig."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2239","DOI":"10.1016\/j.spinee.2015.05.013","article-title":"Candidate gene analysis and exome sequencing confirm LBX1 as a susceptibility gene for idiopathic scoliosis","volume":"15","author":"Grauers","year":"2015","journal-title":"Spine J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1136\/jmedgenet-2015-103684","article-title":"AKAP2 identified as a novel gene mutated in a Chinese family with adolescent idiopathic scoliosis","volume":"53","author":"Li","year":"2016","journal-title":"J. Med. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1093\/hmg\/ddv463","article-title":"A polygenic burden of rare variants across extracellular matrix genes among individuals with adolescent idiopathic scoliosis","volume":"25","author":"Haller","year":"2016","journal-title":"Hum. Mol. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1500","DOI":"10.1002\/humu.23296","article-title":"Rare coding variants in MAPK7 predispose to adolescent idiopathic scoliosis","volume":"38","author":"Gao","year":"2017","journal-title":"Hum. Mutat."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Einarsdottir, E., Grauers, A., Wang, J., Jiao, H., Escher, S.A., Danielsson, A., Simony, A., Andersen, M., Christensen, S.B., and Akesson, K. (2017). CELSR2 is a candidate susceptibility gene in idiopathic scoliosis. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0189591"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2663","DOI":"10.1534\/g3.118.200290","article-title":"Idiopathic Scoliosis Families Highlight Actin-Based and Microtubule-Based Cellular Projections and Extracellular Matrix in Disease Etiology","volume":"8","author":"Baschal","year":"2018","journal-title":"G3"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1002\/humu.24162","article-title":"Mutations in KIF7 implicated in idiopathic scoliosis in humans and axial curvatures in zebrafish","volume":"42","author":"Terhune","year":"2021","journal-title":"Hum. Mutat."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1456","DOI":"10.1093\/hmg\/ddq571","article-title":"Genome-wide association studies of adolescent idiopathic scoliosis suggest candidate susceptibility genes","volume":"20","author":"Sharma","year":"2011","journal-title":"Hum. Mol. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1237","DOI":"10.1038\/ng.974","article-title":"A genome-wide association study identifies common variants near LBX1 associated with adolescent idiopathic scoliosis","volume":"43","author":"Takahashi","year":"2011","journal-title":"Nat. Genet."},{"key":"ref_30","unstructured":"Nelson, L.M., Chettier, R., Ogilvie, J.W., and Ward, K. (2011, January 14\u201317). Candidate Genes for Susceptibility of Adolescent Idiopathic Scoliosis Identified Through a Large Genome-Wide Association Study. Proceedings of the Scoliosis Research Society 46th Annual Meeting & Course, Louisville, KY, USA."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/ng.2639","article-title":"Genetic variants in GPR126 are associated with adolescent idiopathic scoliosis","volume":"45","author":"Kou","year":"2013","journal-title":"Nat. Genet."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Miyake, A., Kou, I., Takahashi, Y., Johnson, T.A., Ogura, Y., Dai, J., Qiu, X., Takahashi, A., Jiang, H., and Yan, H. (2013). Identification of a susceptibility locus for severe adolescent idiopathic scoliosis on chromosome 17q24.3. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0072802"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"8355","DOI":"10.1038\/ncomms9355","article-title":"Genome-wide association study identifies new susceptibility loci for adolescent idiopathic scoliosis in Chinese girls","volume":"6","author":"Zhu","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/j.ajhg.2015.06.012","article-title":"A Functional SNP in BNC2 Is Associated with Adolescent Idiopathic Scoliosis","volume":"97","author":"Ogura","year":"2015","journal-title":"Am. J. Hum. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"6452","DOI":"10.1038\/ncomms7452","article-title":"A PAX1 enhancer locus is associated with susceptibility to idiopathic scoliosis in females","volume":"6","author":"Sharma","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3685","DOI":"10.1038\/s41467-019-11596-w","article-title":"Genome-wide association study identifies 14 previously unreported susceptibility loci for adolescent idiopathic scoliosis in Japanese","volume":"10","author":"Kou","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"17976","DOI":"10.1523\/JNEUROSCI.1809-13.2013","article-title":"Gpr126 functions in Schwann cells to control differentiation and myelination via G-protein activation","volume":"33","author":"Mogha","year":"2013","journal-title":"J. Neurosci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.ygeno.2014.11.009","article-title":"Association of GPR126 gene polymorphism with adolescent idiopathic scoliosis in Chinese populations","volume":"105","author":"Xu","year":"2015","journal-title":"Genomics"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4365","DOI":"10.1093\/hmg\/ddv170","article-title":"Gpr126\/Adgrg6 deletion in cartilage models idiopathic scoliosis and pectus excavatum in mice","volume":"24","author":"Karner","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"E1098","DOI":"10.1097\/BRS.0000000000002123","article-title":"Genetic Variant of GPR126 Gene is Functionally Associated With Adolescent Idiopathic Scoliosis in Chinese Population","volume":"42","author":"Qin","year":"2017","journal-title":"Spine (Phila Pa 1976)"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1097\/BRS.0000000000002866","article-title":"Replication Study for the Association of GWAS-associated Loci with Adolescent Idiopathic Scoliosis Susceptibility and Curve Progression in a Chinese Population","volume":"44","author":"Man","year":"2019","journal-title":"Spine (Phila Pa 1976)"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"11575","DOI":"10.1038\/s41598-018-29011-7","article-title":"A multi-ethnic meta-analysis confirms the association of rs6570507 with adolescent idiopathic scoliosis","volume":"8","author":"Kou","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1964","DOI":"10.1111\/jcmm.13486","article-title":"Genetic polymorphisms of GPR126 are functionally associated with PUMC classifications of adolescent idiopathic scoliosis in a Northern Han population","volume":"22","author":"Liu","year":"2018","journal-title":"J. Cell Mol. Med."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Gao, W., Peng, Y., Liang, G., Liang, A., Ye, W., Zhang, L., Sharma, S., Su, P., and Huang, D. (2013). Association between common variants near LBX1 and adolescent idiopathic scoliosis replicated in the Chinese Han population. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0053234"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e16314","DOI":"10.1097\/MD.0000000000016314","article-title":"Association between ladybird homeobox 1 gene polymorphisms and adolescent idiopathic scoliosis: A MOOSE-compliant meta-analysis","volume":"98","author":"Jiang","year":"2019","journal-title":"Medicine (Baltimore)"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1097\/BRS.0000000000000303","article-title":"Association Between rs11190870 Polymorphism Near LBX1 and Susceptibility to Adolescent Idiopathic Scoliosis in East Asian Population: A Genetic Meta-Analysis","volume":"39","author":"Liang","year":"2014","journal-title":"Spine (Phila Pa 1976)"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2968","DOI":"10.1016\/j.spinee.2014.05.019","article-title":"Association of rs11190870 near LBX1 with adolescent idiopathic scoliosis in East Asians: A systematic review and meta-analysis","volume":"14","author":"Chen","year":"2014","journal-title":"Spine J."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1007\/s00586-012-2532-4","article-title":"Association of rs11190870 near LBX1 with adolescent idiopathic scoliosis susceptibility in a Han Chinese population","volume":"22","author":"Jiang","year":"2013","journal-title":"Eur. Spine J."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.ijsu.2018.01.051","article-title":"The association of rs11190870 near LBX1 with the susceptibility and severity of AIS, a meta-analysis","volume":"54","author":"Li","year":"2018","journal-title":"Int. J. Surg."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Cao, Y., Min, J., Zhang, Q., Li, H., and Li, H. (2016). Associations of LBX1 gene and adolescent idiopathic scoliosis susceptibility: A meta-analysis based on 34,626 subjects. BMC Musculoskelet Disord, 17.","DOI":"10.1186\/s12891-016-1139-z"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Guo, L., Yamashita, H., Kou, I., Takimoto, A., Meguro-Horike, M., Horike, S., Sakuma, T., Miura, S., Adachi, T., and Yamamoto, T. (2016). Functional Investigation of a Non-coding Variant Associated with Adolescent Idiopathic Scoliosis in Zebrafish: Elevated Expression of the Ladybird Homeobox Gene Causes Body Axis Deformation. PLoS Genet., 12.","DOI":"10.1371\/journal.pgen.1005802"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1097\/BRS.0000000000002111","article-title":"Genetic Polymorphism of LBX1 Is Associated with Adolescent Idiopathic Scoliosis in Northern Chinese Han Population","volume":"42","author":"Liu","year":"2017","journal-title":"Spine (Phila Pa 1976)"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"246","DOI":"10.2174\/1389202920666190730132411","article-title":"A Genetic Predictive Model Estimating the Risk of Developing Adolescent Idiopathic Scoliosis","volume":"20","author":"Xu","year":"2019","journal-title":"Curr. Genom."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Chettier, R., Nelson, L., Ogilvie, J.W., Albertsen, H.M., and Ward, K. (2015). Haplotypes at LBX1 have distinct inheritance patterns with opposite effects in adolescent idiopathic scoliosis. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0117708"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1136\/jmedgenet-2013-102067","article-title":"A meta-analysis identifies adolescent idiopathic scoliosis association with LBX1 locus in multiple ethnic groups","volume":"51","author":"Londono","year":"2014","journal-title":"J. Med. Genet."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1097\/BRS.0000000000002280","article-title":"A Replication Study for Association of LBX1 Locus with Adolescent Idiopathic Scoliosis in French-Canadian Population","volume":"43","author":"Nada","year":"2018","journal-title":"Spine (Phila Pa 1976)"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1038\/jhg.2012.11","article-title":"SNP rs11190870 near LBX1 is associated with adolescent idiopathic scoliosis in southern Chinese","volume":"57","author":"Fan","year":"2012","journal-title":"J. Hum. Genet."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1038\/ejhg.2011.31","article-title":"New disease gene location and high genetic heterogeneity in idiopathic scoliosis","volume":"19","author":"Edery","year":"2011","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1905","DOI":"10.1007\/s00586-012-2389-6","article-title":"The genetic epidemiology of idiopathic scoliosis","volume":"21","author":"Gorman","year":"2012","journal-title":"Eur. Spine J."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.2106\/00004623-200008000-00014","article-title":"Etiology of idiopathic scoliosis: Current trends in research","volume":"82","author":"Lowe","year":"2000","journal-title":"J. Bone Jt. Surg. Am."},{"key":"ref_61","unstructured":"Dunwoodie, S.L., and Kusumi, K. (2018). The Genetics and Development of Scoliosis, Springer International Publishing. [2nd ed.]."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1227\/01.NEU.0000320384.93384.28","article-title":"Genetics of scoliosis","volume":"63","author":"Heary","year":"2008","journal-title":"Neurosurgery"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1485","DOI":"10.2106\/JBJS.K.01450","article-title":"Polygenic threshold model with sex dimorphism in adolescent idiopathic scoliosis: The Carter effect","volume":"94","author":"Kruse","year":"2012","journal-title":"J. Bone Jt. Surg. Am."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Arpon, A., Milagro, F.I., Ramos-Lopez, O., Mansego, M.L., Riezu-Boj, J.I., Martinez, J.A., and Project, M. (2019). Methylome-Wide Association Study in Peripheral White Blood Cells Focusing on Central Obesity and Inflammation. Genes, 10.","DOI":"10.3390\/genes10060444"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1007\/s00586-011-2074-1","article-title":"Heritability of scoliosis","volume":"21","author":"Grauers","year":"2012","journal-title":"Eur. Spine J."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1038\/nature16462","article-title":"Competition between DNA methylation and transcription factors determines binding of NRF1","volume":"528","author":"Domcke","year":"2015","journal-title":"Nature"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"e00523","DOI":"10.7554\/eLife.00523","article-title":"Passive and active DNA methylation and the interplay with genetic variation in gene regulation","volume":"2","author":"Lappalainen","year":"2013","journal-title":"eLife"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1038\/nrg.2017.32","article-title":"Associating cellular epigenetic models with human phenotypes","volume":"18","author":"Lappalainen","year":"2017","journal-title":"Nat. Rev. Genet."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Gertz, J., Varley, K.E., Reddy, T.E., Bowling, K.M., Pauli, F., Parker, S.L., Kucera, K.S., Willard, H.F., and Myers, R.M. (2011). Analysis of DNA methylation in a three-generation family reveals widespread genetic influence on epigenetic regulation. PLoS Genet., 7.","DOI":"10.1371\/journal.pgen.1002228"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1002\/art.37753","article-title":"Genome-wide profiling of bone reveals differentially methylated regions in osteoporosis and osteoarthritis","volume":"65","author":"Fernandez","year":"2013","journal-title":"Arthritis Rheum."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/s13148-018-0457-4","article-title":"Epigenome-wide analysis in newborn blood spots from monozygotic twins discordant for cerebral palsy reveals consistent regional differences in DNA methylation","volume":"10","author":"Mohandas","year":"2018","journal-title":"Clin. Epigenet."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"e65715","DOI":"10.7554\/eLife.65715","article-title":"Epigenetic analysis of Paget\u2019s disease of bone identifies differentially methylated loci that predict disease status","volume":"10","author":"Diboun","year":"2021","journal-title":"eLife"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1007\/s00586-017-5309-y","article-title":"Quantitative evaluation of the relationship between COMP promoter methylation and the susceptibility and curve progression of adolescent idiopathic scoliosis","volume":"27","author":"Mao","year":"2018","journal-title":"Eur. Spine J."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Shi, B., Xu, L., Mao, S., Xu, L., Liu, Z., Sun, X., Zhu, Z., and Qiu, Y. (2018). Abnormal PITX1 gene methylation in adolescent idiopathic scoliosis: A pilot study. BMC Musculoskelet Disord, 19.","DOI":"10.1186\/s12891-018-2054-2"},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Janusz, P., Chmielewska, M., Andrusiewicz, M., Kotwicka, M., and Kotwicki, T. (2021). Methylation of Estrogen Receptor 1 Gene in the Paraspinal Muscles of Girls with Idiopathic Scoliosis and Its Association with Disease Severity. Genes, 12.","DOI":"10.3390\/genes12060790"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"22331","DOI":"10.1038\/s41598-020-78454-4","article-title":"Methylation of estrogen receptor 2 (ESR2) in deep paravertebral muscles and its association with idiopathic scoliosis","volume":"10","author":"Chmielewska","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"364","DOI":"10.3389\/fbioe.2019.00364","article-title":"Whole-Genome Methylation Analysis of Phenotype Discordant Monozygotic Twins Reveals Novel Epigenetic Perturbation Contributing to the Pathogenesis of Adolescent Idiopathic Scoliosis","volume":"7","author":"Liu","year":"2019","journal-title":"Front. Bioeng. Biotechnol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1016\/j.ebiom.2018.09.014","article-title":"Value of DNA methylation in predicting curve progression in patients with adolescent idiopathic scoliosis","volume":"36","author":"Meng","year":"2018","journal-title":"EBioMedicine"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.2106\/00004623-195537060-00012","article-title":"The incidence of scoliosis in the state of Delaware; a study of 50,000 minifilms of the chest made during a survey for tuberculosis","volume":"37","author":"Shands","year":"1955","journal-title":"J. Bone Jt. Surg. Am."},{"key":"ref_80","unstructured":"Sambrook, J., Fritsch, E.F., and Maniatis, T. (1989). Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1093\/bioinformatics\/btu049","article-title":"Minfi: A flexible and comprehensive Bioconductor package for the analysis of Infinium DNA methylation microarrays","volume":"30","author":"Aryee","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.2217\/epi-2017-0078","article-title":"The correlation of methylation levels measured using Illumina 450K and EPIC BeadChips in blood samples","volume":"9","author":"Logue","year":"2017","journal-title":"Epigenomics"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1093\/bioinformatics\/bts034","article-title":"The sva package for removing batch effects and other unwanted variation in high-throughput experiments","volume":"28","author":"Leek","year":"2012","journal-title":"Bioinformatics"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"R31","DOI":"10.1186\/gb-2014-15-2-r31","article-title":"Accounting for cellular heterogeneity is critical in epigenome-wide association studies","volume":"15","author":"Jaffe","year":"2014","journal-title":"Genom. Biol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the false discovery rate: A practical and powerful approach to multiple testing","volume":"57","author":"Benjamini","year":"1995","journal-title":"J. R. Stat. Soc. Ser. B (Methodological)"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"3257","DOI":"10.1093\/bioinformatics\/btz096","article-title":"mCSEA: Detecting subtle differentially methylated regions","volume":"35","year":"2019","journal-title":"Bioinformatics"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1551","DOI":"10.1038\/nprot.2013.092","article-title":"Large-scale gene function analysis with the PANTHER classification system","volume":"8","author":"Mi","year":"2013","journal-title":"Nat. Protoc."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1007\/978-1-60761-175-2_7","article-title":"PANTHER pathway: An ontology-based pathway database coupled with data analysis tools","volume":"563","author":"Mi","year":"2009","journal-title":"Methods Mol. Biol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"D183","DOI":"10.1093\/nar\/gkw1138","article-title":"PANTHER version 11: Expanded annotation data from Gene Ontology and Reactome pathways, and data analysis tool enhancements","volume":"45","author":"Mi","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Supek, F., Bosnjak, M., Skunca, N., and Smuc, T. (2011). REVIGO summarizes and visualizes long lists of gene ontology terms. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0021800"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1080\/15592294.2020.1788325","article-title":"Epigenome-wide cross-tissue correlation of human bone and blood DNA methylation\u2014can blood be used as a surrogate for bone?","volume":"16","author":"Ebrahimi","year":"2020","journal-title":"Epigenetics"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"13555","DOI":"10.1038\/ncomms13555","article-title":"Increased DNA methylation variability in type 1 diabetes across three immune effector cell types","volume":"7","author":"Paul","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1186\/s13073-018-0575-9","article-title":"Increased DNA methylation variability in rheumatoid arthritis-discordant monozygotic twins","volume":"10","author":"Webster","year":"2018","journal-title":"Genom. Med."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"4979","DOI":"10.1242\/dev.068155","article-title":"Dpy19l1, a multi-transmembrane protein, regulates the radial migration of glutamatergic neurons in the developing cerebral cortex","volume":"138","author":"Watanabe","year":"2011","journal-title":"Development"},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Watanabe, K., Bizen, N., Sato, N., and Takebayashi, H. (2016). Endoplasmic Reticulum-Localized Transmembrane Protein Dpy19L1 Is Required for Neurite Outgrowth. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0167985"},{"key":"ref_96","unstructured":"Data, Z.H. (2021, May 17). Phenotype Annotation. Available online: https:\/\/zfin.org\/ZDB-FIG-070117-942."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1016\/j.molcel.2018.09.021","article-title":"Regulation of Neuroregeneration by Long Noncoding RNAs","volume":"72","author":"Perry","year":"2018","journal-title":"Mol. Cell"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"e12736","DOI":"10.1111\/cpr.12736","article-title":"Emerging roles of non-coding RNAs in scoliosis","volume":"53","author":"Li","year":"2020","journal-title":"Cell Prolif."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1038\/nrm3932","article-title":"Mechanisms of retinoic acid signalling and its roles in organ and limb development","volume":"16","author":"Cunningham","year":"2015","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1038\/ncb1374","article-title":"Retinoic-acid signalling in node ectoderm and posterior neural plate directs left-right patterning of somitic mesoderm","volume":"8","author":"Sirbu","year":"2006","journal-title":"Nat. Cell Biol."},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Hitier, M., Hamon, M., Denise, P., Lacoudre, J., Thenint, M.A., Mallet, J.F., Moreau, S., and Quarck, G. (2015). Lateral Semicircular Canal Asymmetry in Idiopathic Scoliosis: An Early Link between Biomechanical, Hormonal and Neurosensory Theories?. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0131120"},{"key":"ref_102","unstructured":"Rousie, D., Joly, O., and Berthoz, A. (2009). Posterior Basicranium asymmetry and idiopathic scoliosis. arXiv."},{"key":"ref_103","doi-asserted-by":"crossref","unstructured":"Carry, P.M., Duke, V.R., Brazell, C.J., Stence, N., Scholes, M., Rousie, D.L., and Hadley Miller, N. (2020). Lateral semi-circular canal asymmetry in females with idiopathic scoliosis. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0232417"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1093\/hmg\/ddh017","article-title":"Myopathy phenotype in transgenic mice expressing mutated PABPN1 as a model of oculopharyngeal muscular dystrophy","volume":"13","author":"Hino","year":"2004","journal-title":"Hum. Mol. Genet."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.ygeno.2013.12.001","article-title":"Neuronatin gene: Imprinted and misfolded: Studies in Lafora disease, diabetes and cancer may implicate NNAT-aggregates as a common downstream participant in neuronal loss","volume":"103","author":"Joseph","year":"2014","journal-title":"Genomics"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1006\/dbio.1997.8681","article-title":"Genetic and functional analysis of neuronatin in mice with maternal or paternal duplication of distal Chr 2","volume":"190","author":"Kikyo","year":"1997","journal-title":"Dev. Biol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1006\/geno.2001.6612","article-title":"The neuronatin gene resides in a \u201cmicro-imprinted\u201d domain on human chromosome 20q11. 2","volume":"77","author":"Evans","year":"2001","journal-title":"Genomics"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1016\/j.npep.2009.08.006","article-title":"NPY regulation of bone remodelling","volume":"43","author":"Lee","year":"2009","journal-title":"Neuropeptides"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"986","DOI":"10.4252\/wjsc.v12.i9.986","article-title":"Mechanisms of action of neuropeptide Y on stem cells and its potential applications in orthopaedic disorders","volume":"12","author":"Wu","year":"2020","journal-title":"World J. Stem. Cells"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"15397","DOI":"10.1038\/ncomms15397","article-title":"WNT10A mutation causes ectodermal dysplasia by impairing progenitor cell proliferation and KLF4-mediated differentiation","volume":"8","author":"Xu","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1038\/ejhg.2013.300","article-title":"Variability in dentofacial phenotypes in four families with WNT10A mutations","volume":"22","author":"Vink","year":"2014","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1016\/j.bone.2011.08.010","article-title":"Wnt6, Wnt10a and Wnt10b inhibit adipogenesis and stimulate osteoblastogenesis through a \u03b2-catenin-dependent mechanism","volume":"50","author":"Cawthorn","year":"2012","journal-title":"Bone"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.1126\/science.aaf6419","article-title":"Zebrafish models of idiopathic scoliosis link cerebrospinal fluid flow defects to spine curvature","volume":"352","author":"Grimes","year":"2016","journal-title":"Science"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1016\/j.ajhg.2008.10.004","article-title":"Asymmetric lower-limb malformations in individuals with homeobox PITX1 gene mutation","volume":"83","author":"Gurnett","year":"2008","journal-title":"Am. J. Hum. Genet."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1038\/nature05919","article-title":"Phenotypic plasticity and the epigenetics of human disease","volume":"447","author":"Feinberg","year":"2007","journal-title":"Nature"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1159\/000323874","article-title":"Epigenetics: Principles and practice","volume":"29","author":"Hamilton","year":"2011","journal-title":"Dig. Dis."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1038\/nm.3074","article-title":"WNT signaling in bone homeostasis and disease: From human mutations to treatments","volume":"19","author":"Baron","year":"2013","journal-title":"Nat. Med."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/8\/1191\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:37:56Z","timestamp":1760164676000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/8\/1191"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,30]]},"references-count":117,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2021,8]]}},"alternative-id":["genes12081191"],"URL":"https:\/\/doi.org\/10.3390\/genes12081191","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,30]]}}}