Abstract
DNA is the blueprint of our human body, and the variations in DNA are the source for the phenotypes of different individuals. With the advancement in the DNA sequencing technologies and the completion of the human HapMap project, we can now better determine the status of risk or causative genetic variants that may lead to the development of disease. Not only can we make use of the technologies to discover every type of DNA variations in the genome, such as single nucleotide polymorphisms and microsatellites, but other variations such as rare alleles and the copy number variations can also be unmasked. These variations may explain some more genetics effects for disease phenotypes and can be used as markers to study the relationship between genotypes and phenotypes. The use of linkage analysis on familial subjects, case-control association studies using population-based subjects on biologically relevant candidate genes or case-control association studies on a genome-wide scale using gene-chip arrays have made mapping of the disease gene possible. Scoliosis is a condition in which the spine becomes deformed and bent abnormally. It affects millions of growing children in the world. The cause is still ill defined. However, it is believed that scoliosis is a complex genetic disorder caused by multiple genes with small effects combined with environmental factors. Candidate-gene and genome-wide association studies using case-control design are the best tools to analyze complex disorders like scoliosis. We believe that with better understanding of human genetics, the cause of scoliosis will likely be elucidated in the not-too-distant future.
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Abecasis GR, Cherny SS, Cookson WO et al (2002) Merlin – rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet 30:97–101
Alden KJ, Marosy B, Nzegwu N, Justice CM, Wilson AF, Miller NH (2006) Idiopathic scoliosis: identification of candidate regions on chromosome 19p13. Spine 31:1815–1819
Andersen MO, Thomsen K, Kyvik KO (2007) Adolescent idiopathic scoliosis in twins – a population-based survey. Spine 32:927–930
Axenovich TI, Zaidman AM, Zorkoltseva IV, Tregubova IL, Borodin PM (1999) Segregation analysis of idiopathic scoliosis: demonstration of a major gene effect. Am J Med Genet 86:389–394
Bao S, Jiang R, Kwan W, Wang B, Ma X, Song YQ (2011) Evaluation of next-generation sequencing software in mapping and assembly. J Hum Genet 56(6):406–414
Barnes AM, Chang W, Morello R, Cabral WA, Weis M, Eyre DR, Leikin S, Makareeva E, Kuznetsova N, Uveges TE, Ashok A, Flor AW, Mulvihill JJ, Wilson PL, Sundaram UT, Lee B, Marini JC (2006) Deficiency of cartilage-associated protein in recessive lethal osteogenesis imperfecta. New Engl J Med 355:2757–2764
Bateman JF, Wilson R, Freddi S, Lamande SR, Savarirayan R (2005) Mutations of COL10A1 in Schmid metaphyseal chondrodysplasia. Hum Mutat 25:525–534
Bulman MP, Kusumi K, Frayling TM, Mckeown C, Garrett C, Lander ES, Krumlauf R, Hattersley AT, Ellard S, Turnpenny PD (2000) Mutations in the human delta homologue, dll3, cause axial skeletal defects in spondylocostal dysostosis. Nat Genet 24:438–441
Burmeister M (1999) Basic concepts in the study of diseases with complex genetics. Biol Psychiatry 45:522–532
Chan V, Fong GC, Luk KD, Yip B, Lee MK, Wong MS, Lu DD, Chan TK (2002) A genetic locus for adolescent idiopathic scoliosis linked to chromosome 19p13.3. Am J Hum Genet 71:401–406
Chen Z, Tang NL, Cao X, Qiao D, Yi L, Cheng JC, Qiu Y (2009) Promoter polymorphism of matrilin-1 gene predisposes to adolescent idiopathic scoliosis in a Chinese population. Eur J Hum Genet 17:525–532
Cheung KM, Wang T, Qiu GX, Luk KD (2007) Recent advances in the aetiology of adolescent idiopathic scoliosis. Int Orthop 15:2:16
Connor JM, Conner AN, Connor RA, Tolmie JL, Yeung B, Goudie D (1987) Genetic aspects of early childhood scoliosis. Am J Med Genet 27:419–424
Cordell HJ, Clayton DG (2005) Genetic association studies. Lancet 366:1121–1131
Crawford DC, Nickerson DA (2005) Definition and clinical importance of haplotypes. Annu Rev Med 56:303–320
Editorial (1999) Freely associating. Nat Genet 22:1–2
Edery P, Margaritte-jeannin P, Biot B, Labalme A, Bernard JC, Chastang J, Kassai B, Plais MH, Moldovan F, Clerget-darpoux F (2011) New disease gene location and high genetic heterogeneity in idiopathic scoliosis. Eur J Hum Genet 19:865–869
Erol B, Tracy MR, Dormans JP, Zackai EH, Maisenbacher MK, O’brien ML, Turnpenny PD, Kusumi K (2004) Congenital scoliosis and vertebral malformations: characterization of segmental defects for genetic analysis. J Pediatr Orthop 24:674–682
Fan YH, Song YQ, Chan D, Takahashi Y, Ikegawa S, Matsumoto M, Kou I, Cheah KS, Sham P, Cheung KM, Luk KD (2012) Snp rs11190870 near lbx1 is associated with adolescent idiopathic scoliosis in southern Chinese. J Hum Genet 57:244–246
Fei Q, Wu Z, Wang H, Zhou X, Wang N, Ding Y, Wang Y, Qiu G (2010) The association analysis of Tbx6 polymorphism with susceptibility to congenital scoliosis in a Chinese Han population. Spine (Phila Pa 1976) 35:983–988
Gao W, Peng Y, Liang G, Liang A, Ye W, Zhang L, Sharma S, Su P, Huang D (2013) Association between common variants near Lbx1 and adolescent idiopathic scoliosis replicated in the Chinese Han population. PLoS One 8:E53234
Gao X, Gordon D, Zhang D, Browne R, Helms C, Gillum J, Weber S, Devroy S, Swaney S, Dobbs M, Morcuende J, Sheffield V, Lovett M, Bowcock A, Herring J, Wise C (2007) CHD7 gene polymorphisms are associated with susceptibility to idiopathic scoliosis. Am J Hum Genet 80:957–965
Geoffroy Saint Hilaire E (1820) Differents etats de pesanteur des oeufs au commencement et a la fin de l’incubation. J Complement Sci Med 7:271
Giampietro PF (2012) Genetic aspects of congenital and idiopathic scoliosis. Scientifica 2012:152365
Giampietro PF, Blank RD, Raggio CL, Merchant S, Jacobsen FS, Faciszewski T, Shukla SK, Greenlee AR, Reynolds C, Schowalter DB (2003) Congenital and idiopathic scoliosis: clinical and genetic aspects. Clin Med Res 1:125–136
Giampietro PF, Raggio CL, Reynolds CE, Shukla SK, Mcpherson E, Ghebranious N, Jacobsen FS, Kumar V, Faciszewski T, Pauli RM, Rasmussen K, Burmester JK, Zaleski C, Merchant S, David D, Weber JL, Glurich I, Blank RD (2005) An analysis of Pax1 in the development of vertebral malformations. Clin Genet 68:448–453
Giampietro PF, Raggio CL, Reynolds C, Ghebranious N, Burmester JK, Glurich I, Rasmussen K, Mcpherson E, Pauli RM, Shukla SK, Merchant S, Jacobsen FS, Faciszewski T, Blank RD (2006) Dll3 as a candidate gene for vertebral malformations. Am J Med Genet A 140:2447–2453
Giampietro PF, Raggio CL, Blank RD (2012) Use of synteny conversion in identification of candidate genes for somitogenesis in humans. Open J Orthop 2:62–68
Gudbjartsson DF, Jonasson K, Frigge ML et al (2000) Allegro, a new computer program for multipoint linkage analysis. Nat Genet 25:12–13
Humphries SE, Luong LA, Talmud PJ et al (1998) The 5A/6A polymorphism in the promoter of the stromelysin-1 (MMP-3) gene predicts progression of angiographically determined coronary artery disease in men in the LOCAT gemfibrozil study. Lopid Coronary Angiography Trial. Atherosclerosis 139:49–56
Ingalls TH, Curley FJ (1957) Principles governing the genesis of congenital malformations induced in mice by hypoxia. N Engl J Med 257:1121–1127
Inoue M, Minami S, Nakata Y, Kitahara H, Otsuka Y, Isobe K, Takaso M, Tokunaga M, Nishikawa S, Maruta T, Moriya H (2002) Association between estrogen receptor gene polymorphisms and curve severity of idiopathic scoliosis. Spine 27:2357–2362
Justice CM, Miller NH, Marosy B, Zhang J, Wilson AF (2003) Familial idiopathic scoliosis: evidence of an X-linked susceptibility locus. Spine 28:589–594
Kizawa H, Kou I, Iida A, Sudo A, Miyamoto Y, Fukuda A, Mabuchi A, Kotani A, Kawakami A, Yamamoto S, Uchida A, Nakamura K, Notoya K, Nakamura Y, Ikegawa S (2005) An aspartic acid repeat polymorphism in asporin inhibits chondrogenesis and increases susceptibility to osteoarthritis. Nat Genet 37(2):138–144
Koboldt DC, Steinberg KM, Larson D, Wilson RK, Mard ER (2013) The next-generation sequencing revolution and its impact on genomics. Cell 155:27–38
Kou I, Takahashi Y, Johnson TA, Takahashi A, Guo L, Dai J, Qiu X, Sharma S, Takimoto A, Ogura Y, Jiang H, Yan H, Kono K, Kawakami N, Uno K, Ito M, Minami S, Yanagida H, Taneichi H, Hosono N, Tsuji T, Suzuki T, Sudo H, Kotani T, Yonezawa I, Londono D, Gordon D, Herring JA, Watanabe K, Chiba K, Kamatani N, Jiang Q, Hiraki Y, Kubo M, Toyama Y, Tsunoda T, Wise CA, Qiu Y, Shukunami C, Matsumoto M, Ikegawa S (2013) Genetic variants in GPR126 are associated with adolescent idiopathic scoliosis. Nat Genet 45(6):676–679
Kruglyak L, Daly MJ, Reeve-Daly MP et al (1996) Parametric and nonparametric linkage analysis: a unified multipoint approach. Am J Hum Genet 58:1347–1363
Kruglyak L, Lander ES (1995) Complete multipoint sib-pair analysis of qualitative and quantitative traits. Am J Hum Genet 57:439–454
Lander E, Kruglyak L (1995) Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 11:241–247
Lander ES, Linton LM, Birren B et al (2001) Initial sequencing and analysis of the human genome. Nature 409:860–921
Li L, Krantz ID, Deng Y, Genin A, Banta AB, Collins CC, Qi M, Trask BJ, Kuo WL, Cochran J, Costa T, Pierpont ME, Rand EB, Piccoli DA, Hood L, Spinner NB (1997) Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nat Genet 16:243–251
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, The 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 (2014) A meta-analysis identifies adolescent idiopathic scoliosis association with LBX1 locus in multiple ethnic groups. J Med Genet 51(6):401–406. doi:10.1136/jmedgenet-2013-102067
Maisenbacher MK, Han JS, O’brien ML, Tracy MR, Erol B, Schaffer AA, Dormans JP, Zackai EH, Kusumi K (2005) Molecular analysis of congenital scoliosis: a candidate gene approach. Hum Genet 116:416–419
Marosy B, Justice CM, Nzegwu N, Kumar G, Wilson AF, Miller NH (2006) Lack of association between the aggrecan gene and familial idiopathic scoliosis. Spine 31:1420–1425
Miller NH, Marosy B, Justice CM, Novak SM, Tang EY, Boyce P, Pettengil J, Doheny KF, Pugh EW, Wilson AF (2006) Linkage analysis of genetic loci for kyphoscoliosis on chromosomes 5p13, 13q13.3, and 13q32. Am J Med Genet A 140:1059–1068
Miller NH (2007) Genetics of familial idiopathic scoliosis. Clin Orthop Related Res 462:6–10
Miyake A, Kou I, Takahashi Y, Johnson TA, Ogura Y, Dai J, Qiu X, Takahashi A, Jiang H, Yan H, Kono K, Kawakami N, Uno K, Ito M, Minami S, Yanagida H, Taneichi H, Hosono N, Tsuji T, Suzuki T, Sudo H, Kotani T, Yonezawa I, Kubo M, Tsunoda T, Watanabe K, Chiba K, Toyama Y, Qiu Y, Matsumoto M, Ikegawa S (2013) Identification of a susceptibility locus for severe adolescent idiopathic scoliosis on chromosome 17q24.3. PLoS One 8:E72802
Montanaro L, Parisini P, Greggi T, Di Silvestre M, Campoccia D, Rizzi S, Arciola CR (2006) Evidence of a linkage between matrilin-1 gene (MATN1) and idiopathic scoliosis. Scoliosis 1:21
Morello R, Bertin TK, Chen Y, Hicks J, Tonachini L, Monticone M, Castagnola P, Rauch F, Glorieux FH, Vranka J, Bachinger HP, Pace JM, Schwarze U, Byers PH, Weis M, Fernandes RJ, Eyre DR, Yao Z, Boyce BF, Lee B (2006) CRTAP is required for prolyl 3-hydroxylation and mutations cause recessive osteogenesis imperfecta. Cell 127:291–304
Morocz M, Czibula A, Grozer ZB, Szecsenyi A, Almos PZ, Rasko I, Illes T (2011) Association study of BMP4, IL6, Leptin, MMP3, and MTNR1B gene promoter polymorphisms and adolescent idiopathic scoliosis. Spine (Phila Pa 1976) 36:E123–E130
Morton NE (1955) Sequential tests for the detection of linkage. Am J Hum Genet 7:277–318
Ocaka L, Zhao C, Reed JA, Ebenezer ND, Brice G, Morley T, Mehta M, O’dowd J, Weber JL, Hardcastle AJ, Child AH (2007) Assignment of two loci for autosomal dominant adolescent idiopathic scoliosis (AIS) to chromosomes 9q31.2-q34.2 and 17q25.3-qtel. J Med Genet 45(2):87–92
Oda T, Elkahloun AG, Pike BL, Okajima K, Krantz ID, Genin A, Piccoli DA, Meltzer PS, Spinner NB, Collins FS, Chandrasekharappa SC (1997) Mutations in the human Jagged1 gene are responsible for Alagille syndrome. Nat Genet 16:235–242
Ogilvie JW, Braun J, Argyle V, Nelson L, Meade M, Ward K (2006) The search for idiopathic scoliosis genes. Spine 31:679–681
Ott J (1999) Analysis of human genetic linkaged. Johns Hopkins University Press, Baltimore
Pagon RA (2002) Genetic testing for disease susceptibilities: consequences for genetic counseling. Trends Mol Med 8:306–307
Peng Y, Liang G, Pei Y, Ye W, Liang A, Su P (2012) Genomic polymorphisms of G-protein estrogen receptor 1 are associated with severity of adolescent idiopathic scoliosis. Int Orthop 36:671–677
Penrose LS (1953) The general purpose sibpair linkage test. Ann Eugen 18:120–124
Peters T, Sedlmeier R (2006) Current methods for high-throughput detection of novel DNA polymorphisms. Drug Discov Today 3:123–129
Pourquie O (2011) Vertebrate segmentation: from cyclic gene networks to scoliosis. Cell 145:650–663
Pritchard JK, Cox NJ (2002) The allelic architecture of human disease genes: common disease-common variant… or not? Hum Mol Genet 11:2417–2423
Qiu XS, Tang NL, Yeung HY, Lee KM, Hung VW, Ng BK, Ma SL, Kwok RH, Qin L, Qiu Y, Cheng JC (2007) Melatonin receptor 1B (MTNR1B) gene polymorphism is associated with the occurrence of adolescent idiopathic scoliosis. Spine 32:1748–1753
Qiu XS, Tang NL, Yeung HY, Qiu Y, Cheng JC (2007) Genetic association study of growth hormone receptor and idiopathic scoliosis. Clin Orthop Relat Res 462:53–58
Raggio CL, Giampietro PF, Dobrin S, Zhao C, Dorshorst D, Ghebranious N, Weber JL, Blank RD (2009) A novel locus for adolescent idiopathic scoliosis on chromosome 12p. J Orthop Res 27:1366–1372
Rajab A, Kunze J, Mundlos S (2004) Spondyloepiphyseal dysplasia Omani type: a new recessive type of SED with progressive spinal involvement. Am J Med Genet 126A:413–419
Salehi LB, Mangino M, De Serio S, De Cicco D, Capon F, Semprini S, Pizzuti A, Novelli G, Dallapiccola B (2002) Assignment of a locus for autosomal dominant idiopathic scoliosis (IS) to human chromosome 17p11. Hum Genet 111:401–404
Sanlaville D, Etchevers HC, Gonzales M, Martinovic J, Clement-Ziza M, Delezoide A-L, Aubry M-C, Pelet A, Chemouny S, Cruaud C, Audollent S, Esculpavit C et al (2006) Phenotypic spectrum of CHARGE syndrome in fetuses with CHD7 truncating mutations correlates with expression during human development. J Med Genet 43:211–217
Seki S, Kawaguchi Y, Chiba K et al (2005) A functional SNP in CILP, encoding cartilage intermediate layer protein, is associated with susceptibility to lumbar disc disease. Nat Genet 37:607–612
Sham P (1998) Statistics in human genetics. Arnold, London
Shands AR Jr, Eisberg HB (1955) The incidence of scoliosis in the state of Delaware: a study of 50,000 Minifilms of the chest made during a survey for tuberculosis. J Bone Joint Surg Am 37-a:1243–1249
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 (2011) Genome-wide Association studies of adolescent idiopathic scoliosis suggest candidate susceptibility genes. Hum Mol Genet 20:1456–1466
Song YQ, Cheung KMC, Ho DWH, Poon SCS, Chiba K, Kawaguchi Y, Hirose Y, Alini M, Yee AFY, Leong JCY, Luk KDK, Yip SP, Cheah KSE, Sham P, Ikegawa S, Chan D (2008) Asporin D14 allele increases the risk of lumbar disc degeneration in Chinese and Japanese populations. Am J Hum Genet 82(3):744–747
Sparrow DB, Chapman G, Smith AJ, Mattar MZ, Major JA, O’reilly VC, Saga Y, Zackai EH, Dormans JP, Alman BA, Mcgregor L, Kageyama R, Kusumi K, Dunwoodie SL (2012) A mechanism for gene-environment interaction in the etiology of congenital scoliosis. Cell 149:295–306
Sparrow DB, Chapman G, Wouters MA, Whittock NV, Ellard S, Fatkin D, Turnpenny PD, Kusumi K, Sillence D, Dunwoodie SL (2006) Mutation of the lunatic fringe gene in humans causes spondylocostal dysostosis with a severe vertebral phenotype. Am J Hum Genet 78:28–37
Sparrow DB, Sillence D, Wouters MA, Turnpenny PD, Dunwoodie SL (2010) Two novel missense mutations in hairy-and-enhancer-of-split-7 in a family with spondylocostal dysostosis. Eur J Hum Genet 18:674–679
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 (2011) A genome-wide association study identifies common variants near Lbx1 associated with adolescent idiopathic scoliosis. Nat Genet 43:1237–1240
Takahashi Y, Matsumoto M, Karasugi T, Watanabe K, Chiba K, Kawakami N, Tsuji T, Uno K, Suzuki T, Ito M, Sudo H, Minami S, Kotani T, Kono K, Yanagida H, Taneichi H, Takahashi A, Toyama Y, Ikegawa S (2011) Lack of association between adolescent idiopathic scoliosis and previously reported single nucleotide polymorphisms in Matn1, Mtnr1b, Tph1, and Igf1 in a Japanese population. J Orthop Res 29:1055–1058
Tang NL, Yeung HY, Lee KM, Hung VW, Cheung CS, Ng BK, Kwok R, Guo X, Qin L, Cheng JC (2006) A relook into the association of the estrogen receptor [alpha] gene (PvuII, XbaI) and adolescent idiopathic scoliosis: a study of 540 Chinese cases. Spine 31:2463–2468
The International HapMap Consortium (2003) The international HapMap project. Nature 426:789–796
Thiele H, Sakano M, Kitagawa H, Sugahara K, Rajab A, Hohne W, Ritter H, Leschik G, Nurnberg P, Mundlos S (2004) Loss of chondroitin 6-O-sulfotransferase-1 function results in severe human chondrodysplasia with progressive spinal involvement. Proc Natl Acad Sci U S A 101:10155–10160
Venter JC, Adams MD, Myers EW et al (2001) The sequence of the human genome. Science 291:1304–1351
Wang H, Wu Z, Zhuang Q, Fei Q, Zhang J, Liu Y, Wang Y, Ding Y, Qiu G (2008) Association study of tryptophan hydroxylase 1 and arylalkylamine n-acetyltransferase polymorphisms with adolescent idiopathic scoliosis in Han Chinese. Spine (Phila Pa 1976) 33:2199–2203
Weeks DE, Lange K (1988) The affected-pedigree-member method of linkage analysis. Am J Hum Genet 42:315–326
Weinstein SL (1999) Natural history. Spine (Phila Pa 1976) 24:2592–2600
Whittemore AS, Halpern J (1994) A class of tests for linkage using affected pedigree members. Biometrics 50:118–127
Whittock NV, Sparrow DB, Wouters MA, Sillence D, Ellard S, Dunwoodie SL, Turnpenny PD (2004) Mutated Mesp2 causes spondylocostal dysostosis in humans. Am J Hum Genet 74:1249–1254
Winter RB (1988) Congenital scoliosis. Orthop Clin North Am 19:395–408
Wise CA, Barnes R, Gillum J, Herring JA, Bowcock AM, Lovett M (2000) Localization of susceptibility to familial idiopathic scoliosis. Spine 15(25):2372–2380
Wu J, Qiu Y, Zhang L, Sun Q, Qiu X, He Y (2006) Association of estrogen receptor gene polymorphisms with susceptibility to adolescent idiopathic scoliosis. Spine 31:1131–1136
Wynne-Davies R (1969) Familial idiopathic scoliosis: a family survey. J Bone Joint Surg 50B:24–30
Wynne-Davies R (1975) Congenital vertebral anomalies: aetiology and relationship to spina bifida cystica. J Med Genet 12:280–288
Yeung HY, Tang NL, Lee KM, Ng BK, Hung VW, Kwok R, Guo X, Qin L, Cheng JC (2006) Genetic association study of insulin-like growth factor-I (IGF-I) gene with curve severity and osteopenia in adolescent idiopathic scoliosis. Stud Health Technol Inform 123:18–24
Zhang HQ, Lu SJ, Tang MX, Chen LQ, Liu SH, Guo CF, Wang XY, Chen J, Xie L (2009) Association of estrogen receptor beta gene polymorphisms with susceptibility to adolescent idiopathic scoliosis. Spine (Phila Pa 1976) 34:760–764
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Cheung, K.M.C., To, M., Ho, D.W.H., Song, YQ. (2016). Genetics. In: Akbarnia, B., Yazici, M., Thompson, G. (eds) The Growing Spine. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-48284-1_2
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