Understanding Genetic Factors in Idiopathic Scoliosis, a Complex Disease of Childhood

Wise, Carol A.; Gao, Xiaochong; Shoemaker, Scott; Gordon, Derek; Herring, John A.

doi:10.2174/138920208783884874

Cited by 81 publications

(64 citation statements)

References 79 publications

(65 reference statements)

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“…These deformities range in both severity and progression with a significant bias for severe curves in females. 11,12 Familial clustering and concordance among monozygotic twins indicates a primary genetic cause for IS 13,14 and genome-wide association studies have identified polymorphisms associated with IS in divergent human populations. 15-17 However, phenotypic and genetic heterogeneity have typically made it difficult to define causative mutations in humans.…”

Section: Introductionmentioning

confidence: 99%

ptk7 mutant zebrafish models of congenital and idiopathic scoliosis implicate dysregulated Wnt signalling in disease

et al. 2014

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Scoliosis is a complex genetic disorder of the musculoskeletal system, characterized by three-dimensional rotation of the spine. Curvatures caused by malformed vertebrae (congenital scoliosis/CS) are apparent at birth. Spinal curvatures with no underlying vertebral abnormality (idiopathic scoliosis/IS) most commonly manifest during adolescence. The genetic and biological mechanisms responsible for IS remain poorly understood due largely to limited experimental models. Here we describe zygotic ptk7 (Zptk7) mutant zebrafish, deficient in a critical regulator of Wnt signaling, as the first genetically defined developmental model of IS. We identify a novel sequence variant within a single IS patient that disrupts PTK7 function, consistent with a role for dysregulated Wnt activity in disease pathogenesis. Furthermore, we demonstrate that embryonic loss of gene function in maternal-zygotic ptk7 mutants (MZptk7) leads to vertebral anomalies associated with congenital scoliosis. Our data suggest novel molecular origins of, and genetic links between, congenital and idiopathic forms of disease.

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Section: Introductionmentioning

confidence: 99%

ptk7 mutant zebrafish models of congenital and idiopathic scoliosis implicate dysregulated Wnt signalling in disease

et al. 2014

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“…AIS is a multi-factorial disorder, with genetic factors playing an important role in its etiology [3]. Population studies have shown that its familial incidence is higher than that in general populations [4], while twin studies have consistently shown higher concordance in monozygotic compared with dizygotic twins.…”

Section: Introductionmentioning

confidence: 99%

Identification of a Susceptibility Locus for Severe Adolescent Idiopathic Scoliosis on Chromosome 17q24.3

et al. 2013

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Adolescent idiopathic scoliosis (AIS) is the most common spinal deformity, affecting around 2% of adolescents worldwide. Genetic factors play an important role in its etiology. Using a genome-wide association study (GWAS), we recently identified novel AIS susceptibility loci on chromosomes 10q24.31 and 6q24.1. To identify more AIS susceptibility loci relating to its severity and progression, we performed GWAS by limiting the case subjects to those with severe AIS. Through a two-stage association study using a total of ∼12,000 Japanese subjects, we identified a common variant, rs12946942 that showed a significant association with severe AIS in the recessive model (P = 4.00×10−8, odds ratio [OR] = 2.05). Its association was replicated in a Chinese population (combined P = 6.43×10−12, OR = 2.21). rs12946942 is on chromosome 17q24.3 near the genes SOX9 and KCNJ2, which when mutated cause scoliosis phenotypes. Our findings will offer new insight into the etiology and progression of AIS.

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“…The role of genetic factors in scoliosis is well-documented and widely accepted. [5][6][7][8] Genome-wide linkage analyses have identified susceptibility loci on chromosome 6p, 8q12, 9q31.2-q34.2, 10q, 12p, 17p11, 17q25.30-qtel, 18q, 19p13 and chromosome X. [9][10][11][12][13][14][15][16] Several candidate gene studies have also reported that genes such as COL1A1, COL1A2, FBN1, ESR, MATN1, MTNR1B, CHD7, VDR and GPER were associated with scoliosis.…”

Section: Introductionmentioning

confidence: 99%

SNP rs11190870 near LBX1 is associated with adolescent idiopathic scoliosis in southern Chinese

et al. 2012

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A study was conducted to validate the most significant single nucleotide polymorphism (SNP) from a genome-wide association study of Japanese adolescent idiopathic scoliosis (AIS) patients in an independent southern Chinese population. In total, 300 AIS patients fulfilled the clinical criteria and 788 controls with MRI scans of the spine were included in the replication study. We employed case-control analysis to study the association of SNP rs11190870 near LBX1 (ladybird homeobox 1) with AIS in a southern Chinese population. The results suggest that SNP rs11190870 is significantly associated with AIS (P¼9.1Â10 À10 ; odds ratio¼1.85; 95% confidence interval¼1.52-2.25). The results of this study confirm that SNP rs11190870 is associated with AIS. Keywords: adolescent idiopathic scoliosis; replication study; rs11190870; southern Chinese INTRODUCTIONThe most common form of scoliosis is adolescent idiopathic scoliosis (AIS). AIS affects 1-4% of children aged between 10 and 16 years, 1,2 and affects more females than males. 3,4 It is known that the inheritance of AIS is complex. The role of genetic factors in scoliosis is well-documented and widely accepted. 5-8 Genome-wide linkage analyses have identified susceptibility loci on chromosome 6p, 8q12, 9q31.2-q34. 2, 10q, 12p, 17p11, 17q25.30-qtel, 18q, 19p13 and chromosome X. 9-16 Several candidate gene studies have also reported that genes such as COL1A1, COL1A2, FBN1, ESR, MATN1, MTNR1B, CHD7, VDR and GPER were associated with scoliosis. 10,[17][18][19][20][21][22][23][24] Recently, a genome-wide association study (GWAS) has been applied to identify the susceptibility loci of AIS. 25 The single nucleotide polymorphism (SNP) rs11190870 that is located in the 3¢-flanking region of LBX1 (ladybird homeobox 1) gene at chromosome 10q24.31 was identified as the most significant common variant in Japanese females with P¼1.24Â10 19 ; odds ratio (OR)¼1.56. 25 In the present study, we conducted a study to validate the association of rs11190870 with AIS in an independent southern Chinese population that contains 300 cases and 788 controls. Our results suggest that the SNP rs11190870 is highly significantly associated with AIS. MATERIALS AND METHODS SubjectsInformed consent was obtained from all individuals participating in this study. A cohort consisting of 300 AIS patients was recruited at the Duchess of Kent Children's Hospital in Hong Kong. The patient selection criteria for the study are as follows: (1) Patients with idiopathic scoliosis deformity involving the thoracic plus or minus the lumbar spine with Cobb's angles more than 35 degrees and required surgical operations in Duchess of Kent Children's Hospital. (2) The onset of scoliosis deformity was after 10 years and under 20 years of age. (3) Neuromuscular, congenital and syndromal scoliosis individuals were excluded by history taking, physical examination and X-ray of the spine. The control samples were from a large data set of southern Chinese population (3500 samples) recruited for a study on the genetics of degenera...

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Understanding Genetic Factors in Idiopathic Scoliosis, a Complex Disease of Childhood

Cited by 81 publications

References 79 publications

ptk7 mutant zebrafish models of congenital and idiopathic scoliosis implicate dysregulated Wnt signalling in disease

ptk7 mutant zebrafish models of congenital and idiopathic scoliosis implicate dysregulated Wnt signalling in disease

Identification of a Susceptibility Locus for Severe Adolescent Idiopathic Scoliosis on Chromosome 17q24.3

SNP rs11190870 near LBX1 is associated with adolescent idiopathic scoliosis in southern Chinese

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