Assignment of a locus for autosomal dominant idiopathic scoliosis (IS) to human chromosome 17p11 (original) (raw)
Related papers
PLoS ONE, 2013
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 = 4.00610 28 , odds ratio [OR] = 2.05). Its association was replicated in a Chinese population (combined P = 6.43610 212 , 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.
New disease gene location and high genetic heterogeneity in idiopathic scoliosis
European Journal of Human Genetics, 2011
Idiopathic scoliosis is a spine disorder of unknown origin with 1.5-3% prevalence in the general population. Besides the large multifactorial form sample of idiopathic scoliosis, there is a good evidence for the existence of a monogenic subgroup in which the disease is inherited in a dominant manner. However, results from literature suggest a strong heterogeneity in the locations of the mutated genes. Using a high resolution genome-wide scan, we performed linkage analyses in three large multigenerational idiopathic scoliosis families compatible with dominant inheritance including 9 to 12 affected members or obligate carriers. In two of these families, our results suggested intra-familial genetic heterogeneity whereas, in the other, we observed a perfect marker disease co-segregation in two regions at 3q12.1 and 5q13.3. We can state that one of these two locations is a novel idiopathic scoliosis disease gene locus, since the probability of having this perfect co-segregation twice by chance in the genome is very low (p=0.001). Lastly, in all three families studied, linkage to the previously mapped dominant idiopathic scoliosis loci on chromosomes 19p13.3, 17p11.2, 9q34, 17q25 and 18q is unlikely, confirming that there is a high genetic heterogeneity within the subgroup of dominant forms of idiopathic scoliosis.
Localization of Susceptibility to Familial Idiopathic Scoliosis
Spine, 2000
Study Design. Genome-wide linkage surveys in large multiplex families with apparent inherited idiopathic scoliosis. Objective. To identify chromosomal loci encoding genes involved in susceptibility to idiopathic scoliosis by positional cloning. Summary of Background Data. Although the inheritance of idiopathic scoliosis most often exhibits a complex pattern, autosomal dominant inheritance can be identified in some families. Families exhibiting such an inheritance pattern present an opportunity to identify the predisposing gene(s) by positional cloning. Methods. Probands having clinically relevant idiopathic scoliosis (50°Cobb angle) from large multiplex families were identified. A curve of 15°, made from standing posteroanterior radiographs, was required for a positive diagnosis. A genome-wide search in one large family (seven affected members) was conducted with 385 polymorphic microsatellite markers spaced at an approximate 10-cM resolution. Hot spots identified in this family were subsequently tested in a second large kindred. Results. Maximum evidence of allele-sharing in affected individuals from the first family was detected for three loci on chromosomes 6p, distal 10q, and 18q with nonparametric lod scores of 1.42 (P ϭ 0.020), 1.60 (P ϭ 0.019), and 8.26 (P ϭ 0.002), respectively. Evidence of allele-sharing was also detected in the second family at distal chromosome 10q (nonparametric lod score ϭ 2.02; P ϭ 0.033). Conclusions. These data indicate a limited number of genetic loci predisposing to idiopathic scoliosis.
A Genetic Locus for Adolescent Idiopathic Scoliosis Linked to Chromosome 19p13.3
The American Journal of Human Genetics, 2002
Adolescent idiopathic scoliosis (AIS) is one of the most common orthopedic disorders, affecting up to 4% of schoolchildren worldwide. We studied seven unrelated multiplex families of southern Chinese descent with AIS, consisting of 25 affected members. A genomewide scan with 1400 fluorescent microsatellite markers was performed. Multipoint linkage analysis by GENEHUNTER revealed significant linkage of the abnormal phenotype to the distal short arm of chromosome 19, with both a maximum multipoint LOD score and a nonparametric LOD score of 4.93. Two-point linkage analysis by MLINK gave a LOD score of 3.63 (recombination fraction ) at v p 0.00 [mpf] D19S216. Further high-density mapping and informative recombinations defined the AIS critical region in the vicinity of D19S216, flanked by D19S894 and D19S1034, spanning 5.2 cM on the sex-averaged genetic map on chromosome 19p13.3.
Genetic Association of Complex Traits Using Idiopathic Scoliosis as an Example
Although the exact etiology of adolescent idiopathic scoliosis is still undefined, genetic factors play an important role. Some patients have familial genetic disease that appears to have an autosomal dominant pattern. Linkage studies of these families revealed multiple potential genetic loci that may predispose individuals to the condition. Additional genetic analysis is required to identify the disease-predisposition genes of the loci found in the linkage studies. The initial localization of potential critical loci through large family-based population studies now needs fine mapping by association studies using high-density polymorphic markers (single nucleotide polymorphisms or SNPs). These markers are now available as a result of the Human Genome Project, International HapMap Project, and other genetic diversity projects. The application of this emerging data in a large association study of affected individuals and controls is integral for the identification of putative genes. With these complementary approaches, we will be able to progress with mutational analysis of hopefully a small set of candidate genes in the near future. In this commentary, we illustrate what is possible in the genomic era, and indicate what we should expect from genetic studies in adolescent idiopathic scoliosis, a complex trait disease.
Are Copy Number Variants Associated With Adolescent Idiopathic Scoliosis?
Clinical Orthopaedics and Related Research®, 2014
Background Adolescent idiopathic scoliosis (AIS) is a complex genetic disorder that causes spinal deformity in approximately 3% of the population. Candidate gene, linkage, and genome-wide association studies have sought to identify genetic variation that predisposes individuals to AIS, but the genetic basis remains unclear. Copy number variants are associated with several isolated skeletal phenotypes, but their role in AIS, to our knowledge, has not been assessed.