Genetics of adolescent idiopathic scoliosis in the post-genome-wide association study era.
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ABSTRACT:
SUBMITTER: Zhao L
PROVIDER: S-EPMC4437951 | biostudies-literature | 2015 May
REPOSITORIES: biostudies-literature
Publications
Genetics of adolescent idiopathic scoliosis in the post-genome-wide association study era.
Zhao Linlu L Roffey Darren M DM Chen Suzan S
Annals of translational medicine 20150501 Suppl 1
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Project description:Genome-wide association studies (GWAS) of myopia and refractive error have generated exciting results and identified novel risk-associated loci. However, the interpretation of the findings of GWAS of complex diseases is not straightforward and has remained challenging. This review provides a brief summary of the main focus on the advantages and limitations of GWAS of myopia, with potential strategies that may contribute to further insight into the genetics of myopia in the post-GWAS or omics era.
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Project description:Adolescent idiopathic scoliosis (AIS) is an unexplained and common spinal deformity seen in otherwise healthy children. Its pathophysiology is poorly understood despite intensive investigation. Although genetic underpinnings are clear, replicated susceptibility loci that could provide insight into etiology have not been forthcoming. To address these issues, we performed genome-wide association studies (GWAS) of ?327 000 single nucleotide polymorphisms (SNPs) in 419 AIS families. We found strongest evidence of association with chromosome 3p26.3 SNPs in the proximity of the CHL1 gene (P < 8 × 10(-8) for rs1400180). We genotyped additional chromosome 3p26.3 SNPs and tested replication in two follow-up case-control cohorts, obtaining strongest results when all three cohorts were combined (rs10510181 odds ratio = 1.49, 95% confidence interval = 1.29-1.73, P = 2.58 × 10(-8)), but these were not confirmed in a separate GWAS. CHL1 is of interest, as it encodes an axon guidance protein related to Robo3. Mutations in the Robo3 protein cause horizontal gaze palsy with progressive scoliosis (HGPPS), a rare disease marked by severe scoliosis. Other top associations in our GWAS were with SNPs in the DSCAM gene encoding an axon guidance protein in the same structural class with Chl1 and Robo3. We additionally found AIS associations with loci in CNTNAP2, supporting a previous study linking this gene with AIS. Cntnap2 is also of functional interest, as it interacts directly with L1 and Robo class proteins and participates in axon pathfinding. Our results suggest the relevance of axon guidance pathways in AIS susceptibility, although these findings require further study, particularly given the apparent genetic heterogeneity in this disease.
| S-EPMC3049353 | biostudies-literature
Project description:Adolescent idiopathic scoliosis (AIS) is a structural deformity of the spine affecting millions of children. As a complex disease, the genetic aetiology of AIS remains obscure. Here we report the results of a four-stage genome-wide association study (GWAS) conducted in a sample of 4,317 AIS patients and 6,016 controls. Overall, we identify three new susceptibility loci at 1p36.32 near AJAP1 (rs241215, Pcombined=2.95 × 10(-9)), 2q36.1 between PAX3 and EPHA4 (rs13398147, Pcombined=7.59 × 10(-13)) and 18q21.33 near BCL-2 (rs4940576, Pcombined=2.22 × 10(-12)). In addition, we refine a previously reported region associated with AIS at 10q24.32 (rs678741, Pcombined=9.68 × 10(-37)), which suggests LBX1AS1, encoding an antisense transcript of LBX1, might be a functional variant of AIS. This is the first GWAS investigating genetic variants associated with AIS in Chinese population, and the findings provide new insight into the multiple aetiological mechanisms of AIS.
| S-EPMC4595747 | biostudies-literature
Project description:Adolescent idiopathic scoliosis (AIS) is the most common pediatric spinal deformity. Several AIS susceptibility loci have been identified; however, they could explain only a small proportion of AIS heritability. To identify additional AIS susceptibility loci, we conduct a meta-analysis of the three genome-wide association studies consisting of 79,211 Japanese individuals. We identify 20 loci significantly associated with AIS, including 14 previously not reported loci. These loci explain 4.6% of the phenotypic variance of AIS. We find 21 cis-expression quantitative trait loci-associated genes in seven of the fourteen loci. By a female meta-analysis, we identify additional three significant loci. We also find significant genetic correlations of AIS with body mass index and uric acid. The cell-type specificity analyses show the significant heritability enrichment for AIS in multiple cell-type groups, suggesting the heterogeneity of etiology and pathogenesis of AIS. Our findings provide insights into etiology and pathogenesis of AIS.
| S-EPMC6695451 | biostudies-literature
Project description:Adolescent Idiopathic Scoliosis (AIS) is the most common orthopedic condition requiring surgery, affecting 4% of adolescents. There is currently no proven method or prognostic test to identify symptomatic patients at risk of developing severe scoliosis who could benefit from growth-guided devices or minimally invasive non-fusion instrumentation surgeries. These innovative treatments must be performed at an early disease stage in younger patients to benefit from their growth potential. In this prospective cross-sectional study, we investigated the clinical utility of circulating microRNAs (miRNAs), an important class of small non-coding RNA, as biomarkers to predict the risk of developing severe scoliosis in AIS. Blood samples and clinical data were collected from 116 AIS patients who were followed until skeletal maturity and stratified according to their clinical outcome. Genome-wide expression profiling of miRNAs was performed with plasma obtained at the time of diagnosis of AIS (mean age of 13.3 ± 1.7 years with a mean Cobb angle of 24.4° ± 12.4°). This approach led to the identification of 15 circulating miRNAs that are upregulated in AIS patients who developed a severe scoliosis (Cobb angle ≥45°) at skeletal maturity compared to moderate and mild scoliosis groups (Cobb angle between 25°-44° and <25° respectively). After optimization and the application of Random Forest Models a panel of six miRNAs (miR-1-3p, miR-19a-3p, miR-19b-3p, miR-133b, miR-143-3p, and miR-148b-3p) out of 15 led us to develop an algorithm predicting the risk of developing a severe scoliosis with great accuracy (100%), sensitivity (100%) and specificity (100%). Having a scoliosis predictive bioassay and decision-making tools to predict curve progression in order to find the best treatment plan will undoubtedly transform the orthopedic care system in the field of pediatric scoliosis by integrating innovative precision medicine approaches. In addition, investigation of genes targeted by these miRNAs could fill our gaps in our understanding of AIS pathogenesis and reveal new actionable targets.
2025-01-12 | GSE286204 | GEO
Project description:Adolescent Idiopathic Scoliosis 1000 Exomes Study
| PRJNA488323 | ENA
Project description:Adolescent Idiopathic Scoliosis 1000 Exomes Study
| PRJNA488324 | ENA
Project description:Numerous adolescents diagnosed with adolescent idiopathic scoliosis (AIS) often manifest symptoms indicative of functional gastrointestinal disorders (FGIDs). However, the precise connection between FGIDs and AIS remains unclear. The study involved adolescents drawn from sample datasets provided by the Korean Health Insurance Review and Assessment Service spanning from 2012 to 2016, with a median dataset size of 1,446,632 patients. The AIS group consisted of individuals aged 10 to 19 with diagnostic codes for AIS, while the control group consisted of those without AIS diagnostic codes. The median prevalence of FGIDs in adolescents with AIS from 2012 to 2016 was 24%. When accounting for confounding factors, the analysis revealed that adolescents with AIS were consistently more prone to experiencing FGIDs each year (2012: adjusted odds ratio (aOR), 1.21 [95% confidence interval (CI), 1.10-1.35], p < 0.001; 2013: aOR, 1.31 [95% CI, 1.18-1.46], p < 0.001; 2014: aOR, 1.24 [95% CI, 1.12-1.38], p < 0.001; 2015: aOR, 1.34 [95% CI, 1.21-1.49], p < 0.001; and 2016: aOR, 1.35 [95% CI, 1.21-1.50], p < 0.001). These findings suggest that AIS is correlated with an elevated likelihood of FGIDs, indicating that AIS may function as a potential risk factor for these gastrointestinal issues. Consequently, it is recommended to provide counseling to adolescents with AIS, alerting them to the heightened probability of experiencing chronic gastrointestinal symptoms.
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Project description:Adolescent idiopathic scoliosis (AIS) is a common disease. It is a multi-factorial (polygenic) disease controlled by genetic and environmental factors. Studies searching for genetic factors of AIS using linkage and association analyses have been conducted and several susceptibility genes have been reported. This paper reviews the recent progress in the genome-wide association study of AIS in Japan and comments on its future task.
| S-EPMC4900236 | biostudies-literature
Project description:Epigenetic mechanisms may contribute to idiopathic scoliosis (IS). We identified 8 monozygotic twin pairs with IS, 6 discordant (Cobb angle difference > 10°) and 2 concordant (Cobb angle difference ≤ 2°). 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 < 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.
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