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Genomic characterization of the adolescent idiopathic scoliosis-associated transcriptome and regulome.

ABSTRACT: Adolescent idiopathic scoliosis (AIS), a sideways curvature of the spine, is the most common pediatric musculoskeletal disorder, affecting ~3% of the population worldwide. However, its genetic bases and tissues of origin remain largely unknown. Several genome-wide association studies (GWAS) have implicated nucleotide variants in non-coding sequences that control genes with important roles in cartilage, muscle, bone, connective tissue and intervertebral disks (IVDs) as drivers of AIS susceptibility. Here, we set out to define the expression of AIS-associated genes and active regulatory elements by performing RNA-seq and chromatin immunoprecipitation-sequencing against H3 lysine 27 acetylation in these tissues in mouse and human. Our study highlights genetic pathways involving AIS-associated loci that regulate chondrogenesis, IVD development and connective tissue maintenance and homeostasis. In addition, we identify thousands of putative AIS-associated regulatory elements which may orchestrate tissue-specific expression in musculoskeletal tissues of the spine. Quantification of enhancer activity of several candidate regulatory elements from our study identifies three functional enhancers carrying AIS-associated GWAS SNPs at the ADGRG6 and BNC2 loci. Our findings provide a novel genome-wide catalog of AIS-relevant genes and regulatory elements and aid in the identification of novel targets for AIS causality and treatment.

SUBMITTER: Makki N

PROVIDER: S-EPMC7823110 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Genomic characterization of the adolescent idiopathic scoliosis-associated transcriptome and regulome.

Makki Nadja N Zhao Jingjing J Liu Zhaoyang Z Eckalbar Walter L WL Ushiki Aki A Khanshour Anas M AM Wu Joe J Rios Jonathan J Gray Ryan S RS Wise Carol A CA Ahituv Nadav N

Human molecular genetics 20210101 22

Adolescent idiopathic scoliosis (AIS), a sideways curvature of the spine, is the most common pediatric musculoskeletal disorder, affecting ~3% of the population worldwide. However, its genetic bases and tissues of origin remain largely unknown. Several genome-wide association studies (GWAS) have implicated nucleotide variants in non-coding sequences that control genes with important roles in cartilage, muscle, bone, connective tissue and intervertebral disks (IVDs) as drivers of AIS susceptibili ...[more]

PMID: 33179741

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Project description:BackgroundDespite more than a century of dedicated research, the etiology and pathogenesis of adolescent idiopathic scoliosis (AIS) remain unclear. By definition, 'idiopathic' implies an unknown cause. Nevertheless, many abnormalities concomitant to AIS have been described, often with the suggestion that these abnormalities are related to etio-pathogenesis. Insight in the concomitant abnormalities may assist in improving the understanding of the etiological pathways of AIS. We aimed to systematically review and synthesize available studies on abnormalities concomitant to AIS.MethodsOriginal studies comparing untreated AIS patients with healthy adolescents on abnormalities other than the deformity of the spine were retrieved from PubMed and Embase. We followed PRISMA guidelines and to quantify the relationship between each abnormality and AIS we used a best-evidence-syntheses for relating risk-of-bias to consistency of effect sizes.ResultsWe identified 88 relevant citations, forty-seven carried high risk-of-bias and twenty studies did not report quantitative data in a sufficient manner. The remaining twenty-one publications failed to report data from before initiation of the deformity and blind assessments. These cross-sectional studies provided data on fourteen abnormalities concomitant to AIS. With our best-evidence-syntheses we were unable to find both strong evidence and a consistent pattern of occurrence for AIS and any of these abnormalities. From moderate risk-of-bias studies a relatively consistent pattern of occurrence for AIS and impaired gait control (4 studies; 155 subjects; Cohen's d = 1.00) and decreased bone mineral density (2 studies; 954 subjects; Cohen's d =?-0.83) was found. For nine abnormalities a consistent pattern of occurrence with AIS was found, but the evidence for these was weak.ConclusionsBased on the available literature, strong evidence is lacking for a consistent pattern of occurrence of AIS and any abnormality. The relevance for understanding the multifactorial etiology of AIS is very limited.

Dataset Information

Genomic characterization of the adolescent idiopathic scoliosis-associated transcriptome and regulome.

Publications

Genomic characterization of the adolescent idiopathic scoliosis-associated transcriptome and regulome.

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