Genome-wide association study identifies new susceptibility loci for adolescent idiopathic scoliosis in Chinese girls

Zhu, Zezhang; Tang, Nelson L.S.; Xu, Leilei; Qin, Xiaodong; Mao, Saihu; Song, Yueming; Liu, Limin; Li, Fangcai; Liu, Peng; Yi, Long; Chang, Jiang; Jiang, Long; Ng, Bobby Kin Wah; Shi, Benlong; Zhang, Wen; Qiao, Jie; Sun, Xu; Qiu, Xusheng; Wang, Zhou; Wang, Fei; Xie, Dingding; Chen, Ling; Chen, Zhonghui; Jin, Mengran; Han, Xiao; Hu, Zongshan; Zhang, Zhen; Liu, Zhen; Zhu, Feng; Qian, Bang Ping; Yu, Yang; Wang, Bing; Lee, K. M.; Lee, Wayne; Lam, TP; Qiu, Yong; Cheng, Jack C. Y.

doi:10.1038/ncomms9355

Cited by 110 publications

(81 citation statements)

References 53 publications

(53 reference statements)

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“…To systematically identify genes expressed in AIS-relevant tissues, we carried out RNA-seq on human cartilage, muscle and bone and on mouse IVDs, connective tissue and chondrocytes (as we were not able to obtain equivalent human tissues) ( Fig 1). The above tissues were chosen as they are implicated in AIS-susceptibility through GWAS and animal studies (4)(5)(6)(7)(8)(9)(10)(11)(12)(13). RNA was collected from three biological replicates of each tissue, reverse transcribed and sequenced.…”

Section: Expression Profiling Of Ais Relevant Tissues Identifies Ais-mentioning

confidence: 99%

“…Genome-wide association studies (GWAS) identified at least thirteen genetic loci underlying AIS susceptibility (4)(5)(6)(7)(8)(9)(10)(11)(12), all of which reside within noncoding regions of the genome. These results suggest that nucleotide changes in gene regulatory sequences such as enhancers could be potential drivers of AIS susceptibility (8,9).…”

Section: Introductionmentioning

confidence: 99%

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Genomic characterization of the adolescent idiopathic scoliosis associated transcriptome and regulome

Makki

Jin

Eckalbar

et al. 2020

Preprint

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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 noncoding sequences that control genes with important roles in cartilage, muscle, bone, connective tissue and intervertebral discs (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 ChIP-seq against H3K27ac in these tissues in mouse and human. Our study highlights genetic pathways involving AISassociated 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.

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Section: Expression Profiling Of Ais Relevant Tissues Identifies Ais-mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Genomic characterization of the adolescent idiopathic scoliosis associated transcriptome and regulome

Makki

Jin

Eckalbar

et al. 2020

Preprint

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“…18,19,128 There is mounting evidence that intricate underlying genetic abnormalities contribute to the 3D structural deformities found in scoliosis. Prior studies have identified candidate genes associated with adolescent idiopathic scoliosis, such as GPR126, 77 BNC2, 111 PAX1, 135 LBX1as1, 163 POC5, 114 and AKAP2. 88 More recently, MapK7 was shown to be associated with severe spinal deformity and a defective osteogenesis phenotype in idiopathic scoliosis.…”

Section: Fusionless Spine Surgerymentioning

confidence: 99%

Spinal instrumentation in infants, children, and adolescents: a review

Mendenhall

Mobasser

Relyea

et al. 2019

Journal of Neurosurgery: Pediatrics

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OBJECTIVEThe evolution of pediatric spinal instrumentation has progressed in the last 70 years since the popularization of the Harrington rod showing the feasibility of placing spinal instrumentation into the pediatric spine. Although lacking in pediatric-specific spinal instrumentation, when possible, adult instrumentation techniques and tools have been adapted for the pediatric spine. A new generation of pediatric neurosurgeons with interest in complex spine disorder has pushed the field forward, while keeping the special nuances of the growing immature spine in mind. The authors sought to review their own experience with various types of spinal instrumentation in the pediatric spine and document the state of the art for pediatric spine surgery.METHODSThe authors retrospectively reviewed patients in their practice who underwent complex spine surgery. Patient demographics, operative data, and perioperative complications were recorded. At the same time, the authors surveyed the literature for spinal instrumentation techniques that have been utilized in the pediatric spine. The authors chronicle the past and present of pediatric spinal instrumentation, and speculate about its future.RESULTSThe medical records of the first 361 patients who underwent 384 procedures involving spinal instrumentation from July 1, 2007, to May 31, 2018, were analyzed. The mean age at surgery was 12 years and 6 months (range 3 months to 21 years and 4 months). The types of spinal instrumentation utilized included occipital screws (94 cases); C1 lateral mass screws (115 cases); C2 pars/translaminar screws (143 cases); subaxial cervical lateral mass screws (95 cases); thoracic and lumbar spine traditional-trajectory and cortical-trajectory pedicle screws (234 cases); thoracic and lumbar sublaminar, subtransverse, and subcostal polyester bands (65 cases); S1 pedicle screws (103 cases); and S2 alar-iliac/iliac screws (56 cases). Complications related to spinal instrumentation included hardware-related skin breakdown (1.8%), infection (1.8%), proximal junctional kyphosis (1.0%), pseudarthroses (1.0%), screw malpositioning (0.5%), CSF leak (0.5%), hardware failure (0.5%), graft migration (0.3%), nerve root injury (0.3%), and vertebral artery injury (0.3%).CONCLUSIONSPediatric neurosurgeons with an interest in complex spine disorders in children should develop a comprehensive armamentarium of safe techniques for placing rigid and nonrigid spinal instrumentation even in the smallest of children, with low complication rates. The authors’ review provides some benchmarks and outcomes for comparison, and furnishes a historical perspective of the past and future of pediatric spine surgery.

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“…Auxiliary KCTD subunits have been associated with small brain size, schizophrenia, depression, bipolar I disorder, diabetes, pain and cancer . The sushi domain‐interacting proteins APP, AJAP‐1 and PIANP are linked to Alzheimer's disease, intellectual disability, adolescent idiopathic scoliosis, migraine and cancer . HCN2 mutations are associated with generalized epilepsy.…”

Section: Novel Links Of Receptor Components To Diseasementioning

confidence: 99%

The organizing principle of GABA_B receptor complexes: Physiological and pharmacological implications

Fritzius

Bettler

2019

Basic Clin Pharma Tox

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GABAB receptors (GBRs), the G protein‐coupled receptors for the neurotransmitter γ‐aminobutyric acid (GABA), regulate synaptic transmission at most synapses in the brain. Proteomic approaches revealed that native GBR complexes assemble from an inventory of ~30 proteins that provide a molecular basis for the functional diversity observed with these receptors. Studies with reconstituted GBR complexes in heterologous cells and complementary knockout studies have allowed to identify cellular and physiological functions for obligate and several non‐obligate receptor components. It emerges that modular association of receptor components in space and time generates a variety of multiprotein receptor complexes with different localizations, kinetic properties and effector channels. This article summarizes current knowledge on the organizing principle of GBR complexes. We further discuss unanticipated receptor functions, links to disease and opportunities for drug discovery arising from the identification of novel receptor components.

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Genome-wide association study identifies new susceptibility loci for adolescent idiopathic scoliosis in Chinese girls

Cited by 110 publications

References 53 publications

Genomic characterization of the adolescent idiopathic scoliosis associated transcriptome and regulome

Genomic characterization of the adolescent idiopathic scoliosis associated transcriptome and regulome

Spinal instrumentation in infants, children, and adolescents: a review

The organizing principle of GABA_B receptor complexes: Physiological and pharmacological implications

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Genome-wide association study identifies new susceptibility loci for adolescent idiopathic scoliosis in Chinese girls

Cited by 110 publications

References 53 publications

Genomic characterization of the adolescent idiopathic scoliosis associated transcriptome and regulome

Genomic characterization of the adolescent idiopathic scoliosis associated transcriptome and regulome

Spinal instrumentation in infants, children, and adolescents: a review

The organizing principle of GABAB receptor complexes: Physiological and pharmacological implications

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Product

Resources

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The organizing principle of GABA_B receptor complexes: Physiological and pharmacological implications