A multi-ethnic meta-analysis confirms the association of rs6570507 with adolescent idiopathic scoliosis

Kou, Ikuyo; Watanabe, Kota; Takahashi, Yohei; Momozawa, Yukihide; Khanshour, Anas M.; Grauers, Anna; Zhou, Hang; Liu, Gang; Fan, Yanhui; Takeda, Kazuki; Ogura, Yoji; Zhou, Taifeng; Iwasaki, Yusuke; Kubo, Michiaki; Wu, Zhihong; Matsumoto, Morio; Einarsdottir, Elisabet; Kere, Juha; Huang, Dongsheng; Qiu, Guixing; Qiu, Yong; Wise, Carol A.; Song, You‐Qiang; Wu, Nan; Su, Peiqiang; Gerdhem, Paul; Ikegawa, Shiro

doi:10.1038/s41598-018-29011-7

Cited by 32 publications

(26 citation statements)

References 45 publications

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“…Some of these common variants differed greatly in MAF between JPN and EUR (Supplementary Table 1). However, the association of common lead variants (MAF > 0.05) at the three susceptibility loci (10q24.31, 6q24.1 and 9p22.2) identified in our previous GWAS was replicated even if there is a large difference in MAF between JPN and EUR 14,32,33 . Therefore, it is expected that the association of common lead variants (MAF > 0.05) identified in the present study will also be replicated in a multi-ethnic meta-analysis.…”

Section: Discussionmentioning

confidence: 62%

Genome-wide association study identifies 14 previously unreported susceptibility loci for adolescent idiopathic scoliosis in Japanese

et al. 2019

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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.

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Section: Discussionmentioning

confidence: 62%

Genome-wide association study identifies 14 previously unreported susceptibility loci for adolescent idiopathic scoliosis in Japanese

et al. 2019

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“…Knockout studies in model organisms revealed that GPR126 plays an important role in a variety of tissues/organs, such as heart, sciatic nerve, cartilage, and ear . Moreover, genomic and transcriptomic patient‐based studies, such as whole exome sequencing and genome‐wide association studies, revealed that GPR126 ( ADGRG6 ) mutations are associated with human diseases, like intellectual disability, bladder cancer, adolescent idiopathic scoliosis (AIS), arthrogryposis multiplex congenita, syndromes with auricular phenotypes, lung disease, and neuromuscular disease . Due to its clinical importance, a large effort has been invested in understanding the functional role of GPR126.…”

Section: Introductionmentioning

confidence: 99%

Gpr126 (Adgrg6) is expressed in cell types known to be exposed to mechanical stimuli

Musa

Cazorla-Vázquez

Amerongen

et al. 2019

Annals of the New York Academy of Sciences

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GPR126 (ADGRG6) is an adhesion G protein–coupled receptor that plays an important role in a variety of tissues/organs, such as heart, sciatic nerve, cartilage, and ear. Moreover, GPR126 (ADGRG6) mutations are associated with human diseases, like adolescent idiopathic scoliosis, lung disease, bladder cancer, and intellectual disability. Despite its clinical importance, it remains elusive how GPR126 is activated and mediates signal transduction and what cellular processes depend on GPR126 signaling. Here, we generated a lacZ reporter mouse line to determine endogenous Gpr126 (Adgrg6) expression in a cell type‐specific manner during embryonic development, at postnatal day 5 and in adult animals. Our results confirm Gpr126 expression data previously obtained utilizing antibodies and in situ hybridization in embryonic heart and sciatic nerve. In addition, we provide data with cellular resolution for previously described RT‐PCR–based data, including lung and bladder. Moreover, new Gpr126‐expressing tissues and cell types were identified, such as ureter and acinar secretory cells. Collectively, our data demonstrate that the newly generated lacZ reporter mouse is a suitable model to study Gpr126 expression during development and adulthood, provide detailed insight into Gpr126 expression at the cellular level, and reveal that all identified Gpr126‐expressing cells are known to be exposed to mechanical stimuli.

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“…Recently, large-scale genome-wide association studies (GWAS) of AIS patients have begun to implicate several independent loci in AIS (Ikegawa, 2016). For instance, variants in the ADGRG6 (also called GPR126) locus are associated with AIS in a variety of ethnic backgrounds (Kou et al, 2013;Kou et al, 2018). Importantly, the conditional ablation of Adgrg6 in osteochondral progenitor lineages of the spine generates a faithful model of AIS in mouse (Karner et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Postembryonic screen for mutations affecting spine development in zebrafish

Gray

González

Ackerman

et al. 2020

Preprint

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The spinal vertebral column gives structural support for the adult body plan, protects the spinal cord, and provides muscle attachment and stability, which allows the animal to move within its environment. The development and maturation of the spine and its physiology involve the integration of multiple musculoskeletal tissues including bone, cartilage, and fibrocartilaginous joints, as well as innervation and control by the nervous system. One of the most common disorders of the spine in human is adolescent idiopathic scoliosis (AIS), which is characterized by the onset of an abnormal lateral curvature of the spine of <10° around adolescence, in otherwise healthy children. The genetic basis of AIS is largely unknown. Systematic genome-wide mutagenesis screens for embryonic phenotypes in zebrafish have been instrumental in the understanding of early patterning of embryonic tissues necessary to build and pattern the embryonic spine. However, the mechanisms required for postembryonic maturation and homeostasis of the spine remain poorly understood. Here we report the results from a small-scale forward genetic screen for adult-viable recessive and dominant mutant zebrafish, displaying overt morphological abnormalities of the adult spine. Germline mutations induced with N-ethyl N-nitrosourea (ENU) were transmitted and screened for dominant phenotypes in 1,229 F1 animals, and subsequently bred to homozygosity in F3 families, from these, 314 haploid genomes were screened for recessive phenotypes. We cumulatively found 39 adult-viable (3 dominant and 36 recessive) mutations each leading to a defect in the morphogenesis of the spine. The largest phenotypic group displayed larval onset axial curvatures, leading to whole-body scoliosis without vertebral dysplasia in adult fish. Pairwise complementation testing within this phenotypic group revealed at least 16 independent mutant loci. Using massively-parallel whole genome or whole exome sequencing and meiotic mapping we defined the molecular identity of several loci for larval onset whole-body scoliosis in zebrafish. We identified a new mutation in the skolios/kinesin family member 6 (kif6) gene, causing neurodevelopmental and ependymal cilia defects in mouse and zebrafish. We also report several recessive alleles of the scospondin and a disintegrin and metalloproteinase with thrombospondin motifs 9 (adamts9) genes, which all display defects in spine morphogenesis. Many of the alleles characterized thus far are non-synonymous mutations in known essential scospondin and adamts9 genes. Our results provide evidence of monogenic traits that are critical for normal spine development in zebrafish, that may help to establish new candidate risk loci for spine disorders in humans.

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A multi-ethnic meta-analysis confirms the association of rs6570507 with adolescent idiopathic scoliosis

Cited by 32 publications

References 45 publications

Genome-wide association study identifies 14 previously unreported susceptibility loci for adolescent idiopathic scoliosis in Japanese

Genome-wide association study identifies 14 previously unreported susceptibility loci for adolescent idiopathic scoliosis in Japanese

Gpr126 (Adgrg6) is expressed in cell types known to be exposed to mechanical stimuli

Postembryonic screen for mutations affecting spine development in zebrafish

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