A genome-wide association study identifies susceptibility loci for ossification of the posterior longitudinal ligament of the spine

Nakajima, Masahiro; Takahashi, Atsushi; Tsuji, Takashi; Karasugi, Tatsuki; Baba, H.; Uchida, Kenzo; Kawabata, Shigenori; Okawa, Atsushi; Shindo, Shigeo; Takeuchi, Kazuhiro; Taniguchi, Yuki; Maeda, Shingo; Kashii, Masafumi; Seichi, Atsushi; Nakajima, Hideaki; Kawaguchi, Yoshiharu; Fujibayashi, Shunsuke; Takahata, Masahiko; Tanaka, Toshihiro; Watanabe, Kei; Kida, Kenji; Kanchiku, Tsukasa; Ito, Zenya; Mori, Kanji; Kaito, Takashi; Kobayashi, Sho; Yamada, Kei; Takahashi, Masahito; Chiba, Kazuhiro; Matsumoto, Morio; Furukawa, Ken‐Ichi; Kubo, Michiaki; Toyama, Yoshiaki; Ikegawa, Shiro

doi:10.1038/ng.3045

Cited by 116 publications

(96 citation statements)

References 34 publications

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“…Development of pathological ectopic ossification of the posterior longitudinal ligament induces compression myelopathy or radiculopathy by spinal stenosis and the loss of spinal flexibility by ankylosing spinal hyperostosis [2]. The etiology of OPLL has not been fully clarified [3], but OPLL seems to occur and develop as a result of systemic and local factors in combination with a genetic abnormality [4][5][6][7].…”

Section: Introductionmentioning

confidence: 99%

Circulating sclerostin and dickkopf-1 levels in ossification of the posterior longitudinal ligament of the spine

et al. 2015

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Sclerostin and dickkopf-1(DKK1) are Wnt/β-catenin signal antagonists that play an important role in bone formation. Ossification of the posterior longitudinal ligament (OPLL) of the spine is characterized by pathological ectopic ossification of the posterior longitudinal ligament and ankylosing spinal hyperostosis. The aims of this study were to evaluate serum sclerostin and DKK1 levels in persons with OPLL and to identify its relationship with bone metabolism and bone mass in persons with OPLL. This was a case-control study, and 78 patients with OPLL were compared with 39 age- and sex-matched volunteers without OPLL. We analyzed the relationship with calciotropic hormones, bone turnover markers, OPLL localization, number of ossified vertebrae, and bone mineral density of total hip (TH-BMD). Serum sclerostin levels in men with OPLL were significantly higher than in men in the control group (control group: mean = 45.3 pmol/L; OPLL group: mean = 75.7 pmol/L; P = 0.002). Age and sclerostin levels were positively correlated in men with OPLL (r = 0.43; P = 0.002). Serum sclerostin levels in men with OPLL had a positive correlation with TH-BMD Z-score (r = 0.511; P = 0.011, n = 30). There was a strong negative correlation between serum sclerostin levels and serum DKK1 levels in men with OPLL (r = -0.506; P < 0.001). Bone and mineral metabolism in OPLL differs between men and women. In men with OPLL, systemic secretion of sclerostin increases with advancing age and with higher bone mass. These two Wnt/β-catenin signal antagonists have the opposite effect in persons with OPLL, and higher serum sclerostin levels are counterbalanced by underproduction of DKK1.

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Section: Introductionmentioning

confidence: 99%

Circulating sclerostin and dickkopf-1 levels in ossification of the posterior longitudinal ligament of the spine

et al. 2015

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“…Genetic factors are thought to be involved in ectopic ossification of spinal ligaments, because some patients have a positive family history (15). However, multiple etiologic factors, including some local factors, such as mechanical stress and cytokines, are also thought to be important in ossification of spinal ligaments (3).…”

Section: Introductionmentioning

confidence: 99%

Decreased DNA methylation in the promoter region of the WNT5A and GDNF genes may promote the osteogenicity of mesenchymal stem cells from patients with ossified spinal ligaments

Chiba

Furukawa

Takayama

et al. 2015

Journal of Pharmacological Sciences

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Mesenchymal stem cells (MSCs) isolated from spinal ligaments with ectopic ossification have a propensity toward the osteogenic lineage. To explore epigenetic control of the osteogenic features of MSCs, we treated MSCs obtained from the spinal ligaments of ossification of yellow ligament (OYL) patients and non-OYL patients with the DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine (5AdC). We compared the non-OYL groups (untreated and treated with 5AdC) with the OYL groups (untreated and treated with 5AdC) by genome-wide microarray analysis. Next, we used methylated DNA immunoprecipitation combined with quantitative real-time PCR to assess gene methylation. Ninety-eight genes showed expression significantly increased by 5AdC treatment in MSCs from non-OYL patients but not from OYL patients. In contrast, only two genes, GDNF and WNT5A, showed significantly higher expression in OYL MSCs compared with non-OYL MSCs without 5AdC treatment. Both genes were hypermethylated in non-OYL MSCs but not in OYL MSCs. Small interfering RNA targeted to each gene decreased expression of the target gene and also several osteogenic genes. Both small interfering RNAs also suppressed the activity of alkaline phosphatase, a typical marker of osteogenesis. These results suggest that the osteogenic features of MSCs from OYL patients are promoted by unmethylated WNT5A and GDNF genes.

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“…11,144 control subjects for the GWAS were drawn from the BioBank Japan Project (see Web Resources) and its related projects, as previously described. [13][14][15] The study was approved by the institutional review boards of RIKEN and participating hospitals. A written informed consent was obtained from all participants and/or guardians on the behalf of the minors and/or children participants.…”

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A Functional SNP in BNC2 Is Associated with Adolescent Idiopathic Scoliosis

Ogura

Kou

Miura

et al. 2015

The American Journal of Human Genetics

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Adolescent idiopathic scoliosis (AIS) is the most common spinal deformity. We previously conducted a genome-wide association study (GWAS) and detected two loci associated with AIS. To identify additional loci, we extended our GWAS by increasing the number of cohorts (2,109 affected subjects and 11,140 control subjects in total) and conducting a whole-genome imputation. Through the extended GWAS and replication studies using independent Japanese and Chinese populations, we identified a susceptibility locus on chromosome 9p22.2 (p = 2.46 × 10(-13); odds ratio = 1.21). The most significantly associated SNPs were in intron 3 of BNC2, which encodes a zinc finger transcription factor, basonuclin-2. Expression quantitative trait loci data suggested that the associated SNPs have the potential to regulate the BNC2 transcriptional activity and that the susceptibility alleles increase BNC2 expression. We identified a functional SNP, rs10738445 in BNC2, whose susceptibility allele showed both higher binding to a transcription factor, YY1 (yin and yang 1), and higher BNC2 enhancer activity than the non-susceptibility allele. BNC2 overexpression produced body curvature in developing zebrafish in a gene-dosage-dependent manner. Our results suggest that increased BNC2 expression is implicated in the etiology of AIS.

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A genome-wide association study identifies susceptibility loci for ossification of the posterior longitudinal ligament of the spine

Cited by 116 publications

References 34 publications

Circulating sclerostin and dickkopf-1 levels in ossification of the posterior longitudinal ligament of the spine

Circulating sclerostin and dickkopf-1 levels in ossification of the posterior longitudinal ligament of the spine

Decreased DNA methylation in the promoter region of the WNT5A and GDNF genes may promote the osteogenicity of mesenchymal stem cells from patients with ossified spinal ligaments

A Functional SNP in BNC2 Is Associated with Adolescent Idiopathic Scoliosis

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