Genomewide Linkage and Linkage Disequilibrium Analyses Identify COL6A1, on Chromosome 21, as the Locus for Ossification of the Posterior Longitudinal Ligament of the Spine

Toshihiro Tanaka, Katsunori Ikari, Kozo Furushima, Akihiro Okada, Hiroshi Tanaka, Ken Ichi Furukawa, Kenichi Yoshida, Toshiyuki Ikeda, Shiro Ikegawa, Steven Hunt, Jun Takeda, Satoshi Toh, Seiko Harata, Toshiaki Nakajima, Ituro Inoue

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Abstract

Ossification of the posterior longitudinal ligament (OPLL) of the spine is a subset of "bone-forming" diseases, characterized by ectopic ossification in the spinal ligaments. OPLL is a common disorder among elderly populations in eastern Asia and is the leading cause of spinal myelopathy in Japan. We performed a genomewide linkage study with 142 affected sib pairs, to identify genetic loci related to OPLL. In multipoint linkage analysis using GENE-HUNTER-PLUS, evidence of linkage to OPLL was detected on chromosomes 1p, 6p, 11q, 14q, 16q, and 21q. The best evidence of linkage was detected near D21S1903 on chromosome 21q22.3 (maximum ZIr = 3.97); therefore, the linkage region was extensively investigated for linkage disequilibrium with single-nucleotide polymorphisms (SNPs) covering 20 Mb. One hundred fifty positional candidate genes lie in the region, and 600 gene-based SNPs were genotyped. There were positive allelic associations with seven genes (P < .01) in 280 patients and 210 controls, and four of the seven genes were clustered within a region of 750 kb, ∼1.2 Mb telomeric to D21S1903. Extensive linkage disequilibrium and association studies of the four genes indicated that SNPs in the collagen 6A1 gene (COL6A1) were strongly associated with OPLL (P = .000003 for the SNP in intron 32 [-29]). Haplotype analysis with three SNPs in COL6A1 gave a single-point P value of .0000007. Identification of the locus of susceptibility to OPLL by genomewide linkage and linkage disequilibrium studies permits us to investigate the pathogenesis of the disease, which may lead to the development of novel therapeutic tools.

Original languageEnglish
Pages (from-to)812-822
Number of pages11
JournalAmerican Journal of Human Genetics
Volume73
Issue number4
DOIs
Publication statusPublished - 1 Oct 2003
Externally publishedYes

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ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Tanaka, T., Ikari, K., Furushima, K., Okada, A., Tanaka, H., Furukawa, K. I., Yoshida, K., Ikeda, T., Ikegawa, S., Hunt, S., Takeda, J., Toh, S., Harata, S., Nakajima, T., & Inoue, I. (2003). Genomewide Linkage and Linkage Disequilibrium Analyses Identify COL6A1, on Chromosome 21, as the Locus for Ossification of the Posterior Longitudinal Ligament of the Spine. American Journal of Human Genetics, 73(4), 812-822. https://doi.org/10.1086/378593