title: Genomewide linkage and linkage disequilibrium analyses identify COL6A1, on chromosome 21, as the locus for ossification of the posterior longitudinal ligament of the spine.
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 GENEHUNTER-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 Zlr=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, approximately 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.
authors.affiliation: Division of Genetic Diagnosis, The Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Tanaka
authors.forename: Katsunori
authors.initials: K
authors.lastname: Ikari
authors.forename: Kozo
authors.initials: K
authors.lastname: Furushima
authors.forename: Akihiro
authors.initials: A
authors.lastname: Okada
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tanaka
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Furukawa
authors.forename: Kenichi
authors.initials: K
authors.lastname: Yoshida
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Ikeda
authors.forename: Shiro
authors.initials: S
authors.lastname: Ikegawa
authors.forename: Steven C
authors.initials: SC
authors.lastname: Hunt
authors.forename: Jun
authors.initials: J
authors.lastname: Takeda
authors.forename: Satoshi
authors.initials: S
authors.lastname: Toh
authors.forename: Seiko
authors.initials: S
authors.lastname: Harata
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Nakajima
authors.forename: Ituro
authors.initials: I
authors.lastname: Inoue
mesh_terms: D002874:Chromosome Mapping; D002891:Chromosomes, Human, Pair 21; D024142:Collagen Type VI / Q000235:genetics*; D005091:Exons; D008040:Genetic Linkage; D005819:Genetic Markers; D015894:Genome, Human; D006801:Humans; D007438:Introns; D015810:Linkage Disequilibrium; D018895:Microsatellite Repeats / Q000235:genetics*; D017887:Ossification of Posterior Longitudinal Ligament / Q000235:genetics* / Q000503:physiopathology; D020641:Polymorphism, Single Nucleotide; D035781:Siblings; D013122:Spinal Diseases / Q000235:genetics*; D013131:Spine / Q000473:pathology*
chemical_list: D024142:Collagen Type VI; D005819:Genetic Markers