Genomewide linkage study and identification of susceptibility of ossification of the posterior longitudinal ligament of the spine

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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. 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 Z_<Ir> = 3.97), therefore the linkage region was extensively investigated for linkage disequilibrium analysis 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 7 genes (P < 0.01) in 280 patients and 210 controls and 4 of the 7 genes were clustered within a region of 750 kb, about 1.2 Mb telomeric from D21S1903. Extensive linkage disequilibrium and association studies of the 4 genes indicated that SNPs in the collagen 6A1 gene (COL6A1) were strongly associated with OPLL (P = 0.000003). Haplotype analysis with 3 SNPs in COL6A1 gave a single point P value of 0.0000007. Pinpointing the susceptibility to OPLL by genomewide linkage and linkage disequilibrium studies permits us to investigate the pathogenesis of OPLL, which might lead to the development of novel therapeutic tools.