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

脊柱后纵韧带骨化(OPLL)是一种以脊柱韧带异位骨化为特征的“骨形成”疾病。我们对142个受影响的同胞对进行了全基因组连锁研究，以确定与OPLL相关的遗传位点。在利用GENEHUNTER-PLUS进行的多点连锁分析中，在染色体1p、6p、11q、14q、16q和21q上检测到与OPLL连锁的证据。在染色体21q22.3的D21S1903附近检测到了最好的连锁证据(最大Z&lt；Ir&gt；=3.97)，因此该连锁区域被广泛研究，利用覆盖20Mb的单核苷酸多态(SNPs)进行连锁不平衡分析。150个候选基因位于该区域，600个基于基因的SNPs被分型。在280例患者和210例对照组中，有7个基因存在正等位基因关联(P&lt；0.01)，其中4个基因聚集在750kb的区域，距离D21S1903约1.2Mb端粒。4个基因的广泛连锁不平衡和关联研究表明，胶原6A1基因(COL6A1)中的SNPs与口腔扁平苔藓密切相关(P=0.000003)。用COL6A1的3个SNPs进行单倍型分析，单点P值为0.0000007。通过全基因组连锁和连锁不平衡研究确定OPLL的易感性，使我们能够研究OPLL的发病机制，这可能导致新的治疗工具的开发。

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.