Genome-wide linkage study for ossification of the posterior longitudinal ligament of the spine reveals a major susceptibility locus on chromosome 21q

Abstract

Ossification of the posterior longitudinal ligament of the spine (OPLL) is characterized by ectopic ossification in the spinal ligaments leading to a various degree of myelopathy by a compression of the spinal cord. OPLL is commonly observed among Japanese and throughout other Asian populations. The incidence of OPLL in the general Japanese population was reported to be 1.9 - 4.3% over 30 years of age. Although its etiology is thought to involve a multiplicity of factors, epidemiological and family studies strongly implicate genetic susceptibility in the pathogenesis of OPLL. The disease has a substantial genetic component, a risk in siblings compared to general population risk (λs) of 10. Previously, we have reported of suggestive evidence of linkage to a candidate gene, collagen 11A2, where only a candidate region (HLA region at 6p21.3) was tested for linkage. To define the genetic causalities of OPLL in more extensive manner, we performed a genome-wide scan with 138 affected sib-pairs. Non-parametric linkage analysis was performed with affected sib-pairs by the use of two different programs. Identical by descent (IBD) was tested for possible linkage with SIBPAL from S.A.G.E. package (single point analysis). Multipoint affected sib-pairs linkage analysis was performed using GENEHUNTER. We found that five principal loci of possible linkage were identified on chromosome 1, 6, 13. 16, 21 (p < 0.01) And the most significant evidence of linkage was observed with D21S263 at chromosome 21q (P=0.000009). Multipoint linkage analysis revealed that the peak linkage was also located close to D21S263 (maximum lod score = 3.4). These mapping results could be an important step towards identifying susceptible genes for OPLL.