Using a pedigree from a genetic isolate to identify schizophrenia genes on 5p13

描述（由申请人提供）：我们在来自波多黎各中部山区遗传分离株的一个大型高密度家系中发现了精神分裂症与染色体5q13连锁的强有力证据。在这个家庭中的基因组扫描显示多点lodscore为4.8，我们已经能够缩小最小临界区间（MCI）的精神分裂症易感基因座2.8 Mb包含13个参考基因。该方案的主要目标是通过对外显子、外显子侧翼内含子区进行测序来筛选这些参考基因。非翻译区（3.UTR）和推定的启动子区。将在来自波多黎各同一地区的200例病例和对照的独立样本中检查明确的蛋白质改变突变的频率。如果在这个大的谱系中只有同义和其他变异与疾病分离，我们将在独立的波多黎各病例对照样本中使用LD作图来评估这些变异的疾病风险或指导识别LD峰下非编码区的变异。先前的独立证据表明精神分裂症与5p13的连锁已经被几项研究报道，在对409个精神分裂症家族进行全基因组连锁分析后，同一区域最近再次受到关注，然而，MCI仍然很大（31.8 cM），即使在通过精细定位缩小该区域之后。因此，我们的波多黎各家庭提供了一个机会，以确定5p13区域内的基因，可能有助于精神分裂症不仅在波多黎各人，而且在其他人群。

DESCRIPTION (provided by applicant): We have found strong evidence for linkage of schizophrenia to chr. 5q13 in a large high-density pedigree from a genetic isolate in the central mountain region of Puerto Rico. A genome scan in this family revealed a multipoint lodscore of 4.8 and we have been able to narrow the minimal critical interval (MCI) for a schizophrenia susceptibility locus to 2.8 Mb containing 13 reference genes. The major goal of this proposal is to screen those reference genes by sequencing exons, exon-flanking intronic regions, 3. untranslated (3.UTR) and putative promoter regions. The frequency of clear protein-altering mutations will be examined in an independent sample of 200 cases and controls from the same region in Puerto Rico. If only synonymous and other variants segregate with the disease in this large pedigree, we will use LD mapping in the independent Puerto Rican case-control sample to either assess the disease risk for these variants or for guidance to identify variances in non-coding regions under the LD peak. Prior independent evidence for suggestive linkage for schizophrenia to 5p13 has been reported by several studies and this same region has recently received renewed attention after genome wide linkage analysis of 409 families with schizophrenia, however, the MCI remained large (31.8 cM), even after narrowing this region by fine mapping. Our Puerto Rican family therefore offers the opportunity to identify genes within the 5p13 region that might contribute to schizophrenia not only in Puerto Ricans but also in other populations.