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

描述（由申请人提供）：我们已经发现了精神分裂症与chr相关的有力证据。在波多黎各中部山区的一个遗传分离物的大型高密度谱系中发现5q13。该家族的基因组扫描显示多点lodscore为4.8，我们已经能够将精神分裂症易感位点的最小临界区间（MCI）缩小到2.8 Mb，其中包含13个参考基因。本研究的主要目的是通过外显子、外显子侧翼内含子区、外显子区等测序来筛选内参基因。未翻译（3.UTR）和假定的启动子区域。将在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显改变蛋白质的突变的频率。如果在这个大谱系中只有同义变体和其他变体与疾病分离，我们将在独立的波多黎各病例对照样本中使用LD制图来评估这些变体的疾病风险，或为识别LD峰值下非编码区域的差异提供指导。先前有几项研究报道了5p13与精神分裂症有关联的独立证据，最近在对409个精神分裂症家族进行全基因组连锁分析后，该区域再次受到关注，然而，即使通过精细定位缩小该区域，MCI仍然很大（31.8 cM）。因此，我们的波多黎各家族提供了在5p13区域内识别基因的机会，这些基因不仅可能导致波多黎各人的精神分裂症，也可能导致其他人群的精神分裂症。

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.