Haplotype Mapping of Chromosome 5 Schizophrenia Locus

描述(申请人提供)：精神分裂症是一种常见的精神障碍，在成年初期发病率最高，通常会导致终生疾病。精神分裂症的几个候选基因已经在独立的样本中复制；每个基因对个人的风险只有很小的增加，加在一起只占精神分裂症总体人群风险的一小部分。因此，识别额外的风险基因是至关重要的。在这项修订的应用中，我们建议确定位于染色体区域5q31-35的基因变异，该变异导致精神分裂症易感性增加。已经在多个人群中检测到与该区域的关联，因此识别与精神分裂症相关的候选基因可能识别出一般的危险因素。在详细的单倍型作图之前，将采取三管齐下的方法来缩小基因座的范围，包括详细的家系、与其他研究人员的联合连锁分析以及在有许多受影响成员的家庭中进行精细作图。在缩小的区域内，我们将开始筛选关联研究，最初重点放在5q基因座上的强大生物候选基因上。将在葡萄牙精神分裂症患者(n=631名受影响患者)样本中测试个人SNPs和单倍型与精神分裂症的关联。名义上积极的结果将在四个学术中心(n=3,545个DNA)之间的合作的大复制样本中进行跟踪。对连接区域的进一步测试将通过基于区间的方法和新颖的滑动窗口统计分析在Azorean样本中进行。为了确定5号染色体与其他基因座之间的相互作用，将为先前与精神分裂症有关的基因创建单倍型图谱。这些基因中的单个单倍型将在筛选样本中进行关联测试，并测试与染色体5q上确定的任何基因的基因-基因相互作用。通过潜在类别分析进行深入的表型调查将与单倍型分析相结合，以识别精神分裂症的亚群。我们预计这些研究将具有重要意义，因为它们将确定精神分裂症的常见危险因素，并有助于阐明其在精神分裂症风险中的作用。

DESCRIPTION (provided by applicant): Schizophrenia is a common psychotic disorder with peak incidence in early adulthood that often leads to lifelong morbidity. Several candidate genes for schizophrenia have been replicated in independent samples; each accounts for only a small increase in risk for an individual, and taken together they account for only a small percentage of the overall population risk of schizophrenia. Thus, identification of additional risk genes is crucial. In this revised application, we propose to identify the genetic variation located in chromosomal region 5q31-35 that leads to increased susceptibility to schizophrenia. Linkage to this region has been detected in multiple populations and thus identification of a candidate gene for association with schizophrenia is likely to identify a general risk factor. Prior to detailed haplotype mapping, a three-pronged approach to narrow the locus will be taken that includes detailed genealogy, joint linkage analysis with other investigators, and fine mapping in families with many affected members. Within the narrowed region, we will then commence screening association studies initially focusing on strong biological candidate genes in the 5q locus. Individual SNPs and haplotypes will be tested for association with schizophrenia in a sample of Portuguese schizophrenia patients (n=631 affecteds). Nominally positive results will be followed up in a large replication sample that is a collaboration between four academic centers (n=3,545 DNAs). Further testing of the linked region will occur in the Azorean samples by an interval-based approach with novel sliding window statistical analyses. In order to determine the interactions between the chromosome 5 locus and other loci, haplotype maps will be created for genes previously implicated in schizophrenia. Individual haplotypes in these genes will be tested for association in the screening sample and for gene-gene interactions with any gene identified on chromosome 5q. In depth phenotypic investigation by latent class analysis will be coupled with the haplotype analyses to identify subgroups of schizophrenia. We expect these studies to be significant in that they will identify a common risk factor for schizophrenia and help elucidate its role in schizophrenia risk.