Discovery of Genetic Variation Influencing Schizophrenia Using Next Generation DN

描述(申请人提供)：精神分裂症是一种严重的精神疾病，约占世界人口的百分之一。尽管很明显，大约一半的疾病易感性是遗传的，但很少有基因明确地与疾病的病因学有关。最近一项对精神分裂症拷贝数变异的大型研究(约3000例病例和3000名对照)的数据发现，有证据表明染色体1q、15q和22p上的三个罕见的缺失可能导致精神分裂症。这些缺失的证据不足以确定它们是否会导致精神分裂症，如果是的话，哪些缺失的基因才是罪魁祸首。我们建议在1000名精神分裂症患者和1000名对照中确定这三个缺失所描绘的全部5.3Mb的DNA序列，以寻找缺失区域中常见和罕见的变异。被测序的个体将从葡萄牙岛屿队列(PIC)中选择。DNA序列数据将使用Logistic回归进行分析，以确定与对照相比，病例中基因变异增加的区域。然后，这些区域将在多达20,000个病例和对照的更大样本中进行基因分型，以确定缺失区域中的哪些基因/区域在精神分裂症的发展中起到致病作用。 与公共卫生相关：精神分裂症是一种严重的精神疾病，约占世界人口的1%。尽管很明显，大约一半的疾病易感性是遗传的，但很少有基因明确地与疾病的病因学有关。最近一项对精神分裂症拷贝数变异的大型研究(约3000例病例和3000名对照)的数据发现，有证据表明染色体1q、15q和22p上的三个罕见的缺失可能导致精神分裂症。

DESCRIPTION (provided by applicant): Schizophrenia is a severe mental illness that afflicts approximately one percent of the world's population. Although it is clear that approximately a half of the liability to develop the disorder is genetic, few genes have been unequivocally implicated in the etiology of the disorder. Recent data from a large (~3,000 cases and 3,000 controls) study of copy number variations in schizophrenia found evidence for three rare deletions on chromosomes 1q, 15q and 22p that may cause schizophrenia. The evidence from these deletions is insufficient to conclusively determine if they cause schizophrenia and, if they do, which of the deleted genes are responsible. We propose to determine the DNA sequence of the entire 5.3 Mb delineated by these three deletions in 1,000 individuals with schizophrenia and 1,000 controls to look for both common and rare variants in the deleted regions. The individuals to be sequenced will be chosen from the Portuguese Island Cohort (PIC). The DNA sequence data will be analyzed using logistic regression to determine regions of increased genetic variation in cases as compared to controls. These regions will then be genotyped in a larger sample of up to 20,000 cases and controls to determine which genes/regions in the deleted regions play a causative role in the development of schizophrenia. PUBLIC HEALTH RELEVANCE: Schizophrenia is a severe mental illness that afflicts approximately one percent of the world's population. Although it is clear that approximately a half of the liability to develop the disorder is genetic, few genes have been unequivocally implicated in the etiology of the disorder. Recent data from a large (~3,000 cases and 3,000 controls) study of copy number variations in schizophrenia found evidence for three rare deletions on chromosomes 1q, 15q and 22p that may cause schizophrenia.