Convergent Genetic and Genomic Analyses of Schizophrenia

目的：识别增加精神分裂症(SCZ)风险的常见和罕见的基因变异，并 研究它们对疾病风险的影响以及在大样本中衡量发病率的方法。 背景：精神分裂症是美国退伍军人以及全世界退伍军人残疾的主要原因， 每年公共卫生负担超过600亿美元。最近的研究有力地支持了 疾病风险的常见和罕见变种。然而，已知的导致这种疾病的遗传风险因素仍然 只占总遗传力的一小部分，约为80%。这些变异更有可能发生 在基因组的非编码区域而不是编码区。由于这个和其他原因，全基因组测序 (WGS)已成为识别SCZ和其他常见、复杂的遗传风险变异的首选方法 精神错乱。虽然仅仅在几年前还贵得令人望而却步，但现在大规模实施WGS是可行的 负担得起的数字。在上一个资助期，我们成功地在20个家庭中进行了WGS，这些家庭 SCZ或双相情感障碍，来自地理上与世隔绝的葡萄牙亚速尔群岛和马德拉群岛。我们 已经表明，在这些家庭中，与疾病分离的罕见变异优先聚集在区域 此前曾与GWAS有牵连。在更孤立的环境中，遗传风险因素可能更容易识别 这是因为它们的同质性更大，因此对疾病的遗传投入更少。 建议的方法：我们计划扩大我们目前的多重偶氮菌家族的样本，通过以下方式分离SCZ 确定和收集亚速尔群岛的新家庭，以及跟踪先前研究的家庭 确定已进入SCZ风险年龄的个人。这些家庭将使用 Illumina HiSeqX鉴定常见和罕见的单核苷酸变异和结构变异 生病了。这些家庭将与美国大型基因组精神病学队列(GPC)一起进行测序 SCZ和躁郁症病例和对照的样本(10,000病例和10,000对照)，以及变异呼叫将是 用这个大得多的样本来增加准确度。此外，我们将能够使用GPC作为 两阶段设计中的复制样本，我们演示了这比一阶段设计具有更大的能力。 我们还将检查基因对与精密医学相关的表型的影响，例如症状 维度和结果。

Objective: To identify common and rare genetic variants that increase the risk of schizophrenia (SCZ), and to study their impact on illness risk as well as measures of morbidity in large samples. Background: Schizophrenia is a major cause of disability amongst US veterans as well as worldwide, with an annual public health burden of more than $60 billion. Recent studies have strongly supported the impact of both common and rare variants on illness risk. However, the known genetic risk factors for the illness still comprise a small portion of the overall heritability, which is about 80%. These variants are more likely to occur in non-coding than coding regions of the genome. For this and other reasons, whole-genome sequencing (WGS) has become the method of choice to identify genetic risk variants for SCZ and other common, complex disorders. Although prohibitively expensive only a few years ago, it is now feasible to carry out WGS in large numbers affordably. In the last grant period, we successfully conducted WGS in 20 families segregating either SCZ or bipolar disorder from the geographically isolated Portuguese Islands of the Azores and Madeira. We have shown that rare variants segregating with illness in these families preferentially cluster in regions previously implicated by GWAS. Genetic risk factors are likely to be easier to identify in more isolated populations because of their greater homogeneity, and consequently fewer genetic inputs to disease. Proposed Methods: We plan to enlarge our current sample of multiplex Azorean families segregating SCZ by ascertaining and collecting new families in the Azores as well as following up previously studied families to identify individuals who have entered the age of risk for SCZ. These families will undergo WGS using the Illumina HiSeqX to identify common and rare single nucleotide variants and structural variants associated with illness. These families will be sequenced alongside the Genomic Psychiatry Cohort (GPC), a large US sample of SCZ and bipolar cases and controls (10,000 cases and 10,000 controls), and variant calling will be done with this much larger sample to increase accuracy. Furthermore, we will be able to use the GPC as a replication sample in a two-stage design, which we demonstrate has greater power than a one-stage design. We will also examine genetic influences on phenotypes relevant to Precision Medicine, such as symptomatic dimensions and outcome.