Convergent Genetic and Genomic Analyses of Schizophrenia

目的：确定增加精神分裂症（SCZ）风险的常见和罕见遗传变异， 研究它们对疾病风险的影响以及大样本中的发病率测量。 背景：精神分裂症是美国退伍军人以及全世界残疾的主要原因， 每年的公共卫生负担超过600亿美元。最近的研究有力地支持了 常见和罕见的疾病风险。然而，这种疾病的已知遗传风险因素仍然存在。 包括总遗传力的一小部分，约为80%。这些变异更容易发生 非编码区比编码区更重要。由于这个和其他原因，全基因组测序 (WGS)已经成为识别SCZ和其他常见的、复杂的 紊乱尽管仅仅在几年前还非常昂贵，但现在大规模实施WGS是可行的。 数字负担得起。在上一个资助期内，我们成功地在20个家庭中进行了WGS， SCZ或双相情感障碍，来自地理上孤立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中， 此前曾被GWAS牵连。遗传风险因素在更孤立的人群中可能更容易识别。 这是因为它们具有更大的同质性，因此对疾病的遗传输入更少。 建议的方法：我们计划扩大我们目前的多重Azorean家庭分离SCZ的样本， 在亚速尔群岛确定和收集新的家庭，以及跟踪以前研究的家庭， 识别已进入SCZ风险年龄的个体。这些家庭将使用 Illumina HiSeqX用于鉴定常见和罕见的单核苷酸变体以及与以下相关的结构变体： 病这些家庭将与基因组精神病学队列（GPC）一起进行测序，GPC是美国一个大型的 SCZ和双相情感障碍病例和对照样本（10，000例病例和10，000例对照），并将变异识别 用这个更大的样本来提高准确性。此外，我们将能够使用GPC作为 复制样本在两阶段的设计，我们证明有更大的权力比一个阶段的设计。 我们还将研究遗传对精准医学相关表型的影响，如症状性 尺寸和结果。

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.