Convergent Genetic and Genomic Analyses of Schizophrenia

精神分裂症的融合遗传和基因组分析

• 批准号: 10307986
• 负责人: AYMAN H FANOUS
• 金额: --
• 依托单位: VA NEW YORK HARBOR HLTHCARE/SYS/BROOKLYN
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10307986
• 关键词: Adult; Affect; Age; Azores; Bipolar Disorder; Blood specimen; Catalogs; Code; Collection; Complex; Data; Diagnostic; Dimensions; Disease; Etiology; Family; Family Study; Genes; Genetic; Genetic Risk; Genetic study; Genome; Genomic DNA; Genomics; Genotype; Geography; Goals; Grant; Haplotypes; Heritability; Human Genome; Individual; Interview; Island; Libraries; Measures; Methods; Morbidity - disease rate; Mutation; Noise; Nuclear Family; Nucleotides; Outcome; Patients; Phenotype; Play; Population; Portuguese; Precision Medicine Initiative; Process; Psychiatry; Public Health; Quality Control; Risk; Risk Factors; Role; Sampling; Schizophrenia; Signal Transduction; Single Nucleotide Polymorphism; Structure; System; Untranslated RNA; Variant; Veterans; base; case control; cohort; design; disability; experimental study; gene discovery; genetic risk factor; genetic variant; genome sequencing; genome wide association study; genome-wide; individual patient; individualized medicine; insertion/deletion mutation; member; neuropsychiatric disorder; precision medicine; rare variant; risk variant; schizophrenia risk; whole genome

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.

目的：确定增加精神分裂症风险（SCZ）的常见和罕见的遗传变异，并 研究它们对疾病风险的影响以及大型样本中发病率的措施。 背景：精神分裂症是美国退伍军人和世界各地残疾的主要原因， 年度公共卫生负担超过600亿美元。最近的研究强烈支持 关于疾病风险的常见和稀有变体。但是，疾病的已知遗传危险因素仍然 占整体遗传力的一小部分，约为80％。这些变体更有可能发生 在非编码中，基因组的编码区域。出于这个和其他原因，全基因组测序 （WGS）已成为确定SCZ和其他常见，复杂的遗传风险变异的选择方法 疾病。虽然仅几年前昂贵，但现在可以进行WGS可行 数字负担得起。在最后一个赠款期间，我们成功地进行了20个家庭中的WGS 来自亚速尔群岛和马德拉氏菌的地理孤立葡萄牙岛的SCZ或躁郁症。我们 已经表明，在这些家族中，稀有的变体与疾病分离，优先聚集在地区 以前涉及GWAS。遗传危险因素可能更容易在更孤立的 人群由于较高的同质性，因此疾病的遗传投入更少。 提出的方法：我们计划扩大当前的多路复用Azorean家族样本，将SCZ隔离 确定和收集亚速尔群岛的新家庭，并跟随先前研究的家庭 确定已经进入SCZ风险年龄的个人。这些家庭将使用WG使用 Illumina Hiseqx识别与与 疾病。这些家庭将与基因组精神病学队列（GPC）一起进行测序，这是一个大型美国 SCZ和双极案例和对照的样本（10,000例和10,000个对照），并且变体呼叫将为 用这个更大的样本完成以提高准确性。此外，我们将能够将GPC用作 在两个阶段设计中的复制样本，我们证明，其功率比单级设计更大。 我们还将检查对与精度药物相关的表型的遗传影响，例如有症状 维度和结果。