3/3: Pedigree-Based Whole Genome Sequencing of Affective and Psychotic Disorders

3/3：基于谱系的情感和精神障碍全基因组测序

• 批准号: 8806281
• 负责人: Raquel E Gur
• 金额: $ 14.18万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8806281
• 关键词: Affect; Affective; Australia; Biological; Biomedical Research; Bipolar Disorder; Code; Complex; Consensus; Costa Rica; DNA; Data; Databases; Development; Diagnosis; Diagnostic; Diagnostic and Statistical Manual of Mental Disorders; Disease; Elements; Etiology; Family; Family member; Frequencies; Generations; Genes; Genome; Genomics; Goals; Gur; Heritability; Human; Individual; International; Intervention; Interview; Location; Major Depressive Disorder; Marshal; Methods; Morbidity - disease rate; National Heart, Lung, and Blood Institute; National Institute of Mental Health; Neurocognitive; Nucleotides; Parents; Pathway interactions; Pennsylvania; Phenotype; Population; Population Attributable Risks; Psychiatric Diagnosis; Psychopathology; Psychotic Disorders; Public Health; Quality Control; Quantitative Trait Loci; Research Infrastructure; Research Institute; Risk; Role; Sampling; Schizophrenia; Site; Symptoms; Testing; Texas; Universities; Variant; Western Australia; affective psychoses; base; cost effective; density; design; endophenotype; exome sequencing; genetic analysis; genetic pedigree; genetic variant; genome analysis; genome sequencing; genome wide association study; improved; indexing; insight; meetings; mortality; neuropsychiatry; novel; novel diagnostics; novel therapeutics; offspring; psychogenetics; public health relevance; rare variant; repository; response; risk variant; transmission process

 DESCRIPTION (provided by applicant): Our goal is to identify genes that increase risk for affective and psychotic disorders like schizophrenia, bipolar disorder and major depression. Although these highly heritable diseases are associated with substantial morbidity and mortality, their etiologies remain poorly understood. Identifying genes that contribute to their risk should provide critical information leading to the development of novel diagnostic and therapeutic strategies. We propose an eight site international consortium designed to identify rare causal variants for affective and psychotic illnesses using extended multiplex pedigrees. These multigenerational families were previously identified and include at least three individuals with confirmed diagnoses. We focus on the identification of rare variants (with population MAF d 0.01) that have a large absolute effect size, although it may be present in a small number of related affected individuals. While such rare functional variants may have a small effect on population attributable risk or variant-specific heritability, they can be sufficient to verify tha a given gene is involved in illness risk. Pedigree-based studies represent an implicit enrichment strategy for identifying the rarest (e.g., private or pedigree-specific) variants, as Mendelian transmissions from parents to offspring maximize the chance that multiple copies of rare variants exist in the pedigree. Whole genome sequencing (WGS) allows a comprehensive search for rare single nucleotide variants (SNVs) or more complex sequence variation such as CNVs or INDELS. To identify rare, potentially private, variants that increase risk for affective or psychotic illness, we will create a repository of 4043 individuals from previously collected multiplex pedigrees (n=331) that will be analyzed with WGS. 1915 of these individuals have available WGS and we will obtain sequence data for 2128 additional subjects. Phenotypes include classical dichotomous diagnoses, quantitative scales derived from standardized interviews reflecting dimensional symptom classes, and neurocognitive endophenotypes. Our specific aims are to: 1) synergize phenotypic assessments, create dimensional indices of psychopathology, and rank endophenotypes across sites; 2) obtain WGS on 2128 individuals from extended pedigrees by direct sequencing of 1000 samples at 30x coverage and perform highly accurate pseudo-sequencing using a high density SNP framework to obtained the remaining 1128; 3) localize and identify QTLs influencing illness phenotypes /endophenotypes; 4) perform pedigree-based genome-wide association using likely functional variants; 5) identify rare functional CNV/INDELs influencing illness risk or endophenotypes; 6) perform gene-centric association tests in an independent sample. Our collaborative project includes applications from Yale University (DC Glahn, PD/PI), Texas Biomedical Research Institute (J Blangero, PD/PI) and the University of Pennsylvania (RE Gur, PD/PI). In addition, the Universities of Pittsburgh (V Nimgaonkar), Costa Rica (H Ravents), Edinburgh (AM McIntosh), and Western Australia (A Jablensky) and the intramural NIMH (F McMahon) will participate.

 描述（由申请人提供）：我们的目标是识别增加情感和精神疾病（如精神分裂症、双相情感障碍和重度抑郁症）风险的基因。尽管这些高度遗传性疾病与高发病率和死亡率相关，但其病因仍知之甚少。识别导致其风险的基因应该为开发新的诊断和治疗策略提供关键信息。我们提议成立一个八个站点的国际联盟，旨在利用扩展的多重谱系来识别情感和精神疾病的罕见因果变异。这些多代家庭之前已被识别，其中至少包括三名确诊患者。我们专注于识别具有较大绝对效应量的罕见变异（群体 MAF d 0.01），尽管它可能存在于少数相关受影响个体中。虽然这种罕见的功能变异可能对人群归因风险或变异特异性遗传力影响很小，但它们足以验证给定基因与疾病风险有关。基于谱系的研究代表了一种隐含的富集策略，用于识别最稀有的（例如，私人的或谱系特定的）变异，因为从父母到后代的孟德尔传播最大化了谱系中存在多个稀有变异副本的机会。全基因组测序 (WGS) 可以全面搜索罕见的单核苷酸变异 (SNV) 或更复杂的序列变异，例如 CNV 或 INDELS。识别罕见的、潜在的私人变异，这些变异会增加情感或情感风险 精神病，我们将创建一个包含 4043 名来自先前收集的多重谱系个体 (n=331) 的个体的存储库，这些个体将通过全基因组测序 (WGS) 进行分析。其中 1915 名受试者具有可用的全基因组测序，我们将获得另外 2128 名受试者的序列数据。表型包括经典的二分诊断、源自反映维度症状类别的标准化访谈的定量量表以及神经认知内表型。我们的具体目标是：1）协同表型评估，创建精神病理学维度指数，并对各个站点的内表型进行排名； 2) 通过以30倍覆盖率对1000个样本进行直接测序，获得来自扩展谱系的2128个个体的WGS，并使用高密度SNP框架进行高精度伪测序，以获得剩余的1128个个体； 3）定位并识别影响疾病表型/内表型的QTL； 4) 使用可能的功能变异进行基于谱系的全基因组关联； 5) 识别影响疾病风险或内表型的罕见功能性 CNV/INDEL； 6) 在独立样本中进行以基因为中心的关联测试。我们的合作项目包括来自耶鲁大学（DC Glahn，PD/PI）、德克萨斯生物医学研究所（J Blangero，PD/PI）和宾夕法尼亚大学（RE Gur，PD/PI）的申请。此外，匹兹堡大学 (V Nimgaonkar)、哥斯达黎加大学 (H Ravents)、爱丁堡大学 (AM McIntosh) 和西澳大利亚大学 (A Jablensky) 以及校内 NIMH (F McMahon) 也将参加。