2/3: Pedigree-Based Whole Genome Sequencing of Affective and Psychotic Disorders

2/3：基于谱系的情感和精神障碍全基因组测序

基本信息

批准号：
9209517
负责人：
John Blangero
金额：
$ 94.62万
依托单位：
UNIVERSITY OF TEXAS RIO GRANDE VALLEY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-22 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9209517
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 Genomics Goals Gur Health Heritability Human Individual International Intervention Interview Location Major Depressive Disorder Marshal Methods Mood Disorders 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 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 phenotypic data psychogenetics rare variant repository response risk variant transmission process whole genome

项目摘要

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（由适用提供）：我们的目标是确定增加患情感和精神病患者的风险，例如精神分裂症，躁郁症和严重抑郁症。尽管这些高度可遗传的疾病与大量发病率和死亡率有关，但其病因仍然知之甚少。确定有助于其风险的基因应提供关键信息，从而发展新的诊断和治疗策略。我们提出了一个八个地点国际财团，旨在使用扩展的多重谱系来确定罕见的因果变体，以供情感和精神病性疾病。这些多代家族先前已被鉴定出来，并包括至少三个具有确定诊断的人。我们专注于识别具有较大绝对效应大小的稀有变体（具有群体MAF D 0.01），尽管它可能存在于少数相关受影响的个体中。尽管这种罕见的功能变体可能对归因的风险或特定于变异的遗传力产生较小的影响，但它们足以验证给定基因参与疾病风险。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（例如私有或谱系特定）变体，因为孟德尔从父母到后代的传播最大化了谱系中存在多个稀有变体的副本的机会。整个基因组测序（WGS）允许全面搜索稀有的单核苷酸变体（SNV）或更复杂的序列变化，例如CNV或Indels。确定稀有的，潜在的私人变体，以增加情感风险或精神病性疾病，我们将创建一个由先前收集的多重分子（n = 331）的4043个人组成的存储库，该存储库将通过WGS分析。 1915年，这些人有可用的WGS，我们将获得2128名受试者的序列数据。表型包括经典的二分法诊断，定量量表来自反映维符号类别的标准化访谈和神经认知性内表型。我们的具体目的是：1）协同化表型评估，创建精神病理学的维度指数，并跨越跨越地点的内表型； 2）通过在30倍覆盖范围内直接对1000个样品进行直接测序，并使用高密度SNP框架进行高度准确的伪序列，从而从扩展的血统中获得WGS，并获得其余1128个； 3）本地化并识别QTL会影响疾病表型 /内表型； 4）使用可能的功能变体执行基于血统的全基因组关联； 5）确定罕见的功能性CNV/Indels影响疾病风险或内型型； 6）在独立样本中执行以基因为中心的关联测试。我们的合作项目包括耶鲁大学（DC Glahn，PD/PI），得克萨斯州生物医学研究所（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（H Ravents），爱丁堡（Am McIntosh）和西澳大利亚州（A Jablensky）和壁内Nimh（F McMahon）将参加。