1/3:Pedigree-Based Whole Genome Sequencing of Affective and Psychotic Disorders

 描述（由申请人提供）：我们的目标是鉴定增加情感和精神病性障碍（如精神分裂症、双相情感障碍和重度抑郁症）风险的基因。虽然这些高度遗传性疾病与大量的发病率和死亡率，其病因仍然知之甚少。识别导致其风险的基因应提供关键信息，从而开发新的诊断和治疗策略。我们提出了一个八个网站的国际财团，旨在确定罕见的因果变异的情感和精神疾病使用扩展的多重家系。这些多代同堂的家庭先前已经确定，其中至少有三个人确诊。我们专注于鉴定具有较大绝对效应量的罕见变异（群体MAF d 0.01），尽管其可能存在于少数相关受影响个体中。虽然这种罕见的功能性变异可能对人群归因风险或变异特异性遗传力有很小的影响，但它们足以证实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，私人或谱系特异性）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罕见变异拷贝的机会。全基因组测序（WGS）允许全面搜索罕见的单核苷酸变异（SNV）或更复杂的序列变异，如CNV或INDELS。为了识别罕见的，潜在的私人，变异，增加风险的情感或 对于患有精神病的患者，我们将创建一个包含4043名来自先前收集的多重家系（n=331）的个体的储存库，这些个体将用WGS进行分析。其中1915例有可用的WGS，我们将获得另外2128例受试者的序列数据。表型包括经典的二分诊断，从标准化访谈中反映维度症状类别的定量量表，以及神经认知内表型。我们的具体目标是：1）协同表型评估，创建精神病理学的维度指数，并跨位点对内表型进行排名; 2）通过以30倍覆盖率对1000个样品进行直接测序来获得来自扩展谱系的2128个个体的WGS，并使用高密度SNP框架进行高度准确的伪测序以获得剩余的1128个; 3）定位并鉴定影响疾病表型/内表型的QTL; 4）使用可能的功能变体进行基于谱系的全基因组关联; 5）鉴定影响疾病风险或内表型的罕见功能性CNV/INDEL; 6）在独立样本中进行基因中心关联测试。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）的应用程序。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）将参加。

 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.