1/4 Psychiatric GWAS Consortium: Genomic Follow-up Next-Gen Seq & Genotyping

描述（由申请人提供）：这是协作R 01 MH 094421精神病GWAS联盟的最终提交：基因组随访下一代测序和基因分型。这个应用程序的总体目标是雄心勃勃的：我们的目标是生成一个值得信赖的，高置信度的“地图”的遗传结构的核心重要的精神疾病。这些图谱包括对这些疾病的等位基因谱的系统和全面评估，包括罕见外显子、常见SNP和拷贝数变异。我们的目标的可行性得到了精神病学GWAS联盟（“PGC 1”）第一次迭代的跟踪记录的支持，在那里我们将该领域的几乎所有主要群体联合成一个和谐的功能实体，并以高科学标准完成了我们的初始目标。精神疾病是深入研究的引人注目的目标：它们大多是特发性的，一流的公共卫生问题，并造成巨大的发病率，死亡率和个人/社会成本。与NIH的使命一致，我们的目标是阐明这些疾病的基本知识。在这个“PGC 2”应用中，我们建议利用NIH之前的投资和PGC 1的成功来实现下一个逻辑目标。PGC 2的目标是“大规模”（该领域有史以来最大的样本量）和“全面”（通过仔细应用多种基因组规模技术）。我们的重点是全面在其他意义上-PGC几乎涵盖了整个领域，我们的目标是阐明这些疾病的等位基因谱，通过整合经验数据的所有容易测量类型的遗传变异的病因学相关性（常见的SNP，罕见的外显子，罕见和常见的拷贝数变异-我们称之为“地图”）。有三个分析目标-系统地评估拷贝数变异，为外显子组数据（最终是全基因组数据）的分析创建一个管道，并调查跨越传统疾病边界的遗传关联。最后，我们建议开发“PsychChip”，这是一种针对常见SNP、外显子和CNV的定制20，000个探针阵列，然后用于对115，082名受试者进行基因分型。PGC 2的影响可能非常大-对这些疾病的遗传学的基本理解将是精神病学和生物医学的一个重要里程碑。

DESCRIPTION (provided by applicant): This is the final submission of the collaborative R01 MH094421 Psychiatric GWAS Consortium: Genomic Follow-Up Next-Gen Sequencing & Genotyping. The overall goal of this application is ambitious: we aim to generate a trustworthy, high-confidence "maps" of the genetic architecture of centrally important psychiatric diseases. Such maps consist of systematic and comprehensive evaluation of the allelic spectrum for these disorders including rare exonic, common SNP, and copy number variation. The feasibility of our aims is supported by the track record of the first iteration of the Psychiatric GWAS Consortium ("PGC1") where we united nearly all major groups in the field into a harmonious and functional entity and completed our initial aims to a high scientific standard. Psychiatric diseases are compelling targets for intensive research: they are mostly idiopathic, first-rank public health problems, and cause enormous morbidity, mortality, and personal/societal cost. Consistent with the NIH mission, our goal is to elucidate fundamental knowledge of these diseases. In this "PGC2" application, we propose to capitalize on prior NIH investments and on the success of PGC1 for the next logical set of aims. The PGC2 aims are "large-scale" (largest sample sizes ever in the field) and "comprehensive" (via the careful application of multiple genomic-scale technologies). Our focus is comprehensive in other senses - the PGC encompasses nearly the entire field, and we aim to elucidate the allelic spectrum of these disorders by integrating empirical data for all readily measurable types of genetic variation of etiological relevance (common SNP, rare exonic, and rare and common copy number variation - what we term the "map"). There are three analytic aims - systematically to assess copy number variation, to create a pipeline for the analysis of exome data (and eventually whole-genome data), and to investigate genetic associations that span traditional disease boundaries. Finally, we propose to develop the "PsychChip" a custom 20,000 probe array targeting common SNP, exonic, and CNVs that would then be used to genotype 115,082 subjects. The PGC2 impact is potentially very large - a fundamental understanding of the genetics of these diseases would be a major milestone in psychiatry and in biomedicine.