5/5-The Psychiatric GWAS Consortium: Integrated & Coordinated GWAS Meta-Analyses

描述（由申请人提供）：本申请由五个协作R01组成，以响应NIMH RFA-MH-08-121，“精神障碍基因组全关联研究数据沉积和分析的有限竞争（协作R01）”。这些应用程序来自精神病学GWAS联盟（PGC）。到2008年底，将有47个样本的GWAS数据，这些样本包括注意力缺陷多动障碍（ADHD）、自闭症（AUT）、双相情感障碍（BIP）、重度抑郁症（MDD）或精神分裂症（SCZ）。总的来说，这些GWAS构成了迄今为止在精神病学领域进行的最大的生物实验——超过80,000名受试者（59,000个独立病例/对照和超过7700个家庭三胞胎），每个受试者约500,000个SNP基因型，总计约400亿个基因型。尽管GWAS数据的可用性非常吸引人，但确实存在相互矛盾的声明和混淆的风险。任何疾病的GWAS荟萃分析都是复杂的，需要大量的护理和专业知识才能有效地完成。鉴于迫切需要了解是否存在可复制的基因型-表型关联，需要一种新型的合作。为了实现这些目标，我们在2007年初启动了PGC，进行严格和全面的内部和交叉紊乱的GWAS荟萃分析。PGC的总体理念是尽可能地包容、民主和迅速。PGC正在顺利进行，有一个协调委员会、五个疾病工作组、一个跨疾病小组、统计分析小组和一台用于数据仓库和统计分析的群集计算机。来自11个国家和48个机构的101名科学家。值得注意的是，除了一项符合条件的研究外，所有研究都参与其中，而加入PGC的研究中没有人退出。PGC的具体目的是：(1)障碍内荟萃分析：对ADHD、AUT、BIP、MDD和SCZ的所有可用GWAS数据进行单独的荟萃分析，试图确定令人信服的基因型-表型关联。(2)交叉障碍分析：人们普遍怀疑临床衍生的DSM-IV和ICD-10定义在基本遗传结构方面可能没有“雕刻性质”。有两个子目标：（2a）进行荟萃分析，试图确定ADHD、AUT、BIP、MDD和SCZ共有的令人信服的基因型-表型关联=2。（2b）召集一个专家工作组，将流行病学和遗传流行病学证据转化为关于这些疾病之间重叠的严格和明确的假设。分析计划遵循当前GWAS质量控制和荟萃分析的最佳实践，特别是在调查异质性来源方面。统计能力应该优于任何先前的精神病学遗传学研究。结果将尽快公布。最后，PGC建议尽可能遵守NIH的GWAS数据共享政策，并提供详细的数据共享计划和时间表。

DESCRIPTION (provided by applicant): This application consists of five collaborative R01s submitted in response to NIMH RFA-MH-08-121, "Limited Competition for Data Deposition and Analyses of Genome Wide Association Studies of Mental Disorders (Collaborative R01)". These applications are from the Psychiatric GWAS Consortium (PGC). By the end of 2008, there will be GWAS data on 47 samples of individuals with either attention-deficit hyperactivity disorder (ADHD), autism (AUT), bipolar disorder (BIP), major depressive disorder (MDD), or schizophrenia (SCZ). Taken together, these GWAS constitute the largest biological experiment ever conducted in psychiatry - over 80,000 subjects (59,000 independent cases/controls and over 7700 family trios), ~500,000 SNP genotypes per subject, and ~40 billion total genotypes. Although the availability of GWAS data is highly attractive, there is a real risk of conflicting claims and confusion. GWAS meta-analysis for any disease is complex and requires considerable care and expertise in order to be done validly. Given the urgent need to know if there are replicable genotype-phenotype associations, a new type of collaboration is required. To accomplish these ends, we initiated the PGC in early 2007 to conduct rigorous and comprehensive within- and cross- disorder GWAS meta-analyses. The overall philosophy of the PGC is to be as inclusive, democratic, and rapid as possible. The PGC is well-underway with a coordinating committee, five disease working groups, a cross-disorder group, statistical analysis group, and a cluster computer for data warehousing and statistical analysis. 101 scientists from 11 countries and 48 institutions. It is remarkable that all but one eligible study is participating and that no one who has joined the PGC has left. The Specific Aims of the PGC are: (1) Within-disorder meta-analyses: conduct separate meta-analyses of all available GWAS data for ADHD, AUT, BIP, MDD, and SCZ to attempt to identify convincing genotype-phenotype associations. (2) Cross-disorder analyses: it is widely suspected that the clinically-derived DSM-IV and ICD-10 definitions may not have "carved nature at the joint" with respect to the fundamental genetic architecture. There are two sub-aims: (2a) Conduct meta-analysis to attempt to identify convincing genotype-phenotype associations that are common to =2 of ADHD, AUT, BIP, MDD, and SCZ. (2b) Convene an expert working group to convert epidemiological and genetic epidemiological evidence into rigorous and explicit hypotheses about overlap amongst these disorders. The analytic plan abides to current best practices for GWAS quality control and meta-analysis, particularly in its attention to investigating sources of heterogeneity. Statistical power should be superior to any prior study in psychiatric genetics. Results will be made available as soon as possible. Finally, the PGC proposes to abide as fully as possible with the NIH's GWAS data sharing policies and we provide a detailed data sharing plan and timetable.