1/5-The Psychiatric GWAS Consortium: Integrated & Coordinated GWAS Meta-Analyses

描述(申请人提供)：本申请由五个协作R01组成，以响应NIMH RFA-MH-08-121，“精神障碍全基因组协会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个患有注意力缺陷多动障碍(ADHD)、自闭症(AUT)、双相情感障碍(BIP)、严重抑郁障碍(MDD)或精神分裂症(SCZ)的个体的Gwas数据。总而言之，这些GWAS构成了精神病学中有史以来最大的生物实验--超过8万名受试者(59,000名独立病例/对照和超过7700个家庭三人组)，每个受试者大约500,000个SNP基因类型，以及大约400亿个基因类型。尽管全球气候变化数据的可获得性极具吸引力，但确实存在相互矛盾和混淆的风险。对任何疾病的Gwas荟萃分析都是复杂的，需要相当多的注意和专业知识才能有效地完成。鉴于迫切需要知道是否存在可复制的基因-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年初发起了PGC，以进行严格和全面的GWAS内部和跨无序的荟萃分析。PGC的总体理念是尽可能包容、民主和迅速。PGC正在与一个协调委员会、五个疾病工作组、一个交叉障碍小组、统计分析小组和一台用于数据仓库和统计分析的集群计算机一起顺利开展。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，所有其他研究都在参与，而且没有一个加入PGC的人离开了。PGC的具体目标是：(1)无序内Meta分析：对ADHD、AUT、BIP、MDD和SCZ的所有可用Gwas数据进行单独的Meta分析，试图确定令人信服的基因-表型关联。(2)交叉无序分析：人们普遍怀疑，临床上得出的DSM-IV和ICD-10定义在基本遗传结构方面可能没有“交界处的雕刻性”。有两个子目标：(2A)进行荟萃分析，试图确定ADHD、AUT、BIP、MDD和SCZ的=2共有的令人信服的基因-表型关联。(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。该分析计划遵循目前全球环境监测系统质量控制和荟萃分析的最佳做法，特别是在注意调查异质性来源方面。统计学的力量应该优于精神病学遗传学之前的任何研究。结果将尽快公布。最后，PGC建议尽可能地遵守NIH的Gwas数据共享政策，我们提供了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.