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. ? ? ?
Our intention is to bring all genomewide association data for ADHD, autism, bipolar disorder, major depressive disorder, and schizophrenia into very large combined analyses. We hope that these very large samples will allow us to learn hard facts about the genetic causes of these disorders.
