Schizophrenia is a debilitating psychiatric disorder affecting nearly 1% of the general population. Schizophrenia has been demonstrated to have a substantial genetic component, with common and rare variants contributing to individual risk, however early studies suggested a complex architecture with many genes likely involved. Existing PGC efforts to collaboratively aggregate and analyze genomewide association study (GWAS) data have been extremely successful ? identifying more than 100 robust genetic associations and beginning to unravel the biology of schizophrenia. Similar efforts to mirror this activity of aggregation and analysis of exome and genome sequencing data have to date not been undertaken, despite the clear potential that rare coding variation holds to expand our knowledge of disease etiology. We propose here a PGC supplement to support an effort to aggregate, harmonize, analyze and disseminate results from up to 50,000 cases of schizophrenia and a larger number of population controls to provide a critical enhancement to existing PGC efforts to study common variation. The evidence from rare, coding variants will pinpoint genes of key impact to schizophrenia risk and will develop pipelines and analytic methods that can be applied across PGC disorders.
To tackle schizophrenia and other similarly common, heritable and complex mental illnesses, the Psychiatric Genomics Consortium (http://pgc.unc.edu) ten years ago began one of the most innovative experiments in the history of psychiatry. The PGC has unified much of the field to enable rapid progress in elucidating the genetic basis of psychiatric disorders. We have 800+ investigators from 36 countries and >400K subjects and have attracted a cadre of outstanding scientists whose careers center on our work. In the first two PGC grant cycles, the consortium published 17 main papers plus 31 secondary analysis/methods development papers ? and in the first two years of this third cycle 42 additional PGC papers have been published. Moreover, due to our open-source approach, there are now more than 100 papers using PGC results, and we know of numerous groups that are using our findings to direct basic and applied research (including therapeutic development). Most notable among PGC achievements with this collaborative data-sharing and analysis model, genome-wide association studies spearheaded by the PGC have successfully implicated now over two hundred common risk loci for schizophrenia. The current PGC grant, parent of this supplement request, aims specifically to go beyond studies of common variation in an effort to identify rare and functionally interpretable variation that is ?actionable? in the sense of initiating evidence-based molecular studies and generating genetic-based therapeutic hypotheses. Large- scale exome sequencing provides one of the most effective routes to this end but resource limitations precluded this from being a part of the main proposal.
