The Psychiatric Genomics Consortium (http://pgc.unc.edu), now in its eighth year, is one of the most innovative experiments in the history of psychiatry. We have 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. The PGC has attracted a cadre of outstanding scientists whose careers center on our work. The PGC has published 17 main papers plus 31 secondary analysis/methods development papers. The most important was the landmark Nature paper identifying 108 loci for schizophrenia (SCZ). Due to our open-source approach, there are 75+ papers that use PGC results, and we know of numerous groups that are using our findings to direct basic and applied research (including therapeutic development). More work is needed. Large amounts of new data will be available to the PGC in the next five years (largely without NIMH funding). We have developed a rigorous set of approaches that are yielding discoveries for all of the initial five disorders (which led to adding four new disorders). We thus have the unique opportunity to rapidly and efficiently increase our knowledge of common and rare variation in order to understand the causes and comorbidities of major psychiatric disorders. Our overarching goal is to identify ?actionable? variation via the empirical evaluation of the etiological, clinical, nosological, therapeutic, and biological significance of our genomic findings. We will continue the highly successful work of the PGC in understanding the roles of common genetic variation by: (a) comprehensively analyzing historically large GWA samples for nine major psychiatric disorders; (b) evaluating how genetic risk scores impact development and clinical symptom patterns; (c) understand the genetic relationship among psychiatric disorders and across psychiatric disorders and many other CNS diseases. We will enhance our work on the discovery of rare variation by: (d) conducting mega-analyses of copy number variation across nine psychiatric disorders; (e) efficiently and inexpensively re-sequencing regions implicated by GWAS (200 candidate genes in 20,000 subjects); and (f) using the hundreds of clinicians in the PGC, identify rare densely affected pedigrees to enable searches for rare variants of strong effect. Successful completion of this body of work will advance knowledge of the genetic basis of multiple psychiatric disorders. Our goal is to deliver ?actionable? findings, genomic results that (a) reveal the fundamental biology, (b) inform clinical practice, and (c) deliver new therapeutic targets. This is the central idea of the PGC: to convert the family history risk factor into biologically, clinically, and therapeutically meaningful insights. We have leveraged external funding from multiple sources to minimize NIMH budgetary requests.

Public Health Relevance

/ Relevance The Psychiatric Genomics Consortium (PGC), now in its eighth year, is one of the most innovative experiments in the history of psychiatry. We have unified much of psychiatric genomics to enable rapid progress in discovering the genetic basis of psychiatric disorders. We propose new aims to identify ?actionable? variation, findings with clear etiological, clinical, nosological, therapeutic, and biological significance.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project--Cooperative Agreements (U01)
Project #
3U01MH109528-04S1
Application #
9938772
Study Section
Program Officer
Dutka, Tara
Project Start
2019-07-01
Project End
2021-03-31
Budget Start
2020-02-01
Budget End
2020-03-31
Support Year
4
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Genetics
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Khramtsova, Ekaterina A; Heldman, Raphael; Derks, Eske M et al. (2018) Sex differences in the genetic architecture of obsessive-compulsive disorder. Am J Med Genet B Neuropsychiatr Genet :
Farrell, Martilias; Lichtenstein, Maya; Crowley, James J et al. (2018) Developmental Delay, Treatment-Resistant Psychosis, and Early-Onset Dementia in a Man With 22q11 Deletion Syndrome and Huntington's Disease. Am J Psychiatry 175:400-407
(2018) Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression. Nat Genet 50:668-681
Kim, Y; Giusti-Rodriguez, P; Crowley, J J et al. (2018) Comparative genomic evidence for the involvement of schizophrenia risk genes in antipsychotic effects. Mol Psychiatry 23:708-712
Smeland, Olav B; Wang, Yunpeng; Frei, Oleksandr et al. (2018) Genetic Overlap Between Schizophrenia and Volumes of Hippocampus, Putamen, and Intracranial Volume Indicates Shared Molecular Genetic Mechanisms. Schizophr Bull 44:854-864
Sullivan, Patrick F; Agrawal, Arpana; Bulik, Cynthia M et al. (2018) Psychiatric Genomics: An Update and an Agenda. Am J Psychiatry 175:15-27
(2018) Erratum. Biol Psychiatry 84:857
Thornton, Laura M; Munn-Chernoff, Melissa A; Baker, Jessica H et al. (2018) The Anorexia Nervosa Genetics Initiative (ANGI): Overview and methods. Contemp Clin Trials 74:61-69
Dunn, Erin C; Sofer, Tamar; Wang, Min-Jung et al. (2018) Genome-wide association study of depressive symptoms in the Hispanic Community Health Study/Study of Latinos. J Psychiatr Res 99:167-176
Van der Auwera, Sandra; Peyrot, Wouter J; Milaneschi, Yuri et al. (2018) Genome-wide gene-environment interaction in depression: A systematic evaluation of candidate genes: The childhood trauma working-group of PGC-MDD. Am J Med Genet B Neuropsychiatr Genet 177:40-49

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