UNC investigators receive new NIMH collaborative R01
Now in its 14th year, the Psychiatric Genomics Consortium is one of the largest, most innovative, and productive experiments in the history of psychiatry. The central idea of the PGC is to use a global cooperative network to advance genetic discovery in order to identify biologically, clinically, and therapeutically meaningful insights. The PGC continues to unify the field and attract outstanding scientists to its central mission (800+ investigators from 150+ institutions in 40+ countries). PGC work has led to 380 papers, many in high-profile journals (Nature 3, Cell 5, Science 2, Nat Genet 27, Nat Neurosci 9, Mol Psych 37, Biol Psych 25, JAMA Psych 12). The full results from all PGC papers are freely available, and our findings have fueled analyses by non-PGC investigators and fostered the careers of many junior scientists.
The PGC is now starting the fourth NIMH grant. UNC has been the lead site of the PGC since its beginning under co-PIs Patrick Sullivan and Cynthia Bulik. Other sites are at Harvard MGH, Mt Sinai SOM, UCSC, Wash U St Louis, Trinity College Dublin, Cardiff University, and Univ of Queensland. The PGC has a broad new agenda, and projects to have 2.5 million cases with severe psychiatric disorders in analysis by 2025.
Duke-UNC collaboration funded new R01
UNC Prof Patrick Sullivan and Duke collaborators Profs Greg Crawford and Charlie Gersbach have received a large R01 to micro dissect genetic loci associated with schizophrenia.
Schizophrenia (SCZ) genomics has achieved unprecedented advances. A decade ago, there was perhaps one solid finding, and there are now ~270 loci that meet consensus criteria for significance and replication. As observed for other complex psychiatric disorders, the identified regions are overwhelmingly noncoding, strongly suggesting that genetic variation in gene regulatory elements is a major mechanistic contributor. Further investigation of those regulatory mechanisms is precluded by a fundamental gap in the ability to identify, characterize, and quantify brain-relevant regulatory elements, and limited understanding of how genetic variation within those elements influences their function.
To address this knowledge gap, this project will comprehensively identify, characterize, quantify, and validate noncoding functional noncoding regulatory elements and variants in neuronal cells. The central hypothesis of the proposal is that noncoding variation contributes to psychiatric disorders by directly altering the function of regulatory elements in the brain. The motivation for the proposed study is that identifying regulatory mechanisms of psychiatric disorders has the potential to translate into improved diagnosis and treatment. Powered by a team with strong interdisciplinary expertise in psychiatric disorders, functional genomics, technology development, and statistical genetics, this hypothesis will be tested by completing three specific aims: 1) Comprehensive integration of diverse data types to generate hypotheses that “connect” psychiatric genetic results to specific genes; 2) perform high-throughput CRISPR epigenome editing screens to test Aim 1 hypotheses in a natural biological context; 3) Develop mechanistic understanding and validate functional noncoding SCZ risk variants using TF binding assays and iPS-derived neurons from SCZ cases with high genetic risk scores.
Our approach is innovative because it uses a highly complementary and diverse set of experimental approaches to drive targeted genetic and functional investigation into regulatory mechanisms relevant for SCZ. In doing so, the proposed research provides a much-needed path forward to understand how noncoding variation contributes to complex human phenotypes.